Synthesis of new chiral keto alcohols by baker's yeast

Article abstract of DOI:10.1016/j.tetasy.2014.01.003

Fourteen chiral α- and β-keto alcohols 2a-2r were synthesized by the asymmetric reduction of their corresponding diketones 1a-1r via baker's yeast. In addition, ten corresponding racemic α-keto alcohols were synthesized by the benzoin condensation of their corresponding aldehydes, which were used for the determination of the ee values through their chiral resolution on chiral HPLC. Amongst the 15 diketones, 1j and chiral α-keto alcohols 2i, 2j and chiral β-keto alcohol 2r are novel compounds. Six keto alcohols 2b, 2c, 2d, 2f, 2h and 2p were synthesized by baker's yeast for the first time. There are some studies in the literature where baker's yeast was applied to the diketones 1a, 1g, 1e, 1k and 1n under various conditions different to those reported herein. The yields and the ee values of these studies were not as high as ours. All of the keto alcohols synthesized were characterized by IR, NMR (¹H and ¹³C), and MS. The relationship between the structure of the diketone and the yield, diastereoselectivity and enantiomeric excess is also discussed.

Full text of DOI:10.1016/j.tetasy.2014.01.003

Tetrahedron: Asymmetry 25 (2014) 340–347
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of new chiral keto alcohols by baker’s yeast
⇑
Tülay Yıldız, Nurgül Çanta, Aysße Yusufog˘lu
Department of Chemistry, University of Istanbul, Istanbul, Avcilar 34320, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 November 2013
Accepted 14 January 2014
Fourteen chiral
a
- and b-keto alcohols 2a–2r were synthesized by the asymmetric reduction of their cor-
responding diketones 1a–1r via baker’s yeast. In addition, ten corresponding racemic
were synthesized by the benzoin condensation of their corresponding aldehydes, which were used for
a
-keto alcohols
the determination of the ee values through their chiral resolution on chiral HPLC. Amongst the 15 dike-
tones, 1j and chiral a-keto alcohols 2i, 2j and chiral b-keto alcohol 2r are novel compounds. Six keto alco-
hols 2b, 2c, 2d, 2f, 2h and 2p were synthesized by baker’s yeast for the first time. There are some studies
in the literature where baker’s yeast was applied to the diketones 1a, 1g, 1e, 1k and 1n under various
conditions different to those reported herein. The yields and the ee values of these studies were not as
high as ours. All of the keto alcohols synthesized were characterized by IR, NMR (1H and 13C), and MS.
The relationship between the structure of the diketone and the yield, diastereoselectivity and enantio-
meric excess is also discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
satisfying optimizations of the reaction conditions and the struc-
ture of the substrates. For this reason fourteen a- and b-keto alco-
The asymmetric reduction of carbonyl substrates by biocataly-
sis is a useful preparative method to obtain chiral compounds,
which are necessary for the preparation of natural products and
pharmaceuticals.1 Enzymes are interesting natural bioreactives
and biocatalysts in stereoselective reactions.2
Baker’s yeast (Saccharomyces cerevisiae) is the most frequently
used ketoreductase in green chemistry due to its bioavailability,
feasibility and inexpensive reaction conditions.3,4 1-Phenyl-1,
2-propanedione can be reduced by thermal pre-heated baker’s
yeast to its monohydroxypropanone with high enantiomeric
excess.5 1-Chloro-2,4-alkanediones react with baker’s yeast both
regio- and enantioselectively.6
hols were synthesized with high yields and with high ee values.
2. Results and discussion
It was assumed that the asymmetric reduction of diketones
with baker’s yeast might provide the desired enantiomerically pure
keto alcohols. However, the lack of literature on the asymmetric
reduction of
a- and b-diketones encouraged us to synthesize a ser-
ies of 15 different chiral
a- and b-hydroxy ketones 2a–2r, and to
screen them for enantioselective and regioselective reduction with
baker’s yeast.
The advantages of some important information on baker’s yeast
were used.13–15 Herein we found that there were many factors that
affected the reducibility of baker’s yeast reactions. The most
important factors were organic solvents, pH, cosubstrates, heating
and inhibitors. Benzil 1a was used with different baker’s yeast
reducing methods in order to determine the best conditions. The
first method included a phosphate buffer (pH 7), glucose as the en-
ergy source, ethanol as the solvent and heat treatment was carried
out.5 The second method involved the use of n-hexane as organic
solvent in diverse organic–water solvent systems. In the third
method, glucose was again the energy source and water was used
as the solvent at 30 °C. Allyl alcohol was the inhibitor in hexane–
Et2O mixtures with water (Table 1). The use of inhibitor was suc-
cessful in some cases. Utaka et al.16 obtained (S)-product with
94% ee, by incubating the yeast suspension with allyl alcohol in
the addition of 1-chloro-2,4-alkanediones and glucose, compared
to an ee of 47% without the inhibitor.
Herein we report on the asymmetric synthesis of new chiral
- and b-keto alcohols with different structures via enzymatic ba-
a
ker’s yeast reduction of their corresponding diketones that was
aimed to be studied in this work; since chiral keto alcohols are
valuable building blocks for many applications, pharmaceuticals,
flavours, fragrances7 and natural products.8
a-Hydroxy ketones
are found in some antidepressants, Alzheimer’s treatment
medicals, in antifungal agents and in antitumor antibiotics
(epothilones).9,10 b-Hydroxy ketones are also synthons for the
preparation of various natural compounds such as prelactone
V11 and amphidinolides O and P12 (Scheme 1).
According to the literature, there are only a few studies on the
reduction of diketones by baker’s yeast, these do not involve
⇑
Corresponding author. Tel.: +90 212 473 70 70/17806; fax: +90 212 473 71 80.
E-mail address: ayseyusufoglu@gmail.com (A. Yusufog˘lu).
0957-4166/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2014.01.003

T. Yıldız et al. / Tetrahedron: Asymmetry 25 (2014) 340–347
341
R1
O
S
OH
O
O
N
R2
H
N
O
N
H
R
O
OH
O
OH
O
R
R
1 = R2 = H
1 = Me; R2 = H
agent for Alzheimer's treatment
epothilones
N
N
F
N
N
OH
N
N
OH
O
N
N
HO
F
O
SO2CH3
F
F
F
antifungal agents
Scheme 1. Examples of some chiral synthons bearing
prelactone V (I)
a
- and b-hydroxy ketones.
Table 1
The reduction of benzil with baker’s yeast using different methods
O
OH
baker's yeast
O
O
1a
2a
Entry
Heat treatment T (°C)/time (min)
Buffer
Reduction time (h)
Allyl alcohols (mL)
Org. solvent
Conv. (%)
ee (%)
Config.
1
2
3
4
5
6
53/60
30–40/30
30/30
pH 7
pH 7
—
—
—
48
24
48
3
3
3
—
—
—
0.1
0.15
0.2
EtOH
n-Hexane
—
n-Hexane–Et2O
n-Hexane–Et2O
n-Hexane–Et2O
38
53
46
72
43
40
5
5
27
74
52
48
(S)
(S)
(R)
(R)
(R)
(R)
50/30
50/30
50/30
—
Table 3
Table 2
Effects of organic solvents in the BY reduction of benzil 1a
Effects of sugars in the baker’s yeast reduction of benzil 1a
Entry
Organic solvent
Conv. (%)
ee (%)
Config.
Entry Cosubstrate (g) Conv.
ee
Config.
(%)
(%)
1
2
3
4
5
6
7
8
9
10
Toluene
Tetrahydrofurane
n-Pentane
Dichloromethane
n-Hexane + Et2O (1:1)
n-Hexane + EtOAc (1:1)
n-Heptane + Et2O (1:1)
n-Heptane + EtOAc (1:1)
n-Hexadecane + EtOAc (1:1)
n-Dodecane + EtOAc (1:1)
57
8
48
36
24
12
74
70
74
78
52
56
(R)
(R)
(R)
(S)
(R)
(R)
(R)
(R)
(R)
(R)
1
2
3
4
Glucose (2)
Galactose (2)
Xylose (2)
72
68
55
54
74
54
22
66
(R)
(R)
(R)
(R)
26
87
72
90
94
93
45
27
(ꢀ)-1,2:5,6-Di-O-isopropyliden-
a-D-
glucofuranose (2)
5
1,2:3,4-Di-O-isopropyliden-
galactopyranose (2)
Maltose (2)
a-
D-
40
26
(R)
6
73
0
48
—
(R)
—
7
Tartaric acid (2)
8
9
10
11
Succinic acid (2)
Glucose (1.5) + tartaric acid (0.5)
Glucose (1) + tartaric acid (1)
0
—
—
Substrate 0.5 mmol, dry baker’s yeast 2 g, water 38 mL, glucose 2 g, heat treatment
at 50 °C for 30 min, allyl alcohol 0.1 mL, organic solvent 0.5 mL, 3 h.
85
82
56
73
66
22
(R)
(R)
(R)
Glucose (1.5) + succinic acid (0.5)
Substrate 0.5 mmol, dry baker’s yeast 2 g, water 38 mL, heat treatment at 50 °C for
30 min, alyl alcohol 0.1 mL, n-hexane–Et2O (1:1) 0.5 mL, 3 h.
In these experiments, screening of several sugars and sugar
derivatives as energy sources was investigated (Table 2). In baker’s
yeast, carbohydrate derivatives such as glucose, fructose, mannose,
etc. and also tartaric acid, succinic acid, lactic acid were used as en-
ergy sources in the incubation process. Amongst these sugars and
mixtures, the highest conversion was found in a mixture where
1.5 g glucose and 0.5 g tartaric acid were used (Table 2, entry
10). However, the ee value was found to be similar when no tar-
taric acid was used (Table 2, entries 1 and 10), and thus, only glu-
cose was used for the rest of these reactions.
Amongst these experiments, we observed that the highest ee
and yield values were obtained with heat treatment, allyl alcohol
(0.1 mL) and n-hexane/Et2O mixture (1:1) as the organic solvent
(Table 1, entry 4). The results showed that in the presence of an al-
lyl alcohol, chiral benzoin 2a was recovered in 40–68% conversion
with an ee ranging from 5% to 74%. Moreover the reduction time
was decreased from 24 to 3 h.

342
T. Yıldız et al. / Tetrahedron: Asymmetry 25 (2014) 340–347
a- and b-diketones by baker’s yeast
Table 4
The results of enantioselective reduction of aromatic
Entry
Substrate
Product
Yielda (%)
eeb (%)
Config.c
O
OH
1
85
65
44
78
(R)
O
O
O
1a
2a
OH
O
2
3
98
52
(R)
(R)
O
1b
2b
O
OH
O
O
1c
2c
O
O
O
OH
4
5
62
76
53
84
(R)
(R)
O
O
O
O
O
O
1d
2d
O
O
O
OH
O
O
1e
2e
O
O
OH
6
7
55
57
78
62
(R)
(R)
O
1f
O
2f
O
O
OH
O
O
O
O
O
O
2g
1g
O
OH
8
60
72
(R)
O
O
O
O
O
O
O
2h
1h
O
O
9
45
65
64
50
(R)
(R)
OH
1i
2i
O
O
(CH2)11CH3
(CH2)11CH3
10
O
OH
O
O
2j
1j
O
HO
O
O
11
50
100
(R)
2k
1k

T. Yıldız et al. / Tetrahedron: Asymmetry 25 (2014) 340–347
343
Table 4 (continued)
Entry
Substrate
Product
Yielda (%)
eeb (%)
Config.c
O
O
12
13
No reaction
—
—
—
1m
O
O
O
O
OH
OH
45
100
(R)
2n
1n
O
O
14
62
74
100 (dr = 100:0)d
(1S,2R)
(1S,2R)
2p
1p
O
O
O
OH
15
100 (dr = 3:1)d
1r
Isolated yield of products.
2r
a
b
c
The ees were determined by HPLC analysis using literature data and racemic compounds as references.
The absolute configuration of the products was assigned by comparing the literature values of the compounds. The absolute configurations of 2i, 2j, 2k, 2p and 2r were
attributed to have an (R)-configuration because they have similar structures with others.
d
The drs were determined by 1H NMR.
One of the most important factors that limits the benefit of the
system in the reductions with baker’s yeast is the requirement of
an aqueous reaction medium for water-insoluble substances.17
The water solubility of diketones is very low and they are toxic
for baker’s yeast whole cells. By using an organic solvent, signifi-
cantly better enantioselectivity, yield, as well as regioselectivity
and chemoselectivity can be obtained.18
As shown in Table 3, several organic solvents considerably en-
hanced the enantiomeric excess in favour of the (R)-configuration.
The mixtures of a nonpolar solvent such as hexane and heptane
and a polar solvent such as ethyl acetate and diethyl ether were
more effective than other solvents. The effect of a small amount
of organic solvent mixture was important under the conditions of
heat-treatment with allyl alcohol, and an (R)-configuration was ob-
tained with 78% ee when using a mixture of n-heptane and ethyl
acetate (1:1) (Table 3, entry 8).
herein. Therefore, the other keto alcohols reported herein were
attributed to have an (R)-configuration due to their similar
structures.
The results of the baker’s yeast reduction of diketones 1a–1r are
summarized in Table 4. The diketones in the form of benzil,
showed enantioselectivities between 50% and 98% and always pro-
vided new stereogenic centres with (R)-configurations. The highest
ee value was found for (R)-2b (ee = 98%).
The other
a-diketone 1k (acenaphthene quinone) which had a
different structure from benzil, showed an excellent enantiomeric
excess close to 100%. Compound 2k was obtained by a different ba-
ker’s yeast procedure,22 although with only 23% ee.
New chiral a-keto alcohols 2i and 2j have been synthesized for
the first time in this study. They bear different groups on both
sides. 2i has Ph and 5-Me-furyl groups; and 2j includes p-MeOC6-
H5 and n-C12H25 as substituents. After bioreduction of these com-
pounds, one of the keto groups was always reduced by baker’s
yeast. The steric hindrance of electron flow was found to be effec-
tive on this reduction.
The optimal reaction conditions obtained for benzil 1a with
baker’s yeast were applied to the enantioselective reductions of
the
a- and b-diketones 1a–1r (Table 4). Ten 1,2-diketones 1b–1h
were synthesized from readily available, inexpensive starting
materials in two steps through benzoin condensation19 of their
aldehyde derivatives as the first step and oxidation of the benzoin
derivatives to diketones.20 Compound 1j was prepared by a differ-
ent route; by oxidation of its alkene derivative.21 Compounds 1a
and 1k were commercially available 1,2-diketones. The four pur-
chased 1,3-diketones 1m–1r of different structures were reduced
to their corresponding keto alcohols 2m–2r by baker’s yeast.
Except for 1a, 1e, 1g, 1k and 1n, all of the other diketones were re-
duced to their corresponding keto alcohols using baker’s yeast for
the first time. From the chiral keto alcohols synthesized, 2a,18 2e,18
2g,18 2k22 and 2n23,24 were obtained by other baker’s yeast
procedures.
In the bioreduction of the b-diketones 1n, 1p and 1r, excellent
regioselectivity and enantioselectivity except for 1,3-diphenyl 1m
were observed. While nearly 100% ee for 2n, 2p and 2r were found,
no reaction was observed for 1m. Compound 1m is resistant
against bioreduction due to its very stable structure. Compounds
1n, 1p and 1r all have nearly the same skeleton (Scheme 2).
According to the experimental results obtained in this study,
only one of the both carbonyl groups is reduced by baker’s yeast.
In the presence of the inhibitor allyl alcohol, the bioreduction
showed only R-selectivity. Bioreduction of 1-phenyl-1,3-butadione
(1n) with baker’s yeast previously furnished the (S)-enantiomer
The ee values and the diastereomeric ratios of the aforemen-
tioned chiral keto alcohols were determined by chiral HPLC and
were analysed by IR, NMR (1H and 13C) and MS. The configurations
of the keto alcohols, except for 2i, 2j, 2k, 2p and 2r, were consid-
ered according to the data in the literature18–24 and were assigned
as having an (R)-configuration. Baker’s yeast gave alcohols with an
(R)-configuration, which was in agreement with the conditions
O
O
O
O
O
O
1
2
1
2
1
2
1n
1p
1r
Scheme 2. The structures of 1n, 1p and 1r.

344
T. Yıldız et al. / Tetrahedron: Asymmetry 25 (2014) 340–347
Racemic 2e
Enantiomerically enriched 2e (84 % ee)
Scheme 3. The HPLC chromatograms of racemic and enantiomerically enriched 2e as an example of a-keto alcohol.
Racemic 2n
Enantiomerically enriched 2n (100 % ee)
Scheme 4. The HPLC chromatograms of racemic and enantiomerically enriched 2n as an example of b-keto alcohol.
with 77% enantiopurity.24 The other b-keto alcohols 2p and 2r
were synthesized for the first time by baker’s yeast reduction.
The absolute configuration of the keto alcohols was determined
by using literature data and their retention times on HPLC were
compared (Schemes 3 and 4). The (R)-configuration was confirmed
by these analyses. However, keto alcohols 2i, 2j, 2k, 2p and 2r,
which have no literature data were determined to have an (R) con-
figuration by comparing the results from the rest of the findings in
this work.
cerevisiae as an active and dry solid form was purchased by Sigma
(Cat. No: YSC2-500G). -Diketone 1j were obtained from oxidation
of the corresponding alkene using KMnO4 and a phase transfer
agent.25 The racemic
-keto alcohols were prepared via benzoin
condensation of the corresponding aldehydes with KCN in etha-
nol–H2O. The other -diketones were synthesized by oxidation
a
a
a
of the corresponding racemic keto alcohols using I2/K2CO3 in
t-BuOH.23 The racemic b-keto alcohols were prepared by con-
trolled reduction with NaBH4. Their resolution on chiral HPLC
was used for determining the ee values of the chiral b-keto alco-
hols. The reactions were monitored by TLC using silica gel plates
and the products were purified by flash column chromatography
on silica gel (Merck; 230–400 mesh) with hexane–ethyl acetate.
NMR spectra were recorded at 500 MHz for 1H and at 125 MHz
for 13C using Me4Si as the internal standard in CDCl3. GC–MS were
recorded on Shimadzu/QP2010 Plus. Optical rotations were mea-
sured with an Optical Activity AA-55 digital polarimeter at room
temperature. IR spectra were recorded on Mattson 1000. Melting
points were determined with Buchi melting point B-540. The
enantiomeric excesses (ee) of the product chiral alcohols were
determined with Shimadzu/DGU-20A5 HPLC apparatus fitted with
a 25 cm Chiralcel OD, Chiralcel OD-H and Chiralpac AD-H chiral
columns.
3. Conclusion
The enantioselectivity of the synthesized keto alcohols 2a–2r
(Table 4) was controlled by the additives of an enzyme inhibitor,
heat treatment and small amounts of organic solvent. The used or-
ganic solvent and inhibitor play a role in solubilizing and enhanc-
ing the substrate concentration in favour of the (R)-selectivity.
Bioreduction by dry baker’s yeast presents an excellent example
of natural, efficient, green, low energy and compatible multistep
synthesis. In addition, water is the solvent of choice for many of
the bio-transformations. The economic and easy to handle baker’s
yeast can be the reagent of choice for biotransformations with high
stereoselectivities. We have shown herein that the baker’s yeast
reduction is a very effective, environmentally sensitive and inex-
pensive method, especially for synthesizing chiral
alcohols.
a- and b-keto
4.2. General procedure using heat-treated baker’s yeast with an
inhibitor and a small amount of organic solvent
A mixture of dry baker’s yeast (2 g), water (38 mL), glucose (2 g)
and allyl alcohol (0.1 mL) was stirred at 50 °C for 30 min. After the
mixture was cooled to 30 °C, the substrate (0.05 mmol) dissolved
in 0.5 mL of organic solvent was added and the reaction was con-
tinued to stir at 30 °C for 3 h. The work-up procedure was essen-
tially the same as that described in the foregoing experiment.
4. Experimental
4.1. General
The majority of the chemicals used herein were commercially
available from Merck or Aldrich. Commercial baker’s yeast, S.

T. Yıldız et al. / Tetrahedron: Asymmetry 25 (2014) 340–347
345
4.3. Data for starting diketones synthesized
28.02–29.63, 37.51, 55.30, 130.00, 131.40, 162.94, 190.71, 202.78.
MS m/z: 41, 57, 77, 97, 107, 108, 122, 136, 145, 164, 223, 226,
302, 318, 332 (M+). Anal. Calcd for C21H32O3: C, 75.86; H, 9.70.
Found: C, 75.30; H, 10.01.
4.3.1. 1,2-Bis(2-methylphenyl)-1,2-ethanedione 1b26
90% Yield (oily liquid). IR (neat, cmꢀ1): 3061, 2961, 2923, 1676,
1607, 1461, 1269, 1200, 1130, 884, 746 cmꢀ1 1H NMR (CDCl3): d
.
2.57 (s, 6H), 7.20 (m, 2H), 7.28 (m, 2H), 7.43 (m, 2H), 7.60 (m,
2H). MS m/z: 41, 51, 65, 77, 89, 91, 102, 119, 120, 165, 193, 207,
220, 238 (M+).
4.4. Spectroscopic data of the chiral keto alcohols synthesized
4.4.1. (R)-2-Hydroxy-1,2-diphenyl ethanone 2a31
Mp 135.4–136.7 °C, ½a D25
ꢁ
¼ ꢀ81:5 (c 0.27, CH3COCH3), {lit.31
4.3.2. 1,2-Bis(3-methylphenyl)-1,2-ethanedione 1c26
½
a 2D5
ꢁ
¼ ꢀ114 (c 1.5, CH3COCH3) for 99% ee, (R)-enantiomer},
Mp 102.4–103.4 °C, 95% yield (oily liquid). IR (neat, cmꢀ1):
ee = 78%. HPLC analysis: Chiralcel OD chiral column, mobile phase
iso-PrOH/hexane: 10:90, flow rate: 1.0 mL/min, wavelength:
210 nm; tR (retention time): 11.03 min for (S)-isomer, 18.87 min
for (R)-isomer. IR (neat, cmꢀ1): 3415, 3038, 2923, 2853, 1676,
3038, 2923, 2861, 1669, 1600, 1476, 1515, 1253, 1153, 730 cmꢀ1
.
1H NMR (CDCl3): d 2.33 (s, 6H), 7.32 (m, 2H), 7.40 (m, 2H), 7.68
(m, 4H). MS m/z: 41, 65, 75, 89, 91, 105, 119, 128, 238 (M+).
1461, 1438, 1384, 1269, 1092, 753, 700 cmꢀ1 1H NMR (CDCl3): d
.
4.3.3. 1,2-Bis(2-methoxyphenyl)-1,2-ethanedione 1d26
4.45 (br s, 1H), 5.88 (s, 1H), 7.20 (m, 2H), 7.25 (m, 4H), 7.35 (m,
2H), 7.46 (m, 1H), 7.82 (dd, 1H, J1 = 8.7 Hz, J2 = 1.5 Hz).
Mp 118.2–120 °C, 88% yield. IR (neat, cmꢀ1): 3048, 2938, 2838,
1669, 1600, 1492, 1292, 1281, 1187, 1023, 761 cmꢀ1 1H NMR
.
(CDCl3): d 3.49 (s, 6H), 6.86 (m, 2H), 7.02 (m, 2H), 7.45 (m, 2H),
8.02 (d, 2H, J = 7.8 Hz). MS m/z: 44, 51, 64, 77, 92, 105, 120, 135,
207, 270 (M+).
4.4.2. (R)-2-Hydroxy-1,2-bis(2-methylphenyl)ethanone 2b31
Mp 76.4–77.7 °C,
½
a 2D5
ꢁ
¼ ꢀ112 (c 0.08, CH3OH) {lit.31
½
a 2D5
ꢁ
¼ þ47:5 (c 0.5, CH3OH) for 41% ee, (S)-enantiomer},
ee = 98%. HPLC analysis: Chiralcel OD chiral column, mobile phase
iso-PrOH/hexane: 10:90, flow rate: 1.0 mL/min, wavelength:
210 nm; tR (retention time): 11.59 min for (S)-isomer, 13.75 min
for (R)-isomer. IR (neat, cmꢀ1): 3469, 3061, 2961, 1676, 1607,
4.3.4. 1,2-Bis(4-methoxyphenyl)-1,2-ethanedione 1e26
Mp 131.4–132.2 °C, 89% yield. IR (neat, cmꢀ1): 3048, 2923,
2853, 1661, 1600, 1515, 1438, 1269, 1169, 1023, 838 cmꢀ1 1H
.
NMR (CDCl3): d 3.81 (s, 6H), 6.89 (dd, 4H, J1 = 1.9 Hz, J2 = 6.8 Hz),
7.86 (dd, 4H, J1 = 1.9, Hz, J2 = 6.8 Hz). MS m/z: 44, 50, 64, 77, 92,
107, 135, 207, 270 (M+).
1515, 1453, 1392, 1287, 1176, 1084, 738 cmꢀ1 1H NMR (CDCl3):
.
d 1.18 (s, 1H), 2.63 (s, 6H), 5.95 (s, 1H), 7.18–7.22 (m, 4H), 7.40–
7.62 (m, 4H). 13C NMR (CDCl3): d 20.19, 73.88, 124.82, 124.99,
130.48, 130.88, 131.58, 132.03, 132.59, 140.53, 195.89. MS m/z:
41, 51, 65, 77, 89, 91, 119, 128, 152, 165, 178, 206, 224, 238 (M+).
4.3.5. 1-(2-Methylphenyl)-2-phenyl-1,2-ethanedione 1f27
30% Yield (oily liquid). IR (neat, cmꢀ1): 3076, 2976, 2938, 1676,
1600, 1453, 1207, 884, 730 cmꢀ1
.
1H NMR (CDCl3): d 2.60 (s, 3H),
4.4.3. (R)-2-Hydroxy-1,2-bis(3-methylphenyl)ethanone 2c31
7.20 (m, 2H), 7.28 (d, 1H, J = 8.3 Hz), 7.45 (m, 3H), 7.55 (m, 2H),
7.91 (ddd, 1H, J1 = 1.5 Hz, J2 = 1.9 Hz, J3 = 6.8 Hz). MS m/z: 41, 51,
65, 77, 91, 105, 119, 128, 139, 152, 178, 208, 224 (M+).
½
a 2D5
ꢁ
¼ ꢀ51 (c 0.14, CH3OH) {lit.31
½
a 2D5
ꢁ
¼ þ49:4 (c 1, CH3OH) for
36% ee, (S)-enantiomer}, ee = 52%. HPLC analysis: Chiralcel OD chi-
ral column, mobile phase iso-PrOH/hexane: 10:90, flow rate:
1.0 mL/min, wavelength: 210 nm; tR (retention time): 8.20 min
for (S)-isomer, 13.44 min for (R)-isomer. IR (neat, cmꢀ1): 3453,
3023, 2923, 1684, 1607, 1492, 1455, 1392, 1284, 1084, 792,
4.3.6. 1,2-Di-2-furanyl-1,2-ethanedione 1g28
Mp 163–165 °C, 850% yield. IR (neat, cmꢀ1): 3069, 2976, 2938,
1676, 1600, 1453, 1284, 1184, 1038, 869, 769 cmꢀ1
.
1H NMR
707 cmꢀ1 1H NMR (CDCl3): d 2.19 (s, 3H), 2.32 (s, 3H), 4.49 (br s,
.
(CDCl3): d 6.58 (dd, 2H, J1 = 1.4 Hz, J2 = 3.9 Hz), 7.58 (d, 2H,
J = 3.9 Hz), 7.72 (d, 2H, J = 1.4 Hz). MS m/z: 40, 51, 62, 67, 78, 95,
105, 134, 162, 176, 190 (M+).
1H), 5.82 (s, 1H), 6.80–7.20 (m, 6H), 7.65 (m, 2H). 13C NMR (CDCl3):
d 21.54, 21.61, 76.42, 125.20, 126.69, 128.51, 128.73, 129.58,
129.84, 133.80, 134.94, 138.81, 139.11, 139.27, 199.42. MS m/z:
41, 51, 65, 77, 89, 91, 119, 128, 152, 165, 195, 206, 222, 238 (M+).
4.3.7. 1,2-Bis(5-methyl-2-furanyl)-1,2-ethanedione 1h29
Mp 164–167 °C, 90% yield. IR (neat, cmꢀ1): 3069, 2923, 2938,
4.4.4. (R)-2-Hydroxy-1,2-bis(2-methoxyphenyl)ethanone 2d32
1638, 1507, 1453, 1284, 1184, 1038, 815, 769 cmꢀ1
.
1H NMR
Mp 96.6–98.8 °C,
½
a 2D5
ꢁ
¼ ꢀ35:4 (c 0.1, CH3OH) {lit.33
(CDCl3): d 2.40 (s, 2H), 6.18 (dd, 2H, J1 = 0.9 Hz, J2 = 3.4 Hz), 7.45
(d, 2H, J = 2.9 Hz). 13C NMR (CDCl3): d 13.25, 109.13, 125.74,
147.61, 160.24, 175.68. MS m/z: 43, 51, 63, 75, 93, 107, 115, 128,
143, 156, 170, 184, 213, 216 (M+).
½
a 2D5
ꢁ
¼ ꢀ21:5 (c 0.1, CH3OH) for 28% ee, (R)-enantiomer},
ee = 53%. HPLC analysis: Chiralcel OD-H chiral column, mobile
phase iso-PrOH/hexane: 10:90, flow rate: 1.0 mL/min, wavelength:
210 nm; tR (retention time): 21.20 min for (S)-isomer, 30.38 min
for (R)-isomer. IR (neat, cmꢀ1): 3469, 3069, 2938, 2892, 1679,
4.3.8. 1-(5-Methyl-furan2-yl)-2-phenyl-ethane-1,2-dione 1i30
1600, 1492, 1292, 1253, 984, 761 cmꢀ1 1H NMR (CDCl3): d 3.63
.
Mp 61.2–62.4 °C, 65% yield. IR (neat, cmꢀ1): 3082, 2953, 2860,
(s, 3H), 3.65 (s, 3H), 4.38 (br s, 1H), 6.03 (s, 1H), 6.66 (dd, 2H,
J1 = 8.3 Hz, J2 = 10.7 Hz), 6.71 (dd, 1H, J1 = 0.9 Hz, J2 = 8.3 Hz), 6.84
(dd, 1H, J1 = J2 = 7.8 Hz), 7.06–7.14 (m, 2H), 7.28 (ddd, 1H,
J1 = J2 = 14.1 Hz, J3 = 1.9 Hz), 7.62 (dd, 1H, J1 = 1.4 Hz, J2 = 7.3 Hz).
13C NMR (CDCl3): d 55.10, 55.36, 76.12, 111.10, 111.43, 120.72,
120.74, 125.52, 127.78, 129.79, 130.21, 130.87, 134.07, 157.48,
158.37, 201.86. MS m/z: 43, 51, 64, 77, 92, 105, 135, 152, 165,
209, 224, 240, 255, 270 (M+).
1715, 1700, 1607, 1456, 1407, 1302, 1153, 1078, 708, 698 cmꢀ1
.
1H NMR (CDCl3): d 2.17 (s, 3H), 6.19 (d, 1H, J = 3.4 Hz), 7.11 (d,
1H, J = 3.4 Hz), 7.45 (m, 2H), 7.54 (m, 1H), 7.81 (m, 2H). 13C NMR
(CDCl3): d 14.7, 108.4, 108.4, 122.3, 129, 129.7, 134.3, 136.7,
151.4, 157.9, 185, 190.6. MS m/z: 43, 51, 77, 97, 105, 109, 115,
128, 143, 157, 170, 186, 200, 214, 216 (M+).
4.3.9. 1-(4-Methoxyphenyl)-1,2-tetradecanedione 1j25
Mp 35.4–36.7 °C, 20% yield. IR (neat, cmꢀ1): 3038, 2923, 2861,
4.4.5. (R)-2-Hydroxy-1,2-bis(4-methoxyphenyl)ethanone 2e34
1715, 1669, 1615, 1469, 1438, 1323, 1269, 1184, 869, 723 cmꢀ1
.
Mp 103.2–104.4 °C,
½
a 2D5
ꢁ
¼ ꢀ75 (c 0.25, CH3OH) {lit.34
1H NMR (CDCl3): d 0.80 (t, 3H, J = 7.3 Hz), 1.10–1.70 (m, 22H),
2.78 (t, 2H, J = 7.8 Hz), 3.8 (s, 3H), 6.9 (d, 2H, J = 9.2 Hz), 7.9
(d, 2H, J = 9.2 Hz). 13C NMR (CDCl3): d 13.96, 22.44, 24.57, 26.85,
½
a 2D0
ꢁ
¼ þ88:6 (c 1, CH3OH) for 98% ee, (S)-enantiomer}, ee = 84%.
HPLC analysis: Chiralcel OD chiral column, mobile phase iso-
PrOH/hexane: 10:90, flow rate: 1.0 mL/min, wavelength: 210 nm;

346
T. Yıldız et al. / Tetrahedron: Asymmetry 25 (2014) 340–347
tR (retention time): 21.14 min for (S)-isomer, 22.80 min for
(R)-isomer. IR (neat, cmꢀ1): 3446, 3069, 2930, 1676, 1607, 1515,
4.4.10. (R)-1-(4-Methoxyphenyl)-2-hydroxy-1-tetradecaneone 2j
Mp 31.3–32.6 °C, ½a D25
¼ ꢀ28:4 (c 0.12, CHCl3), ee = 50%. HPLC
ꢁ
1461, 1261, 1176, 1038, 838 cmꢀ1
.
1H NMR (CDCl3): d 1.18
analysis: Chiralcel OD-H chiral column, mobile phase iso-PrOH/
hexane: 2:98, flow rate: 1.0 mL/min, wavelength: 275 nm; tR
(retention time): 5.87 min for the major isomer, 6.48 min for the
minor isomer. IR (neat, cmꢀ1): 3440, 3069, 2940, 1675, 1607,
(br s, 1H), 3.68 (s, 3H), 3.75 (s, 3H), 5.77 (s, 1H), 6.78 (dd, 4H,
J1 = 6.8 Hz, J2 = 7.8 Hz), 7.18 (dd, 2H, J1 = 7.8 Hz, J2 = 1.9 Hz), 7.82
(dd, 2H, J1 = 1.9 Hz, J2 = 6.8 Hz). 13C NMR (CDCl3): d 54.20, 54.52,
74.22, 112.90, 113.53, 125.32, 127.94, 130.52, 130.78, 158.59,
162.91, 196.36. MS m/z: 41, 51, 64, 77, 92, 109, 135, 152, 169,
183, 207, 227, 256, 270 (M+).
1515, 1453, 1284, 1176, 1038, 838 cmꢀ1 1H NMR (CDCl3): d 0.81
.
(t, 3H, J = 6.8 Hz), 1.18 (m, 15H), 1.48 (m, 8H), 1.93–2.09 (m, 2H),
3.81 (s, 3H), 5.01 (dd, 1H, J1 = 5.8 Hz, J2 = 8.3 Hz), 6.88 (dd, 2H,
J1 = 2.4 Hz, J2 = 6.8 Hz), 7.91 (dd, 2H, J1 = 2.4 Hz, J2 = 6.8 Hz). 13C
NMR (CDCl3): d 13.10, 21.67, 25.34, 28.13, 28.33, 28.37, 28.49,
28.58, 28.61, 28.62, 30.90, 32.80, 54.53, 56.67, 112.99, 130.28,
162.97, 191.30. MS m/z: 43, 55, 69, 77, 92, 107, 121, 135, 150,
163, 184, 207, 290, 316 (M+ꢀH2O). Anal. Calcd for C21H34O3: C,
75.41; H, 10.25. Found: C, 74.62; H, 11.05.
4.4.6. (R)-2-Hydroxy-1-(2-methylphenyl)-2-phenyl-ethanone 2f35
Mp 64.5–65.8 °C, ½a D25
¼ ꢀ160 (c 0.25, CH3COCH3), ee = 78%.
ꢁ
HPLC analysis: Chiralcel OD-H chiral column, mobile phase iso-
PrOH/hexane: 10:90, flow rate: 1.0 mL/min, wavelength: 210 nm;
tR (retention time): 16.23 min for (S)-isomer, 12.92 min for
(R)-isomer. IR (neat, cmꢀ1): 3446, 3061, 2961, 2938, 1684, 1600,
1453, 1253, 1184, 1076, 976, 761, 700 cmꢀ1
.
1H NMR (CDCl3): d
4.4.11. (R)-1-2-Dihydro-1-hydroxy-2-acenaphthyleneone 2k23
2.48 (s, 3H), 4.40 (br s, 1H), 5.98 (s, 1H), 6.95 (d, 1H, J = 7.8 Hz),
7.02 (m, 2H), 7.10 (m, 2H), 7.32 (m, 2H), 7.41 (m, 1H) 7.75 (dd,
1H, J1 = 0.9 Hz, J2 = 7.3 Hz). 13C NMR (CDCl3): d 19.53, 74.57,
125.69, 126.96, 128.57, 128.70, 128.93, 128.98, 129.01, 129.14,
131.70, 133.90, 134.06, 136.78, 137.64, 200.21. MS m/z: 41, 51,
63, 65, 77, 91, 105, 121, 128, 139, 152, 165, 178, 195, 210, 224 (M+).
Mp 211.6–213 °C,
½
a 2D5
ꢁ
¼ ꢀ73:2 (c 0.41, CHCl3) {lit.36
½
a 2D5
ꢁ
¼ þ60:03 (c 0.5, CHCl3) for 81% ee, (S)-enantiomer},
ee = 100%. HPLC analysis: Chiralpac AD-H chiral column, mobile
phase iso-PrOH/hexane: 10:90, flow rate: 1.0 mL/min, wavelength:
240 nm; tR (retention time): not observed (for racemic 12.55 min)
for (1) enantiomer, 13.75 min for (2) enantiomer. IR (neat, cmꢀ1):
3438, 3038, 1723, 1607, 1430, 1261, 1069, 1015, 815, 776 cmꢀ1
.
4.4.7. (R)-2-Hydroxy-1,2-bis(2-furanyl)-ethanone 2g34
1H NMR (CDCl3): d 3.28 (br s, 1H), 5.31 (s, 1H), 7.58–7.65 (m,
3H), 7.80 (d, 1H, J = 8.9 Hz), 7.86 (d, 1H, J = 6.4 Hz), 8.04 (d, 1H,
J = 8.4 Hz). 13C NMR (CDCl3): d 73.58, 120.50, 121.06, 124.41,
127.27, 127.41, 127.73, 129.68, 129.68, 131.11, 135.23, 140.73,
203.13. MS m/z: 44, 51, 63, 70, 77, 87, 101, 115, 128, 140, 152,
155, 168, 184 (M+).
Mp 133.7–135 °C,
½
a 2D5
ꢁ
¼ ꢀ96:3 (c 0.08, CHCl3) {lit.34
½
a 2D0
ꢁ
¼ þ123 (c 1, CHCl3) for 93% ee, (S)-enantiomer}, ee = 62%.
HPLC analysis: Chiralcel OD-H chiral column, mobile phase iso-
PrOH/hexane: 10:90, flow rate: 1.0 mL/min, wavelength: 210 nm;
tR (retention time): 16.94 min for (S)-isomer, 20.89 min for (R)-iso-
mer. IR (neat, cmꢀ1): 3423, 3030, 2961, 1653, 1515, 1292, 1100,
1030, 800 cmꢀ1
.
1H NMR (CDCl3): d 1.19 (br s, 1H), 5.72 (s, 1H),
4.4.12. (R)-1-Phenyl-3-hydroxy-1-butanone 2n24
6.27 (dd, 1H, J1 = 1.5 Hz, J2 = 2.9 Hz), 6.28 (d, 1H, J = 3.4 Hz), 6.46
(dd, 1H, J1 = 1.4 Hz, J2 = 3.9 Hz), 7.18 (d, 1H, J = 3.9 Hz), 7.31 (d,
1H, J = 0.9 Hz), 7.54 (s, 1H). 13C NMR (CDCl3): d 68.29, 108.12,
109.79, 111.59, 119.10, 142.19, 146.67, 148.68, 150.28, 183.40.
MS m/z: 41, 51, 69, 81, 97, 108, 118, 131, 147, 163, 176, 192 (M+).
½
a 2D5
ꢁ
¼ ꢀ68:1 (c 0.11, CHCl3) {lit.24
½
a 2D5
ꢁ
¼ ꢀ67:5 (c 1.2, CHCl3)
for 99% ee, (R)-enantiomer}, ee = 100%. HPLC analysis: Chiralcel
OD-H chiral column, mobile phase iso-PrOH/hexane: 5:95, flow
rate: 0.8 mL/min, wavelength: 240 nm; tR (retention time):
15.47 min for (R)-isomer, not observed (for racemic 17.69 min)
for (S)-isomer. IR (neat, cmꢀ1): 3415, 3061, 2923, 2853, 1715,
4.4.8. (R)-2-Hydroxy-1,2-bis(5-methyl-2-furanyl)-ethanone 2h13a
1684, 1453, 1376, 1284, 1215, 1069, 703 cmꢀ1 1H NMR (CDCl3):
.
Mp 93–94.2 °C, ½a D25
ꢁ
¼ ꢀ42:4 (c 0.66, CHCl3) {lit.13a
½
a 2D0
ꢁ
¼ ꢀ58
d 1.24 (d, 3H, J = 7.3 Hz), 2.12 (s, 1H), 2.98 (dd, 1H, J1 = 18 Hz,
J2 = 9.2 Hz), 3.09 (dd, 1H, J1 = 17 Hz, J2 = 2.4 Hz), 4.34 (m, 1H),
7.50 (m, 3H), 7.90 (d, 2H, J = 8.3 Hz). 13C NMR (CDCl3): d 22.64,
46.71, 64.26, 128.30, 128.80, 133.80, 136.95, 201.11. MS m/z: 41,
51, 77, 91, 105, 120,140, 164 (M+).
(c 0.1, CHCl3) for 96% ee, (R)-enantiomer}, ee = 72%. HPLC analysis:
Chiralcel OD-H chiral column, mobile phase iso-PrOH/hexane:
10:90, flow rate: 1.0 mL/min, wavelength: 220 nm; tR (retention
time): 10.73 min for (S)-isomer, 13.03 min for (R)-isomer. IR (neat,
cmꢀ1): 3476, 3123, 2923, 2861, 1676, 1515, 1369, 1215, 1030, 800,
723 cmꢀ1
.
1H NMR (CDCl3): d 2.17 (s, 3H), 2.31 (s, 3H), 4.13 (br s,
4.4.13. (1S,2R)-2-Hydroxycyclohexyl-phenylmethanone 2p37
1H), 5.58 (s, 1H), 5.84 (d, 1H, J = 3.4 Hz), 6.07 (d, 1H, J = 3.4 Hz),
6.17 (d, 1H, J = 2.9 Hz), 7.06 (d, 1H, J = 3.4 Hz). 13C NMR (CDCl3):
d 13.76, 14.30, 69.23, 106.96, 109.66, 110.18, 122.41, 148.56,
150.10, 153.28, 159.52, 183.87. MS m/z: 43, 53, 67, 83, 95, 111,
121, 145, 161, 175, 204, 205, 220 (M+).
Mp 74.2–75.5 °C, ½a D25
¼ þ40 (c 0.1, CHCl3), 100% ee for syn and
ꢁ
dr = 100:0, HPLC analysis: Chiralcel OD chiral column, mobile
phase iso-PrOH/hexane: 10:90, flow rate: 0.5 ml/min, wavelength:
240 nm; tR (retention time): tsyn(major) = 14.37 min, other isomers
not observed. IR (neat, cmꢀ1): 3476, 2930, 2853, 1669, 1453, 1353,
1215, 976, 707 cmꢀ1 1H NMR (CDCl3): d 1.18–1.43 (m, 5H), 1.73–
.
4.4.9. (R)-2-Hydroxy-1-(5-methyl-2-furanyl)-2-phenyl-ethanone
1.90 (m, 4H), 3.36 (m, 1H), 4.40 (m, 1H), 7.40 (m, 2H), 7.56 (m,
1H), 7.85 (m, 2H). 13C NMR (CDCl3): d 18.62, 23.65, 24.62, 30.95,
47.17, 65.41, 127.39, 132.46, 134.77, 204.99. MS m/z: 41, 51, 55,
67, 77, 82, 105, 115, 123, 133, 145, 157, 167, 176, 186, 204 (M+).
2i
Mp 125.2–126.5 °C, ½a D25
¼ ꢀ66:6 (c 0.15, CHCl3), ee = 64%. HPLC
ꢁ
analysis: Chiralcel OD-H chiral column, mobile phase iso-PrOH/
hexane: 10:90, flow rate: 1 mL/min, wavelength: 210 nm; t1
(retention time): 12.18 min for major isomer, 16.13 min for minor
isomer. IR (neat, cmꢀ1): 3446, 3038, 2923, 1769, 1661, 1515, 1453,
4.4.14. (1S,2R)-(2-(1-Hydroxyethyl)-1,2,3,4-tetrahydro-1-oxo-
naphthalene 2r
1323, 1289, 1038, 815, 700 cmꢀ1
.
1H NMR (CDCl3): d 2.30 (s, 3H),
100% ee for syn, 4% ee for anti, and syn/anti (dr) = 3:1, HPLC anal-
ysis: Chiralcel OD-H chiral column, mobile phase iso-PrOH/hexane:
10:90, flow rate: 0.5 ml/min, wavelength: 210 nm; tR (retention
time): tsyn(minor) = not observed (for racemic 13.647 min),
tsyn(major) = 14.53 min, tanti(minor) = 16.13 min, tanti(major) =
16.34 min. IR (neat, cmꢀ1): 3430, 3038, 2969, 2930, 1676, 1600,
4.45 (br s, 1H), 5.65 (s, 1H), 6.02 (dd, 1H, J1 = 10.9 Hz, J2 = 3.4 Hz),
7.02 (d, 1H, J = 3.4 Hz), 7.22 (m, 1H), 7.35 (m, 2H), 7.38 (m, 2H).
13C NMR (CDCl3): d 14.31, 75.99, 109.72, 122.32, 127.87, 128.75,
129.06, 139.52, 148.77, 159.28, 186.63. MS m/z: 43, 53, 65, 79,
91, 105, 109, 111, 128, 141, 157, 170, 186, 200, 214, 253 (M+). Anal.
Calcd for C13H12O3: C, 72.21; H, 5.59. Found: C, 72.53; H, 5.40.
1461, 1307, 1230, 1115, 869, 753 cmꢀ1 1H NMR (CDCl3):38 major:
.

T. Yıldız et al. / Tetrahedron: Asymmetry 25 (2014) 340–347
347
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; ; Springer: Berlin, 1999; Vol. 2, p 1093.
d 1.21 (d, 3H, J = 6.8 Hz), 1.75 (m, 2H), 2.20 (m, 1H), 2.40–2.52
(m, 2H), 2.95 (m, 1H), 4.40 (m, 1H), 7.18–7.40 (m, 3H), 7.95 (m,
1H). 1H NMR (CDCl3): minor: d 1.21 (d, 3H, J = 6.8 Hz), 1.75–1.90
(m, 2H), 2.20 (m, 1H), 2.40–2.52 (m, 2H), 2.95 (m, 1H), 4.15 (m,
1H), 7.18–7.40 (m, 3H), 7.95 (m, 1H). 13C NMR (CDCl3): d 19.45,
25.95, 29.32, 54.42, 67.31, 126.91, 127.65, 128.91, 129.02, 133.09,
134.10, 201.13. MS m/z: 43, 44, 63, 77, 89, 90, 103, 115, 118, 131,
146, 157, 172, 188, 190 (M+). Anal. Calcd for C12H14O2: C, 75.76;
H, 7.42. Found: C, 75.85; H, 7.25.
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Bioorg. Med. Chem. Lett. 2003, 13, 1203–1206; (c) Fang, Q. K.; Han, Z.; Grover, P.;
Kessler, D.; Senanayake, C. H.; Wald, S. A. Tetrahedron: Asymmetry 2000, 11,
3659–3663.
10. (a) Adam, W.; Lazarus, M.; Saha-Möller, C. R.; Schreier, P. Acc. Chem. Res. 1999,
32, 837–845; (b) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919–934.
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919–922.
12. Chakraborty, T. K.; Das, S. Chem. Lett. 2000, 80–81.
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Acknowledgment
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This study was supported by The Istanbul University Depart-
ment of Scientific Research Project with Project number 22741.
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