Regio- and enantioselective reduction of diketones: Preparation of enantiomerically pure hydroxy ketones catalysed by Candida parapsilosis ATCC 7330

Article abstract of DOI:10.1016/j.tetasy.2015.09.001

Enantiomerically enriched hydroxy ketones were prepared by the reduction of the corresponding diketones with excellent enantiomeric excess (98%) and in good yields (up to 75%) using whole cells of Candida parapsilosis ATCC 7330. Cyclic diketones, such as 1,2-cyclohexanedione and 1,4-cyclohexanedione, resulted in hydroxy ketones as products. Cyclohexane-1,3-dione and 5,5-dimethylcyclohexane-1,3-dione gave dimerised products, such as 2,2′-(ethane-1,1-diyl)bis(3-hydroxycyclohex-2-enone) and 2,2′-(ethane-1,1-diyl)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) with acetaldehyde generated in situ from whole cells of Candida parapsilosis ATCC 7330, which is reported here for the first time.

Full text of DOI:10.1016/j.tetasy.2015.09.001

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Regio- and enantioselective reduction of diketones: preparation
of enantiomerically pure hydroxy ketones catalysed by Candida
parapsilosis ATCC 7330
Pula Mahajabeen a, Anju Chadha a,b,
⇑
a Laboratory of Bioorganic Chemistry, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600 036, India
b National Center for Catalysis Research, Indian Institute of Technology Madras, Chennai 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically enriched hydroxy ketones were prepared by the reduction of the corresponding dike-
tones with excellent enantiomeric excess (98%) and in good yields (up to 75%) using whole cells of
Candida parapsilosis ATCC 7330. Cyclic diketones, such as 1,2-cyclohexanedione and 1,4-cyclohexane-
dione, resulted in hydroxy ketones as products. Cyclohexane-1,3-dione and 5,5-dimethylcyclohexane-
1,3-dione gave dimerised products, such as 2,20-(ethane-1,1-diyl)bis(3-hydroxycyclohex-2-enone) and
2,20-(ethane-1,1-diyl)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) with acetaldehyde generated
in situ from whole cells of Candida parapsilosis ATCC 7330, which is reported here for the first time.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 22 July 2015
Accepted 1 September 2015
Available online xxxx
1. Introduction
cells or isolated pure forms. Often whole cells are preferred over
isolated enzymes due to the availability of all of the necessary
Selective reduction of one of the two ketone moieties within the
same molecule leads to the formation of hydroxy ketones. Enan-
tiomerically enriched hydroxy ketones have found many applica-
tions in pharmaceutical and the chemical industry as valuable
building blocks, for example, in the synthesis of drugs for the treat-
ment of Alzheimer’s disease. They are found in a wide range of
polyketide natural products, and in antifungal agents, anticancer
agents and in some antitumor antibiotics.1
cofactors in the natural cell environment, which also avoids the
tedious enzyme purification processes. Various microorganisms
reported
for
the
asymmetric
reduction
of
benzil
(1,2-diphenylethanedione) to enantiomerically enriched benzoin
are summarised in Table 1.
The asymmetric reduction of a b-diketone, that is, 1-phenyl-1,3-
butadione mediated by Pichia capsulata and Zygosaccharomyces
rouxii to give enantiomerically enriched (S)- and (R)-3-hydroxy-
1-phenyl-1-butanone with 99% ee has been reported.22 A dehydro-
genase from Saccharomyces cerevisiae has been reported for the
asymmetric reduction of 2,5-hexanedione to (2S,5S)-hexanediol
with >99% conversion yield and in >99.9% de and ee. Apart from
2,5-hexanedione, the enzyme also reduces various aliphatic
Among the various chemical methods available for the synthe-
sis of
a-hydroxy ketones (acyloins), the most well-known and
commonly used are Sharpless asymmetric dihydroxylations of silyl
enol ethers derived from ketones,2 and
a-hydroxylations of
ketones.3 Apart from these, ketohydroxylations of olefins,4 selec-
tive oxidations of 1,2-diols to the corresponding acyloins,5 kinetic
a-
and b-diketones.23 The other purified enzyme, Bacillus
stearothermophilus diacetyl reductase has been used in the
asymmetric reduction of aliphatic and aromatic -diketones to
resolutions of racemic
reductions of
a
-hydroxy ketones6 and regioselective
a
-diketones7 are also reported. Numerous b-hydroxy
a
ketones have been prepared by using aldol transformations.8 Most
of these are multistep syntheses, which lower the overall yield of
the products.
give their (S)-hydroxyl ketones with >98% ee and in 65–96%
yields.24 All these reports include the asymmetric reduction of
either benzil and substituted benzils, aliphatic
or aliphatic and aromatic -diketones. Herein, the biocatalyst
Candida parapsilosis ATCC 7330 was used for the stereoselective
reduction of various structurally diverse aromatic -, b- and cyclic
a- and b-diketones
Biocatalytic methods, generally considered as ‘green’, utilise
enzymes such as lyases,9 hydrolases10 and oxidoreductases11 for
the synthesis of acyloins. These enzymes could be used as whole
a
a
diketones to produce enantiomerically enriched hydroxy ketones.
Over the past decade, we have shown that whole cells of
Candida parapsilosis ATCC 7330 effectively catalyse deracemiza-
tions,25 asymmetric reductions26 of a large variety of aliphatic
⇑
Corresponding author. Tel.: +91 44 2257 4106; fax: +91 44 2257 4102.
E-mail address: anjuc@iitm.ac.in (A. Chadha).
http://dx.doi.org/10.1016/j.tetasy.2015.09.001
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
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2
P. Mahajabeen, A. Chadha / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 1
Asymmetric reduction of benzil to benzoins by different biocatalysts
Biocatalyst
Type
ee (%), configuration
Reaction time (h)
References
Bacillus cereus Tim-r01
Bacillus cereus Tim-r01
Penicillium claviforme IAM 7294
Pichia glucozyma CBS 5766
Fusarium roseum OUT4019
Aspergillus oryzae OUT 5048
Baker’s yeast
Baker’s yeast
Baker’s yeast
Xanthomonas oryzae IAM 1657
Sulfolobus acidocaldarius DSM 639
Candida parapsilosis ATCC 7330
Wild type
94, (S)
99, (S)
99, (S)
75, (S)
98, (S)
94, (S)
78, (R)
95.6, (R)
50, (R)
—, (R)
12
6
3 days
2.5
24
12
13
14
15
16
Purified enzyme
Growing cells
Lyophilised whole cells
Whole cells
3
3
24
72
Dry powder
Dry powder
Dry powder
Growing cells
Recombinant enzyme
Whole cells
17
18
19
20
3 days
24
98, (R)
98, (S)
21
8
Present study
(—): not mentioned.
and aromatic substrates, resolutions of N-acyl amino esters,27
oxidative kinetic resolutions of secondary alcohols, enantioselec-
tive oxidations of diols28 and N-acylations of aromatic amines.29
In order to address the question of regio- and enantioselectivity
of the biocatalyst Candida parapsilosis ATCC 7330 towards reduc-
tions, we herein report the asymmetric reduction of various
diketones.
ee) and dichloromethane (85%, 92% ee). Considering both the con-
version (90%) and ee (98%), 1,4-dioxane was used as the cosolvent
for further reactions.
2.2. Effect of pH on the asymmetric reduction of 1a
Herein the asymmetric reduction of 1a was carried out at three
different pH values and the stereochemical outcome of the product
was monitored. Demir et al.11g showed that an inversion in the
chirality of the benzoins depends on the pH of the reaction
medium: when the asymmetric reduction was carried out with
the microorganism Rhizopus oryzae ATCC 9363 under basic
conditions, pH 6.5–8.5, (R)-benzoin was formed with ee >99%,
while under acidic conditions, pH 4.2–5.0, (S)-benzoin was
formed (80% ee). Herein the biocatalyst Candida parapsilosis ATCC
7330 gave (S)-benzoin at different pH values (Table 3). At all
three pH values (acidic, near neutral and basic) the absolute
configuration of the product benzoin formed was (S), but the
maximum conversion (91%) and ee (98%) was observed at pH 6.8.
Having optimised the cosolvent to 1,4-dioxane and the pH as
6.8, the reaction time was optimised to 8 h for the asymmetric
reduction of benzil to give 2a with maximum conversion (91%)
and ee (98%).
2. Results and discussion
Initially, the asymmetric reduction of benzil (a symmetric dike-
tone) 1a was carried out by whole cells of Candida parapsilosis
ATCC 7330 as reported earlier26e using ethanol as the cosolvent
(2.5% v/v). The reaction was monitored by HPLC at regular
intervals of time by determining the conversion and
enantiomeric excess (ee). Product 2a was obtained in 59%
conversion and with 91% ee in 24 h. As the starting material
benzil 1a was partially soluble in the cosolvent ethanol;
a
cosolvent study was carried out to improve the solubility and
conversion. The results are shown in Table 2.
2.1. Effect of the cosolvent on the biocatalytic asymmetric
reduction of 1a
Reportedly17,18,36 in biocatalytic asymmetric reductions, a sig-
nificant increase in enantioselectivity and conversion was
observed with the use of organic solvents. The cosolvent ethanol,
gave product 2a in only 59% conversion and with 91% ee. Other
water miscible (IPA, THF, 1,4-dioxane, MeOH, EtOH, DMF, DMSO)
and immiscible organic cosolvents (toluene, diethyl ether, dichlor-
omethane) were used (2.5% v/v) for the asymmetric reduction of 1a
(Table 2). In water miscible organic solvents, the conversion of pro-
duct benzoin 2a improved from 59% to 98% as did the enantioselec-
tivity (from 91% to 98%). In water immiscible organic solvents this
effect was not seen: toluene (19%, 43% ee), diethyl ether (72%, 77%
2.3. Biocatalytic reduction of diketones 1a–1h to hydroxy
ketones 2a–2h using whole cells of C. parapsilosis ATCC 7330
The biocatalytic asymmetric reduction of different a-diketones
1a–1d bearing symmetric, unsymmetric and cyclic substituents
and b-diketones 1e–1g bearing symmetric, unsymmetric and ali-
phatic substituents, was studied using whole cells of Candida para-
psilosis ATCC 7330 at 25 °C. Enantiomerically pure hydroxy ketones
were obtained in 35–75% yields (Scheme 1, Table 4).
In the case of unsymmetric a-diketones, such as 1b and 1c, the
carbonyl group attached to the less bulky alkyl group was
selectively reduced first compared to the carbonyl attached to
the phenyl group to give the corresponding enantiomerically pure
(S)-hydroxy ketones. The reduction of 1-phenylpropane-1,2-dione
1b yielded product 2b in 70% yield and with high ee (98%). Exten-
sion of the alkyl chain to ethyl, in 1-phenylbutane-1,2-dione 1c
resulted in product 2c in 67% yield and low enantioselectivity
Table 2
Biocatalytic asymmetric reduction of benzil in various cosolvents
S. no.
Solvent
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
EtOH
DCM
58.8
85.0
90.0
72.5
19.3
79.5
88.5
76.5
87.6
97.0
91.5
92.3
98.0
76.8
43.0
82.0
74.7
86.7
50.5
68.0
Dioxane
Diethyl ether
Toluene
MeOH
DMF
THF
DMSO
IPA
Table 3
Biocatalytic asymmetric reduction of benzil at different pH values
S. no.
pH
Conversion (%)
ee (%)
1
2
3
4.5
6.8
8.5
78.3
91
61.1
81.1
98.1
78.2
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P. Mahajabeen, A. Chadha / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Candida parapsilosis
prolonging the reaction time to 30 h. An aliphatic symmetric
b-diketone 1g (pentane-2,4-dione) resulted in (R)-hydroxyketone
2g with a lower yield (35%) and moderate ee (85%).
O
OH
O
O
ATCC 7330
*
R
R'
R
R'
n
n
2a-2h
When the reduction procedure was applied to
a cyclic
1a-1h
c
-diketone 1h (1,4-cyclohexanedione) resulted in the corresponding
n = 0, R = Ph, R' = CH3, C2H5, Ph
n = 0, R, R' = -CH2-CH2-CH2-
n = 1, R = Ph, R' = CH3, Ph
n = 1, R = R' = CH3
yield = 35-75%
ee = 10-98%
hydroxy ketone 2h with 70% conversion and 63% isolated yield.
Therefore, these experiments suggest that the biocatalyst
Candida parapsilosis ATCC 7330 accepts both symmetrical,
unsymmetrical diketones for reduction regardless of their position
Scheme 1. Asymmetric reduction of diketones 1a–1h using the whole cells of
Candida parapsilosis ATCC 7330.
(a
, b or
c).
Prolonging the reaction time to 48 h for 1a resulted in the for-
mation of (1S,2S)-1,2-diphenylethane-1,2-diol 3a with ee of 80%
(Table 5). Using 1b resulted in the formation of (1S,2S)-1-phenyl-
propane-1,2-diol 3b with 84% ee; the diastereomeric ratio between
(1S,2S) and (1R,2S)-1-phenylpropane-1,2-diol is 60:40 which was
determined by NMR analysis. Diketones 1c and 1d only gave trace
(36%), which did not improve when increasing the reaction time to
12 h. A cyclic a-diketone, such as 1,2-cyclohexanedione 1d gave 2d
in moderate yield (66%) and with moderate ee (69%).
An unsymmetric b-diketone 1e resulted in enantiomerically
enriched (R)-hydroxy ketone 2e by selective reduction of the car-
bonyl group attached to the methyl group with good isolated yield
(72%) and ee (92%). A sterically more demanding symmetrical dike-
tone 1,3-diphenylpropane-1,3-dione 1f gave in (R)-hydroxy ketone
2f with poor conversion and ee (10%), which did not improve when
amounts of the diols. The biocatalytic reduction of a-diketones to
diols proceeded in a stepwise fashion via the corresponding
hydroxy ketones. b-Hydroxy ketones 2e and 2g remained unre-
acted even after prolonging the reaction time to 48 h showing
complete regioselectivity.
Table 4
Biocatalytic reduction of various diketones 1a–1h to hydroxy ketones by whole cells of Candida parapsilosis ATCC 7330
S. no.
Reactant
Product
Reaction time (h)
Conversiona (%)
Yield (%)
75
eeb (%)
98
Absolute configurationc
O
O
1
8
90
(S)
O
OH
1a
2a
O
O
2
3
3
3
89
76
70
67
98
36
(S)
(S)
O
O
OH
OH
2b
1b
O
O
1c
2c
O
OH
O
O
4
5
3
9
75
95
66
72
69
92
(S)
(R)
1d
2d
O
O
O
O
OH
OH
2e
1e
O
O
O
6
7
30
30
10
38
Nd
35
10
85
(R)
(R)
2f
OH
1f
O
O
O
2g
1g
O
8
8
70
63
—
—
O
OH
1h
2h
Nd: not determined.
a
Conversion was determined by HPLC using a reverse phase column.
ee was determined by chiral HPLC.
b
c
Determined by comparing the specific rotation values with the literature.30,33,39–41
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P. Mahajabeen, A. Chadha / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 5
Biocatalytic reduction of
a-diketones 1a–1d to diols by whole cells of Candida parapsilosis ATCC 7330
S. no.
Reactant
Product
Yielda (%)
eeb (%)
80
Absolute configurationc
O
OH
1
15
(1S,2S)
OH
O
O
1a
3a
O
OH
2
85
84
(1S,2S)
OH
1b
3b
O
3
4
Traces
Traces
—
—
—
—
—
—
O
1c
O
O
1d
a
Isolated yield.
b
Determined by Chiral HPLC.
c
Determined by comparing the specific rotation values with the literature.24,43
a
-Diketones 1a–1d gave (S)-hydroxy ketones (Prelog products)
whereas b-diketones 1e–1g gave (R)-hydroxy ketones (anti-Prelog
products).
2.4. Biotransformation of cyclohexane-1,3-dione and 5,5-
dimethylcyclohexane-1,3-dione
In the case of cyclohexane-1,3-dione 1i in ethanol as cosolvent
(2.5% v/v) at 25 °C and whole cells of Candida parapsilosis ATCC
7330, product 2i was obtained as the sole product instead of the
expected products (Scheme 2). The conversion to the product
was monitored at regular intervals of time by TLC and at 4 h the
starting material was consumed completely to give product 2i
(42% yield). Initially, when dioxane was used as the cosolvent, 2i
was obtained in only 10% conversion. In an attempt to improve
the conversion ethanol was used and it was found that ethanol
gave 98% conversion to 2i. The formation of 2i was attributed to
the fact that whole cells of Candida parapsilosis ATCC 7330 are cap-
able of producing acetaldehyde in situ during the
biotransformation.29
Figure 1. ORTEP depiction of compound 2i.
In addition to spectroscopic techniques (1H, 13C NMR and IR
spectroscopy), the formed product was characterised by single
crystal XRD (Fig. 1). Ramachary and Kishor35 reported that the
reaction of 1,3-cyclohexanedione with aldehydes and Hantzsch
ester resulted in 2-alkyl-cyclohexane-1,3-dione as the product.
Apart from 2-alkyl-cyclohexane-1,3-dione, 2,20-(ethane-1,1-diyl)
bis(3-hydroxycyclohex-2-enone) was also observed during the
course of reaction. A plausible mechanism for the formation of 2i
as per the literature35 is shown in Scheme 3.
As another example, when 5,5-dimethylcyclohexane-1,3-dione
(dimedone) 1j was incubated with the biocatalyst, the dimerised
OH
*
O
OH
Candida parapsilosis
Candida parapsilosis
HO
O
ATCC 7330
ATCC 7330
*
*
(or)
H2O, EtOH, 25 °C, 4 h
O
O
OH
O
OH
CH3
1i
2i
Yield 42%
Expected products
Scheme 2. Biotransformation of cyclohexane-1,3-dione 1i.
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5
O
H
O
O
O
OH
H
O
H
-H2O
CH3
H
CH3
CH3
H
O
O
O
O
H
CH3
OH
CH3
O
O
O
OH
H
O
HO
O
Scheme 3. Plausible mechanism for the formation of 2i.35
All substrates were purchased locally. 1H and 13C NMR spectra
were recorded in CDCl3 solution on a Bruker AVANCE III 500 MHz
spectrometer operating at 500 MHz and 125 MHz. Chemical shifts
are expressed in ppm values using TMS as an internal standard.
Analytical thin layer chromatography (TLC) was performed on
Kieselgel 60 F254 aluminium sheets (Merck 1.05554). Column
chromatography was performed on silica gel (100–200 mesh).
High-resolution mass spectra were recorded with Q-TOF micro-
mass spectrometer. Infrared spectra were recorded on a Shimadzu
IR 470 Instrument. HPLC analysis of hydroxy ketones and diols was
carried out on a Jasco PU-1580 liquid chromatograph equipped
with a PDA detector using Daicel OD-H, AD-H chiral columns to
determine the ee. A hexane/iso-propanol (90:10) mixture was used
as the mobile phase with a flow rate of 1 mL/min. The proportion of
solvents was varied for different hydroxy ketones and diols. Ali-
phatic substrates were analysed by gas chromatography (GC) using
a Perkin Elmer Clarus 600 gas chromatograph fitted with a flame
ionisation detector using VARIAN Chirasil dex CB chiral column
Table 6
Biocatalytic preparation of the bis adducts using whole cells of Candida parapsilosis
ATCC 7330
S. no.
Reactant
Product
Yield (%)
42
O
O
CH3 OH
1
O
OH
O
O
1i
2i
O
CH3 OH
2
40
O
OH
O
1j
2j
product
2,20-(ethane-1,1-diyl)bis(3-hydroxy-5,5-dimethylcyclo-
hex-2-enone) 2j was formed (Table 6). These bis adducts and their
tautomeric tetraketone forms are used as key units in the synthesis
of xanthenes.38
(0.25
l
m ꢀ 25 mm ꢀ 25 m). Helium was used as the carrier gas
with a flow rate of 1 ml/min with a split factor of 50:1. X-ray crys-
tallographic analysis was performed with a Bruker AXS Kappa
APEX II single crystal CCD Diffractometer equipped with gra-
3. Conclusion
phite-monochromated MoKa radiation (k = 0.71073 Å) at room
temperature.
In conclusion, a series of diketones underwent asymmetric
reduction to hydroxy ketones using whole cells of Candida parap-
silosis ATCC 7330 with excellent enantiomeric excesses (98%) and
good yields (up to 75%) in 3–9 h. The regioselectivity of the biocat-
alyst towards diketones showed that the carbonyl group attached
to the alkyl group was reduced first in preference to the carbonyl
4.2. Growth conditions of Candida parapsilosis ATCC 733031
Candida parapsilosis ATCC 7330 was grown in yeast malt broth
medium (50 mL) in 250 mL Erlenmeyer flasks incubated at 25 °C,
200 rpm. The cells were harvested by centrifuging the 14th h cul-
ture broth at 10,000 rpm for 10 min at 4 °C and subsequently
washed with distilled water. The process was repeated twice,
and the wet cells were used for the biotransformation. In total,
1 g wet cells were obtained per 50 mL medium in 250 mL Erlen-
meyer flask.
group attached to the aryl group. All the
a-diketones gave their
corresponding diols when the reaction time was extended to
48 h whereas the b-diketones gave only the mono-reduced prod-
ucts showing complete regioselectivity. 1,3-Cyclohexanedione
and dimedone gave dimerised products 2,20-(ethane-1,1-diyl)bis
(3-hydroxycyclohex-2-enone) and 2,20-(ethane-1,1-diyl)bis(3-hy-
droxy-5,5-dimethylcyclohex-2-enone) with in situ generated
acetaldehydes instead of the reduced products, which is reported
here for the first time.
4.3. Typical procedure for asymmetric reduction of diketones
using the whole cells of Candida parapsilosis ATCC 7330
At first, 10 g of wet cells of Candida parapsilosis ATCC 7330 sus-
pended in 10 mL of water, and 40 mg (0.2 mmol) of benzil 1a dis-
solved in 1 mL of dioxane (for other diketones ethanol was used) as
a cosolvent were added into the cell suspension and incubated at
25 °C, 200 rpm for 8 h in a water bath shaker. The reaction was car-
ried out in triplicate. Control experiments were carried out in par-
allel without the whole cells and with heat treated cells under
identical conditions. In order to determine the isolated chemical
yield, the asymmetric reduction of 1a was carried out with
80 mg of the substrate, wet cells and cosolvent were taken
4. Experimental
4.1. General
C. parapsilosis ATCC 7330 was purchased from ATCC, Manassas,
VA 20108, USA, and maintained at 4 °C in yeast malt agar medium
that contained 5 g/L peptic digest of animal tissue, 3 g/L malt
extract, 3 g/L yeast extract, 10 g/L dextrose and 20 g/L agar and
precultured in yeast malt broth medium purchased from HiMedia.
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P. Mahajabeen, A. Chadha / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
118.9, 191.0, 191.1; IR (neat) 2943, 2626, 1580, 1376, 1265, 1190,
1136, 925, 873 cmꢁ1; HRMS: Calcd for C14H19O4 251.1283 [M+1];
obsd 251.1284.
accordingly. After completion of the reaction the product 2a was
extracted with ethyl acetate (3 ꢀ 10 mL) and the organic layer
was dried over anhydrous sodium sulfate and concentrated under
vacuum. The crude product obtained was purified by column chro-
matography using hexane/ethyl acetate (75:25) as the mobile
phase to give 2a in 75% yield as a colourless solid. The ee was found
to be 98%, as determined by HPLC OD-H column using 9:1 hexane/
4.4.8. 2,20-(Ethane-1,1-diyl)bis(3-hydroxy-5,5-dimethylcyclo-
hex-2-enone) 2j
isopropanol mixture. The specific rotation of 2a {[a]
25 = +71.2 (c
D
0.25, acetone) for 98% ee} was compared with the literature value
to assign the absolute configuration, and it was found be (S). The
same procedure was followed for the remaining diketones 1b–1j.
The spectroscopic data of 2a,40 2b,32 2c,32 2d,42 2e,34 2g30b and
2h37 were in accordance with the literature values.
O
CH3 OH
OH
O
4.4. Spectroscopic characterization of substrates
Colourless solid, mp 162–165 °C; 1H NMR (500 MHz, CDCl3) d 1.04
(s, 12H), 1.48 (d, 3H, J = 7.5 Hz), 2.16–2.32 (m, 8H), 4.14 (q, 1H,
J = 7.5 Hz), 12.5 (1H, s, OH), 12.89 (1H, br s, OH); 13C NMR
(125 MHz, CDCl3) d 15.6, 15.9, 23.5, 26.5, 29.7, 31.2, 45.9, 46.1,
47.0, 113.4, 117.6, 189.4, 189.6; IR (neat) 2962, 2635, 1581, 1381,
4.4.1. (S)-2-Hydroxy-1,2-diphenylethanone 2a
[a] [a]
25 = +71.2 (c 0.25, acetone), 98% ee, {lit.40 25 = +37.4 (c 1,
D
D
acetone), 43% ee}. The enantiomeric excess was determined by
HPLC analysis using Chiracel OD-H column (eluent, hexane/2-pro-
panol = 90:10, flow rate: 0.5 mL/min) tR = 9.8 min (major, (S)-iso-
mer); tR = 13.7 min (minor, (R)-isomer).
1249, 1169, 1149, 1113, 926, 887 cmꢁ1
18H27O4 307.1895 [M+1]; obsd 307.1904.
; HRMS: Calcd for
C
4.5. X-ray analysis of compound 2i
4.4.2. (S)-2-Hydroxy-1-phenylpropan-1-one 2b
[
a]
25 = ꢁ82.4 (c 2, CHCl3), 98% ee, {lit.30a
[a
]
20 = ꢁ80.9 (c 2,
D
D
Empirical formula = C14H18O4, formula weight = 250.28, tem-
perature = 293(2) K, wavelength = 0.71073, crystal system, space
group = monoclinic, P21/n, Unit cell dimensions a = 8.1370(3) Å
alpha = 90°, b = 12.1820(4) Å beta = 94.6170(10)°, c = 12.5930(4) Å
gamma = 90°, volume = 1244.23(7) Å3, Z, calculated density = 4,
1.336 mg/m3, absorption coefficient = 0.097 mmꢁ1, F(000) = 536,
crystal size = 0.30 ꢀ 0.20 ꢀ 0.20 mm, theta range for data collec-
tion = 2.33–25.00°, limiting indices ꢁ9 6 h 6 9, ꢁ14 6 k 6 14,
ꢁ13 6 l 6 14, reflections collected/unique = 10,591/2203 [R(int)
= 0.0277], completeness to theta = 25.00 100.0%, absorption
correction = semi-empirical from equivalents, max. and min. trans-
mission = 0.9945 and 0.9634, refinement method = full-matrix
least-squares on F2, data/restraints/parameters = 2203/0/168,
Goodness-of-fit on F2 = 1.052. Further details on the crystal struc-
ture are available upon request from Cambridge Crystallographic
Data Centre, with deposition number CCDC 1405068.
CHCl3), 95% ee}. The enantiomeric excess was determined by
HPLC analysis using Chiracel OD-H column (eluent, hexane/2-
propanol = 90:10, flow rate: 0.5 mL/min) tR = 15.7 min (major, (S)-
isomer); tR = 17.8 min (minor, (R)-isomer).
4.4.3. (S)-2-Hydroxy-1-phenylbutan-1-one 2c
[
a
]
25 = ꢁ11.2 (c 1, CHCl3), 36% ee, {lit.41
[
a
]
20 = ꢁ29.3 (c 1.1,
D
D
CHCl3), 93% ee}. The enantiomeric excess was determined by HPLC
analysis using Chiracel OD-H column (eluent, hexane/2-propa-
nol = 95:05, flow rate: 0.4 mL/min) tR = 15.7 min (minor, (R)-iso-
mer); tR = 18.9 min (major, (S)-isomer).
4.4.4. (S)-2-Hydroxycyclohexanone 2d
[
a
]
25 = ꢁ10.2 (c 0.5, CHCl3), 69% ee, {lit.33
[
a]
20 = ꢁ13.3 (c 0.5,
D
D
CHCl3, 90% ee}.
4.4.5. (R)-3-Hydroxy-1-phenylbutan-1-one 2e
25 = –48.5 (c 1, CHCl3), 92% ee, {lit.39
CHCl3), 97% ee}. The enantiomeric excess was determined by HPLC
analysis using Chiracel OD-H column (eluent, hexane/2-propa-
nol = 95:05, flow rate: 0.5 mL/min) tR = 20.1 min (minor, (S)-iso-
mer); tR = 22.1 min (major, (R)-isomer).
Acknowledgements
[
a]
[
a
]
23 = ꢁ58.1 (c 1,
D
D
Pula Mahajabeen gratefully acknowledges the Council of Scien-
tific and Industrial Research (CSIR), India for the fellowship. We
thank the Sophisticated Analytical Instrumentation Facility (SAIF)
IIT Madras for the NMR analysis. We thank Dr Sudhadevi for XRD
analysis and Mr C. Kabilan for mass spectrometry analysis.
4.4.6. (R)-4-Hydroxypentan-2-one 2g
[
a
]
25 = ꢁ54.5 (c 2, CHCl3), 85% ee, {lit.30b
[
a
]
20 = ꢁ68 (c 2.34,
D
D
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