Asymmetric synthesis of long chain β-hydroxy fatty acid methyl esters as new elastase inhibitors

Article abstract of DOI:10.1016/j.tetasy.2012.07.004

Herein, β-hydroxy methyl esters with an even carbon chain length of 12-20 1b-5b were synthesized by three different asymmetric reduction methods I, II III from their corresponding β-keto methyl esters 1a-5a with the aim of determining their elastase activities. In method I, chiral catalyst A was prepared from chiral ligand (R)-binaphthol 1, while in method II, chiral catalyst B was synthesized from (2R,3R)-diisopropyl tartrate 2. Chiral catalyst B has not previously been used in asymmetric borane reductions or in the asymmetric synthesis of chiral β-hydroxy methyl esters. In method III, an asymmetric reduction was catalysed by (R)-Me-CBS oxazaborolidine 3. Hydride transfer was carried out in all of these methods by BH₃· SMe₂. Chiral hydroxy methyl esters with an (S)-configuration were synthesized by method I and with an (R)-configuration via methods II and III. The chiral hydroxy methyl esters obtained were analysed by chiral HPLC for their ee % values. Methods I, II and III were applied to long chain β-keto methyl esters for the first time. The reduction methods I, II and III were examined in terms of reaction yield and enantiomeric excess according to carbon chain length and the variable ratio of chiral catalysts to β-keto methyl ester. The highest enantiomeric excess of 90% ee was found in method III for 12 and 14 carbon numbers.

Full text of DOI:10.1016/j.tetasy.2012.07.004

Tetrahedron: Asymmetry 23 (2012) 1100–1105
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of long chain b-hydroxy fatty acid methyl esters as
new elastase inhibitors
⇑
Belma Hasdemir , Hülya Çelik Onar, Aysße Yusufog˘lu
Department of Chemistry, Faculty of Engineering, Istanbul University, 34320 Avcılar, Istanbul, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2012
Accepted 12 July 2012
Herein, b-hydroxy methyl esters with an even carbon chain length of 12–20 1b–5b were synthesized by
three different asymmetric reduction methods I, II III from their corresponding b-keto methyl esters 1a–
5a with the aim of determining their elastase activities. In method I, chiral catalyst A was prepared from
chiral ligand (R)-binaphthol 1, while in method II, chiral catalyst B was synthesized from (2R,3R)-diiso-
propyl tartrate 2. Chiral catalyst B has not previously been used in asymmetric borane reductions or in
the asymmetric synthesis of chiral b-hydroxy methyl esters. In method III, an asymmetric reduction
was catalysed by (R)-Me-CBS oxazaborolidine 3. Hydride transfer was carried out in all of these methods
by BH3ꢀSMe2. Chiral hydroxy methyl esters with an (S)-configuration were synthesized by method I and
with an (R)-configuration via methods II and III. The chiral hydroxy methyl esters obtained were analysed
by chiral HPLC for their ee % values. Methods I, II and III were applied to long chain b-keto methyl esters
for the first time. The reduction methods I, II and III were examined in terms of reaction yield and enan-
tiomeric excess according to carbon chain length and the variable ratio of chiral catalysts to b-keto
methyl ester. The highest enantiomeric excess of 90% ee was found in method III for 12 and 14 carbon
numbers.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
b-Hydroxy fatty acids are formed during mitochondrial b-oxida-
tion of fatty acids and are related to disorders in fatty acid
The asymmetric synthesis of enantiomerically enriched long
chain b-hydroxy fatty acids has gained great importance since
these compounds can be useful synthons for synthesis of pharma-
ceuticals, vitamins, flavours, antibiotics and pheromones.1 (R)-b-
Hydroxyalkanoic acids represent an important class of biologically
active compounds often found in lipopeptides exhibiting antimi-
crobial, insecticidal and antiviral activities.2,3 It is well known that
(R)-b-hydroxyalkanoic acid exists in the pathway of fatty acid syn-
thesis as an adduct of ACP and (S)-b-hydroxyalkanoic acid as an es-
ter of CoA. (R)-(ꢁ)-b-Hydroxytetradecanoic acid is the major fatty
acid component of lipid A in endotoxin.4 The choline ester of (S)-
b-acetoxyhexadecanoic acid is a fish toxin5 while b-hydroxyeicosa-
noic acid is found in a different microorganism.6
oxidation.
According to the literature, no b-hydroxy fatty acid isomers
have been examined for their elastase activity except for our pub-
lished study7 which reports the excellent elastase inhibition of
racemic 3–13 monohydroxy eicosanoic acid isomers. Until now,
there has been no report on the elastase activity of chiral b-hydro-
xy acid methyl ester isomers.
Herein our aim was to synthesize chiral b-hydroxy methyl es-
ters with a 12–20 carbon chain length 1b–5b in order to analyse
them for their elastase activity in relation to the enantiomeric pur-
ity of their (R)- and (S)-enantiomers.
Enantiomerically pure b-hydroxy esters can be obtained from
the corresponding prochiral b-keto esters by asymmetric reduc-
tion. Previously, the asymmetric reduction of b-keto esters was
carried out by using modified Raney-Nickel,8,9 chiral ruthenium
(II) complexes10 at higher hydrogen pressures and chiral modi-
fied NaBH4 at atmospheric pressure.11 In these studies, (S)-b-hy-
droxy tetradecanoic acid methyl ester was obtained with 85% ee
by using a modified Raney-Nickel catalyst and with 98.7% ee
using a chiral ruthenium catalyst. We have also studied the
asymmetric reduction of methyl b-keto tetradecanoate with
modified NaBH4 at atmospheric pressure and synthesized the
(S)-enantiomer of methyl b-hydroxy tetradecanoate with 57%
ee.11
Hydroxy fatty acid isomers play an important role in cancer
chemotherapy, but in the literature there is no data on their anti-
elastase activity. Elastase activity has gained increasing interest
in recent years due to its important role in diseases of the lung,
arteries, skin and ligaments. Elastase inhibition activity is a useful
and protective tool against these diseases. a-Hydroxy acids (AHAs)
have become increasingly popular as skin rejuvenating agents.
⇑
Corresponding author. Tel.: +90 2124737070; fax: +90 2124737180.
E-mail address: karaefe@istanbul.edu.tr (B. Hasdemir).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.07.004

B. Hasdemir et al. / Tetrahedron: Asymmetry 23 (2012) 1100–1105
1101
In the recent years, chiral oxazaborolidines and chiral organo
aluminium compounds have been used as chiral catalysts in the
asymmetric borane reduction of prochiral ketones. Organo-alu-
minium compounds, which are easily available and inexpensive,
have been reported to accelerate the catalytic asymmetric borane
reduction of ketones.12,13 Uang et al. have employed chiral BINOL
derivatives in the asymmetric reduction of aromatic prochiral ke-
tones.14,15 In our previous work, we have also used BINOL induced
asymmetric Meerwein–Ponndorf–Verley reductions for the mono
methyl 3-, 7- and 13-oxo tetradecanoates.16 Asymmetric borane
reduction with CBS is one of the most useful methods for the syn-
thesis of chiral alcohols.17
(Scheme 2). It should be noted that chiral ligand 2 has not been used
before as a ligand in an asymmetric borane reduction.
CH2Cl2
25°C
OH
OH
Al(OiPr)3
Chiral catalyst A
Herein the (R)- and (S)-enantiomers of methyl b-hydroxyalk-
anoates 1b–5b were synthesized with high enantiomeric excess
by three different asymmetric reduction methods (I, II and III)
which were also compared with each other in this work (Scheme 1).
To the best of our knowledge, there has been no study on the syn-
thesis of chiral b-hydroxy esters with 12, 14, 16, 18 and 20 carbon
chain lengths using the methods applied herein and their elastase
activities.
COOCH(CH3)2
COOCH(CH3)2
HO
HO
CH2Cl2
25°C
Al(OiPr)3
Chiral catalyst B
Scheme 2. Synthesis of chiral catalysts A and B.
In methods I, II and III, BH3ꢀSMe2 was used as a hydride transfer
agent in the presence of the chiral catalysts. The mechanism in
Scheme 3 was based on Uang et al. postulated working model.14,15
Chiral b-hydroxy methyl esters with an (S)-configuration were ob-
tained via chiral catalyst A and with an (R)-configuration with chi-
ral catalyst B. Chiral catalyst A is more sterically hindered than
chiral catalyst B; therefore the enantiomeric excesses of method I
were higher than method II (Table 1). Due to the steric hinderance
of the long chain methylene groups and naphthyl group, the hypo-
thetical transition structure III would be more favourable than II
for method I, which gave hydroxy esters with an (S)-configuration.
The postulated model II was preferred in method II because of the
less sterically hindered structure of (2R,3R)-diisopropyl tartrate.
Therefore, the hypothetical transition structure II could explain
why the products had an (R)-configuration in method II (See Figs. 1
and 2).
The ratio of catalyst A (or B) to b-keto ester as (0.1:1; 0.5:1 and
1:1) was examined and the results are shown in Table 1. Different
ratios of chiral catalysts A and B changed the enantiomeric excess
and yield of the asymmetric reduction of the b-keto esters. The
highest enantiomeric excess was observed for the ratio: chiral cat-
alyst A (or B): b-keto ester = 1:1 (Table 1). The enantiomeric excess
increased but the reduction yield decreased when increasing the
amount of chiral catalyst A (or B). However, the carbon chain
length did not have a significant effect on the reduction yields or
ee values.
2. Results and discussion
Long chain chiral b-hydroxy acids and their methyl esters are
important components of biological molecules. For their asymmet-
ric synthesis their corresponding b-keto acid methyl esters 1a–5a
with 12, 14, 16, 18 and 20 carbon chain lengths were chosen as
prochiral compounds.
Herein we had two aims; the first was to synthesize chiral b-hy-
droxy methyl esters 1b–5b with high enantiomeric excess and to
examine the influence of the carbon length on the asymmetric
reduction. The second aim was to study the elastase activity of
these isomers 1b–5b and analyse the effect of (R)- and (S)-enanti-
omers with different enantiomeric purities on elastase inhibition,
outlined in our previous publication.7 Three methods I, II and III
were chosen for the asymmetric reduction reaction (Scheme 1).
OH
Method I
H3COOC
Chiral catalyst A
n
(S)-1b-5b
O
The ratio of catalyst A: b-keto ester = 1:1 gave the highest enan-
tiomeric excess of 81% ee for (S)-1b and the lowest of 65% ee for
(S)-4b and (S)-5b (Table 1, entries 1, 4 and 5). The same molar ratio
of chiral catalyst B: b-keto ester = 1:1 was used for the asymmetric
reduction of 1a and gave an enantiomeric excess of 67% ee (Table 1,
entry 1).
H3COOC
1a-5a
OH
n
Method II
H3COOC
Chiral catalyst B
n
1a (n=8); 2a (n=10);
3a (n=12); 4a (n=14);
5a (n=16)
(R)-1b-5b
The CBS-oxazaborolidine catalyst obtained from (S)-(diph-
enylhydroxymethyl)pyrrolidine with BH3 is an effective catalyst
for the asymmetric borane reduction of ketones.17,18 However, this
catalyst is air and moisture sensitive.19 Therefore, modified cata-
lysts have been developed and successfully applied to enantiose-
lective reductions.20
OH
Method III
H3COOC
(R)-Me-CBS
n
In method III, (R)-Me-CBS 3 was preferred for the asymmetric
reduction of b-keto esters and b-hydroxy esters with high ee values
being obtained. The results are summarized in Table 1. The general
mechanistic model of Corey helps to explain the selectivity ob-
tained in the catalytic reduction (Scheme 4). The first step of the
reaction involves the coordination of BH3 to the nitrogen atom of
the oxazaborolidine CBS. This coordination serves to activate BH3
as a hydride donor and to enhance the Lewis acidity of the cata-
lyst’s endocyclic boron. The strongly Lewis acidic complex readily
(R)-1b-5b
Scheme 1. The three asymmetric reduction methods I, II and III.
In method I, chiral (R)-BINOL 1 and in method II, (2R,3R)-diiso-
propyl tartrate 2 were chosen as chiral ligands for the preparation
of chiral catalysts A and B. The chiral catalysts A and B were prepared
from 21 mol % of 1 or 2 and 10 mol % of aluminium tri-isopropoxide

1102
B. Hasdemir et al. / Tetrahedron: Asymmetry 23 (2012) 1100–1105
H2B
H
H2
BH3
O
O
O
O
O
O
O
Al
Al
O
I
chiral catalyst A
O
BH2
O
CH2COOCH3
H3C(CH2)n
CH2COOCH3
H C(CH )
3
2 n
BH3
(CH2)nCH3
H
(CH2)nCH3
H
H3COOCCH2
H3COOCCH2
O
BH
O
O
BH
O
O
O
O
O
Al
Al
O
O
IV
III
CH2COOCH3
H
CH3(CH2)n
O
BH
O
O
O
Al
O
II
Scheme 3. Postulated working model for method I.
binds to the b-keto ester at the sterically more accessible electron
lone pair. As a result, the stable six-membered transition state
obtained leads to high ee values. In method I, a six-membered
coordination state was also formed (Scheme 4), although the met-
als in the cyclic transition state are not the same in methods I, II
and III. This may influence the balance and stability of the ring sys-
tem, in a negative fashion. Furthermore, the Lewis acid ability of
the aluminium as in methods I and II is weaker than the boron in
method III; this coordination state may be formed with more diffi-
culty than in method III because of the steric hindrance of the chi-
ral aluminium catalyst. Therefore the ee values of method I and II
were lower than those of III.
methods marked as I, II and III were used. In method I, chiral cat-
alyst A from Al(OiPr)3-1 and in method II, chiral catalyst B from
Al(OiPr)3-2 were prepared (Scheme 2). Chiral catalyst B was used
for the first time in such reductions. Method III was achieved by
using the known (R)-Me-CBS 3.
The configuration of the mentioned chiral b-hydroxy esters was
assigned as (S) in the presence of chiral catalyst A, as (R) with chiral
catalyst B and as (R) with (R)-Me-CBS. The absolute configuration
of the chiral b-hydroxy methyl esters 1b–5b was determined by
comparing the sign of their specific rotation with the literature val-
ues.11,21,22 The starting b-keto methyl esters herein were synthe-
sized by using acetoacetate chemistry.
The highest enantiomeric excess of 90% ee was found for (R)-1b
and (R)-2b in method III (Table 1, entries 1 and 2) and the lowest
enantiomeric excess of 49% ee for (R)-4b and (R)-5b in method I
(Table 1, entries 4 and 5).
The different ratios of catalyst A (or B):b-keto ester (0.1:1;
0.5:1; 1:1) were studied in methods I and II as seen in Table 1.
The highest enantiomeric excesses were observed from the ratio
of the catalyst to b-keto ester = 1:1 (Table 1). The results showed
that the enantiomeric excess increased while the reduction yield
decreased when increasing the amounts of the chiral catalyst.
The reduction yields and the enantiomeric excesses of method III
were better than those obtained with methods I and II. This could
be explained by the fact that the Lewis acid ability of the boron in
3. Conclusion
In the asymmetric reduction of b-keto methyl esters with the
chain length of 12, 14, 16, 18 and 20 carbon atoms, their different

B. Hasdemir et al. / Tetrahedron: Asymmetry 23 (2012) 1100–1105
1103
Table 1
Asymmetric reduction of prochiral b-keto ester isomers with methods I, II and III
OH
H3COOC
n
(S)-1b-5b
OH
O
H3COOC
n
H3COOC
1a-5a
chiral catalyst B, BH3SMe2
method II
n
(R)-1b-5b
OH
H3COOC
n
(R)-1b-5b
Entry
b-Hydroxy ester
Yielda (%)
Method II
% eegh (config.)
Method II
Method I
Method III
Method I
Method III
1
2
3
4
5
1b
2b
3b
4b
5b
65b
60b
50b
50b
50b
55c
50c
40c
40c
40c
40d
40d
30d
30d
30d
40e
40e
30e
30e
30e
80f
80f
70f
70f
70f
53(S)b
53(S)b
51(S)b
49(S)b
49(S)b
69(S)c
65(S)c
65(S)c
58(S)c
58(S)c
81(S)d
67(S)d
67(S)d
65(S)d
65(S)d
67(R)e
63(R)e
63(R)e
63(R)e
63(R)e
90(R)f
90(R)f
85(R)f
75(R)f
75(R)f
a
b
c
Isolated yield of products.
Molar ratio of chiral catalyst A: b-keto ester = 0.1:1 (method I).
Molar ratio of chiral catalyst A: b-keto ester = 0.5:1 (method I).
Molar ratio of chiral catalyst A: b-keto ester = 1:1 (method I).
Molar ratio of chiral catalyst B: b-keto ester = 1:1 (method II).
Molar ratio of (R)-Me-CBS: b-keto ester = 0.1:1 (method III).
d
e
f
g
h
The ee values were determined by HPLC analysis using Chiralcel OD column.
Absolute configuration of the products was determined by comparing the sign of their specific rotation with the literature value.11,21,22,24–26.
The methods used herein were carried out at atmospheric pres-
sure. Method I and II were accomplished by inexpensive materials,
but the ee values were not better than those in method III. (R)-Me-
CBS is more expensive than Al(OiPr)3 but method III might be the
preferred option in order to achieve high ee values (Table 1).
The enantiomeric purity of chiral b-hydroxy methyl ester iso-
mers were checked by chiral HPLC with Chiralcel OD column (Ta-
ble 1). The chiral hydroxy esters 1b–5b synthesized with (R)- and
(S)-configuration were characterized by IR, 1H NMR and their mea-
sured specific rotations. Chiral hydroxy esters 1b–5b with (R)- and
(S)-configurations will be analysed for their elastase activity.
OH
OH
COOCH(CH3)2
COOCH(CH3)2
HO
HO
(R)-(+)-1,1'-Binaphthyl-2,2'-diol 1
(2R,3R)-Diisopropyl tartrate 2
Figure 1. Chiral ligands used in method I and II.
4. Experimental
4.1. General
Ph
Ph
O
N
B
The chemicals used herein were commercially available from
Merck and Fluka. The b-keto methyl ester isomers used as starting
materials were synthesized by acetoacetate chemistry.23 The reac-
tions were purified by flash column chromatography on silica gel
(Merck; 230–400 mesh) with hexane-acetone and hexane-ethyl-
acetate. 1H NMR spectra were recorded at 400 MHz using TMS as
the internal standard in CDCl3. IR were run on a Mattson 1000 ser-
ies FTIR (as 1% KBr tablets). Melting points were determined with
Büchi Melting Point B-540. The specific rotations were measured
with an optical activity AA-55 digital polarimeter at room temper-
ature. The enantiomeric excesses (ee) of the chiral b-hydroxy es-
CH3
3
Figure 2. Chiral catalysts used in method III.
the oxazaborolidine catalyst is stronger than the aluminium of the
chiral catalysts A or B. In all three methods, the size of the carbon
chain lengths had no significant effect on the reduction yields or
enantiomeric excesses.

1104
B. Hasdemir et al. / Tetrahedron: Asymmetry 23 (2012) 1100–1105
O
Ph
Ph
Ph
Ph
O
Ph
O
H3COOC
BH3
n
O
B
CH3
N
N
N
B
B
Ph
CH3
CH3
O
BH3
H2B
COOCH3
H
(R)-Me-CBS
Scheme 4. Postulated working model for method III.
ters were determined with a Shimadzu/DGU-20A5 HPLC apparatus
fitted with a Chiralcel OD (0.46 ꢂ 25 cm) chiral column. Hexane
and isopropanol (98/2, v/v) were used as the mobile phase, flow
rate: 1.0 ml/min, wavelength: 210 nm. All reactions were per-
formed under an inert atmosphere (nitrogen).
1743, 1186 cmꢁ1 1H NMR (400 MHz, CDCl3): d (ppm): 0.88 (t,
.
3H, J = 7.1, –CH3), 1.26–1.58 (m, 20H, (–CH2)10), 2.44 (dd, 1H,
J = 16.3, J = 8.9), 2.55 (dd, 1H, J = 16.3, J = 3.3), 2.94(s, 1H, –OH),
3.71 (s, 3H, –OCH3), 4.0 (m, 1H, –CH(OH)). HPLC analysis: Chiralcel
OD chiral column, mobile phase iso-PrOH/hexane: 2:98, flow rate:
1.0 ml/min, wavelength: 210 nm; Rt (retention time): 8.063 min
for (R)-isomer, 10.522 min for (S)-isomer; purity: 94.3% for (R),
4.3% for (S).
4.2. General procedure for the asymmetric reduction of
prochiral b-keto esters using methods I and II
To
a 1
mixture of Al(OiPr)3 (1.95 mmol) and (R)-BINOL
4.4.3. b-Hydroxyhexadecanoic acid methyl ester 3b
21Mp 49–50 °C, (lit.21 mp 49–50 °C). ½a 2D5
ꢃ
¼ ꢁ15:2 (c 1, CHCl3),
(3.9 mmol) in 5 ml dichloromethane stirred for 1 h, b-keto ester
1a–5a (1.95 mmol) was added under N2 at room temperature.
After stirring for 0.5 h, the reaction mixture was heated to 40 °C
and a borane dimethylsulfide complex (2.3 ml, 1 M in CH2Cl2)
was added. After stirring for 1 h, the reaction mixture was treated
with 1 M HCl and extracted with CH2Cl2. The combined organic ex-
tracts were washed with brine, dried over Na2SO4 and concen-
trated. The crude product containing the hydroxy ester was
purified by flash column chromatography (hexane/acetone 9:1, v/
v).
IR (KBr, cmꢁ1): 3407, 2946, 2865, 1754, 1186 cmꢁ1
.
1H NMR
(CDCl3): d (ppm): 0.88 (t, 3H, J = 6.9, –CH3), 1.26–1.60 (m, 24H, (–
CH2)12), 2.36 (dd, 1H, J = 16.3, J = 8.9), 2.56 (dd, 1H, J = 16.3,
J = 3.3), 2.94 (s, 1H, –OH), 3.71 (s, 3H, –OCH3), 4.0 (m, 1H, –CH(OH).
HPLC analysis: Chiralcel OD chiral column, mobile phase iso-PrOH/
hexane: 2:98, flow rate: 1.0 ml/min, wavelength: 210 nm; Rt
(retention time): 7.736 min for the (R)-isomer, 10.080 min for the
(S)-isomer; purity: 92.1% for (R), 6.7% for (S).
4.4.4. b-Hydroxyoctadecanoic acid methyl ester 4b
4.3. General procedure for the asymmetric reduction of
prochiral b-keto esters using method III
26Mp 51–52 °C, (lit.26 mp 51.1–51.4 °C). ½a 2D5
ꢃ
¼ ꢁ12:3 (c 1,
CHCl3), IR (KBr, cmꢁ1): 3407, 2930, 2863, 1754, 1186 cmꢁ1
.
1H
NMR (CDCl3): d (ppm): 0.88 (t, 3H, J = 6.9, –CH3), 1.26–1.60 (m,
28H, (–CH2)14), 2.41 (dd, 1H, J = 16.4, J = 8.9), 2.56 (dd, 1H,
J = 16.4, J = 3.3), 2.92 (s, 1H, –OH), 3.72 (s, 3H, –OCH3), 4.0 (m,
1H, –CH(OH). HPLC analysis: Chiralcel OD chiral column, mobile
phase iso-PrOH/hexane: 2:98, flow rate: 1.0 ml/min, wavelength:
210 nm; Rt (retention time): 7.442 min for the (R)-isomer,
9.761 min for the (S)-isomer; purity: 87.4% for (R), 12.6% for (S).
To a solution of (R)-Me-CBS 3 (0.195 mmol, 0.2 ml of 1 M solu-
tion in toluene) was added BH3ꢀSMe2 (2 M in THF, 2.93 mmol,
1.5 ml) and the mixture was stirred under a nitrogen atmosphere
at room temperature, then cooled to 0 °C. After 10 min stirring,
the solution of b-keto methyl ester 1a–5a (1.95 mmol) in 5 ml of
THF was added dropwise within 45 min at 0 °C. The reaction mix-
ture was stirred for 1 h and then quenched with 2 M HCl. The solu-
tion was extracted with ether (3 ꢂ 20 ml). The organic layers were
washed with water and dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was purified by flash
column chromatography (hexane/ethylacetate 7:3,v/v).
4.4.5. b-Hydroxyeicosanoic acid methyl ester 5b
22Mp 56–57 °C, (lit.22 mp 56.5–57.5 °C). ½a 2D5
ꢃ
¼ ꢁ12:2 (c 1,
1H
CHCl3), IR (KBr, cmꢁ1): 3407, 2930, 2863, 1754, 1186 cmꢁ1
.
NMR (CDCl3): d (ppm): 0.88 (t, 3H, J = 6.9, –CH3), 1.26–1.58 (m,
32H, (–CH2)16), 2.44(dd, 1H, J = 16.4, J = 8.9), 2.60 (dd, 1H, J = 16.3,
J = 3.3), 2.94 (s, 1H, –OH), 3.72 (s, 3H, –OCH3), 4.1 (m, 1H, –CH(OH).
HPLC analysis: Chiralcel OD chiral column, mobile phase iso-PrOH/
hexane: 2:98, flow rate: 1.0 ml/min, wavelength: 210 nm; Rt
(retention time): 7.086 min for the (R)-isomer, 9.213 min for the
(S)-isomer; purity: 87.4% for (R), 12.6% for (S).
4.4. Spectroscopic data of chiral b-hydroxy methyl ester isomers
synthesized
4.4.1. b-Hydroxydodecanoic acid methyl ester 1b
24Mp 28–29 °C, ½a 2D5
ꢃ
¼ ꢁ15:7 (c 1, CHCl3); lit24
½
a 3D0
ꢃ
¼ ꢁ15:5 (c
1.17, CHCl3), IR (KBr, cmꢁ1): 3407, 2858, 2925, 1739, 1152 cmꢁ1
.
1H NMR (CDCl3): d (ppm): 0.88 (t, 3H, J = 6.8, –CH3), 1.26–1.59
(m, 16H, (–CH2)8), 2.40 (dd, 1H, J = 16.4, J = 8.9), 2.51(dd, 1H,
J = 16.4, J = 3.2), 2.75 (s, 1H, –OH), 3.71 (s, 3H, –OCH3), 3.96–4.03
(m, 1H, –CH(OH). HPLC analysis: Chiralcel OD chiral column, mo-
bile phase iso-PrOH/hexane: 2:98, flow rate: 1.0 ml/min, wave-
length: 210 nm; Rt (retention time): 8.024 min for the (R)-isomer,
10.234 min for the (S)-isomer; purity: 94.3% for (R), 4.3% for (S).
Acknowledgments
This work was supported by the Scientific Research Projects
Coordination Unit of Istanbul University. Project number 325/
03062005.
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