Enzymatic resolution of chroman-4-ol and its core analogues with Burkholderia cepacia lipase

Article abstract of DOI:10.1016/j.tetasy.2014.02.010

A convenient protocol for lipase resolution of chroman-4-ol and its analogues (six- and seven-membered rings with O, S, SO₂) has been elaborated. The structure of substrates has minor influence on the efficiency of resolution.

Full text of DOI:10.1016/j.tetasy.2014.02.010

Tetrahedron: Asymmetry 25 (2014) 563–567
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enzymatic resolution of chroman-4-ol and its core analogues with
Burkholderia cepacia lipase
Olexandr V. Kucher a,b, , Anastasiya O. Kolodyazhnaya a,b, Oleg B. Smolii b, Alexandr I. Boiko a,c
,
⇑
Vladimir S. Kubyshkin a, Pavel K. Mykhailiuk a,d, Andrey A. Tolmachev a,d
a Enamine Ltd, Matrosova Str., 23, Kyiv 01103, Ukraine
b Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Murmanska Str., 1, Kyiv 02094, Ukraine
c National Technical University of Ukraine ‘Kyiv Politechnic Institute’, Peremohy prosp., 37, Kyiv 03056, Ukraine
d Taras Shevchenko National University of Kyiv, Chemistry Department, Volodymyrska Str., 64, Kyiv 01601, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient protocol for lipase resolution of chroman-4-ol and its analogues (six- and seven-membered
rings with O, S, SO2) has been elaborated. The structure of substrates has minor influence on the efficiency
of resolution.
Received 4 February 2014
Accepted 6 February 2014
Available online 27 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
redox processes in M. isabellina and Helminthosporium fungus.9
The resolution of racemic chroman-4-ol and its substituted ana-
Enzymes and cells in modern organic chemistry have been uti-
lized in many popular synthetic strategies. Different substances are
required in enantiomerically pure form for both scientific and
industrial needs. Enzymatic resolution offers a simple fruitful path
toward enantiomerically pure species.1
logues by lipase-catalyzed cross-acylation with vinylacetate was
reported in the 1990s.10,11 In the paper of Ramadas and Krupada-
nam,11 the resolution was carried out with Burkholderia cepacia
lipase (BCL) giving moderate to good ee values. In particular, the
unsubstituted chroman-4-ol 1a was obtained with 50% and 70%
ee for acetylated (R)-(+)-2a and intact (S)-(ꢀ)-1a enantiomers,
respectively, (Scheme 1B).
Herein we report a protocol which enables a better performance
with ee P94%. The key changes to the reported conditions were
the use of tert-butylmethylether (TBME) as the solvent and carry-
ing out the reaction at room temperature (23 °C). Furthermore,
we used our optimized protocol for the kinetic resolution of the
chroman-4-ol core 1 modifications. The steric properties were also
varied. The difference in the electronic properties of sulfur and
oxygen12 could lead to a dramatic change in the substance reactiv-
ity. A general protocol for the lipase resolution of 1 to enantiome-
rically pure forms was also attempted.
The enantiomerically enriched substances obtained represent
variations of the chroman-4-ol fragment. Chroman is the struc-
tural core of many natural products, such as the tocopherols,
flavonoids, iso- and neoflavanoids. A major function of the latter
compounds is their anti-oxidative activity,13 which is important
for the prevention of cancer14 as well as aging in general. The
4-hydroxylated chroman was found in a number of natural
products,15 such as compounds 3 and 4, which were recently ex-
tracted from the plants B. zenkeri and T. yannanensis, respectively,
(Chart 1).16
The use of lipases is one of the most developed enzymatic pro-
cesses yielding asymmetric secondary alcohols, amines, and other
substances.2,3 Crude, purified, or immobilized lipases can be used
in water, organic solvents, or ionic liquids in a straightforward
manner. Recently, the efficacy of lipases was improved upon by io-
nic surfactant coating.4 Coupling with a metal-based racemization
step leads to the dynamic kinetic resolution of secondary alcohols
with twice as high maximum yields in comparison to traditional
kinetic resolution methods (100% vs 50%).5,6 The former still re-
quires development since more drastic reaction conditions can
lead to unwanted side processes, decreasing the yields and purity
of the final products. Finally, simple rules have been formulated
for determining the absolute configuration of a secondary alcohol
by observing the lipase selectivity.7 These rules indicated that
the lipase resolution is in addition an analytical method. The scope
of lipase substrates that can be effectively separated in a routine
and reliable manner therefore requires development.8
The enzymatic enantiomeric synthesis of chroman-4-ol (1a,
X = O, n = 1) and thiochroman-4-ol was previously carried out via
⇑
Corresponding author. Tel.: +380 935851552.
E-mail address: kucher87@ukr.net (O.V. Kucher).
http://dx.doi.org/10.1016/j.tetasy.2014.02.010
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

564
O. V. Kucher et al. / Tetrahedron: Asymmetry 25 (2014) 563–567
O
A
OH
B
OH
O
O
O
OH
O
BCL
+
( )n
X
1
1a
rac-
1a
(S)-
2a
(R)-
X = O, S, SO2, n = 1, 2
Scheme 1. (A) General structure of the chroman-4-ol analogues. (B) Lipase resolution of chroman-4-ol.
OH
O
OH
O
the reported protocol (Scheme 2, entry 2). These results inspired
OH
us to apply the BCL kinetic resolution to the thio-, homothiocrom-
anols (X = S) and their dioxides (X = SO2). Racemic thiochroman-4-
ol 1c was obtained according to the known pathway starting from
thiophenol.20 Our BCL kinetic resolution procedure gave the corre-
sponding 1c enantiomers with an ee of 95% (Scheme 2, entry 3).
The racemic homothiochromanol 1d was obtained by alkylation
of thiophenol with butyrolactone, followed by cyclization and
reduction of the carbonyl group. The BCL resolution efficacy for this
substrate exhibited a significant drop. When the procedure was
performed in an analogous manner to the previous substrates
(1:10 mass amount of the enzyme, 23 °C, TBME), the conversion
was only 2% after 14 h. We then attempted the reaction under
more vigorous conditions (1:3 mass amount of the lipase, 40 °C)
in different solvents. After 8 h, the conversion was found to be
15% in TBME, 4% in acetonitrile and 6% in THF, indicating that
TBME gave the fastest reaction. We carried out the resolution in
this solvent until 50% conversion was reached (after 50 h). The
resulting resolution was only 85% ee for both enantiomers (S)-1d
and (R)-2d (Scheme 2, entry 4).
O
O
O
O
O
3
4
Chart 1. The structures of the chroman-4-ol based natural products 3 and 4.
2. Results and discussion
Racemic alcohol 1a (X = O, n = 1) was obtained by sodium boro-
hydride reduction of chroman-4-one.17 It was then subjected to the
kinetic enzymatic resolution with BCL, with vinyl acetate as the
acetyl donor (Scheme 2, entry 1). The use of TBME as the solvent
led to 50% conversion after 14 h at room temperature as monitored
by 1H NMR spectroscopy. The alcohol (S)-1a and the ester (R)-2a
were then separated on a silica gel column. The (R)-2a ester hydro-
lysis with potassium carbonate in methanol gave the second enan-
tiomer (R)-1a. Both were subjected to conventional Mosher ester
derivatization with MTPA chloroanhydride.18 The 19F NMR spectra
of the derivatives showed (S)- and (R)-1a to possess an ee of P94%
and 95%, respectively.
In order to complete the resolution, we took the reaction prod-
ucts and performed additional manipulations. Compound (S)-1d
with 85% ee was subjected to the second resolution step with
BCL (Scheme 3). After 11 h, we obtained the starting material with
99% ee. The acetyl-ester (R)-2d was also subjected to the lipase-
catalyzed hydrolysis in the TBME-phosphate buffer mixture. The
Next we took a substrate with a larger heterocycle size. The cor-
responding homochromanol19 1b (X = O, n = 2) was resolved with
even better ee P99% for both enantiomers after application of
O
OH
O
X
OH
Burkholderia cepacia
lipase
+
O
O
( )n
( )n
( )n
X
X
(R)-2a-f
1a-f
(S)-1a-f
(R)-1a-f
(rac)-
K2CO3,
methanol
Scheme 2. Enzymatic resolution of enantiomeric chroman-4-ol and its analogues with BCL. The cross-acylation reactions were run until 50% conversion was reached.

O. V. Kucher et al. / Tetrahedron: Asymmetry 25 (2014) 563–567
565
O
HO
HO
O
HO
BCL (1:1 mass)
BCL (3:1 mass)
TBME, 40°C, 11 h
TBME:PB (pH = 7.2)
50°C, 60 h
O
O
S
S
S
S
3
1d
(S)-1d
(S)-
(R)-1d
(R)-2d
ee 99 %
ee 85 %
ee 95 %
(ee 85 %)
yield 88 %
yield 26 %
Scheme 3. Second BCL kinetic resolution of the homothiochromanol enantiomers 1d after the first acylation.
reaction gave only a barely detectable conversion after 12 h at
40 °C (the lipase was taken as 1:3 by mass). Therefore, we per-
formed this procedure for 60 h at 50 °C and with an excess of the
lipase (3:1 mass amount). A conversion of 26% was eventually
achieved and the resulting alcohol (R)-1d was obtained with 95%
ee.
We then carried out additional optimization for the sulfonic
compounds 1e and 1f (X = SO2, n = 1 and 2, respectively). The start-
ing materials were obtained by peroxide oxidation of the thiochro-
manone and homothiochromanone, followed by borohydride
reduction of the carbonyl function.21 The racemic substances were
subjected to BCL resolution under more drastic conditions (50 °C,
4 days) until 50% conversion was reached. Since, the substrates
were less soluble in TBME, we employed larger amounts of this sol-
vent. The resolution was still quite good, with the corresponding
alcohols (S)- and (R)-1e being obtained in ee P94% (Scheme 2, en-
try 5). For 1f, the enantiomeric alcohols were obtained in ee P90%
(entry 6).
Alternatively, the kinetic resolution for the sulfonic species 1e
and 1f can be performed in acetonitrile. These substrates are more
soluble in this solvent. For 1e, we carried out the resolution in ace-
tonitrile under the same conditions as shown in Scheme 2 for the
TBME reaction. We found that the conversion in acetonitrile
(2.5 l/mol substrate) reached 46% only after 72 h, whereas in TBME
(5 l/mol substrate) it was 50% after 14 h. A similar effect was ex-
pected for 1f.
Finally, we obtained all of the desired enantiomers with ee val-
ues of 94–99% for (S)-1a-1f and 90–99% for (R)-1a–1f. Over the
past two decades, a number of methods have been reported for
the separation of chroman-4-ol 1a and its thio-analogue 1b
employing chemical catalysis.20,22 Mostly, these are based on a
ketone–alcohol redox conversion on metallic catalysts,22 but also
enantioselective sylilation.20 However, the lipase cross-acylation
remains a powerful and robust method for the separation of such
secondary alcohols.
cepacia lipase catalyzed acylation of the alcohols with vinylace-
tate as the acetyl donor. We obtained the corresponding enantio-
meric species with ee P94% for chroman-4-ol itself and 90–99%
for the rest of the structures examined. The observed resolution
values showed good selectivity of the lipase toward (R)-substrates
according to Kazlauskas’s rule, despite the variation in the ring
size and heteroatom nature. All of the compounds were obtained
with high degrees of enantiomerical purity and can then be used
elsewhere.
4. Experimental
4.1. General
All starting chemicals were supplied by Enamine Ltd or pre-
pared according to the literature as mentioned in the main text.
Amano-PS lipase from Burkholderia cepacia immobilized on
diatomaceous earth was obtained from Amano Enzyme USA
Co., Ltd.
1H and 13C NMR spectra were recorded on Bruker Avance DRX
500 (at 500 and 126 MHz respectively) and 19F NMR on Varian
UNITY Plus 400 (at 376 MHz) spectrometers. Optical rotation val-
ues were measured on JASCO J-20 polarimeter with a 50 mm cell
at 20 °C and 589 nm (sodium D-line). Chiral HPLC analysis was
done at Agilent 1100 system equipped by ChiralpakÒ or ChiracelÒ
(Chiral Technologies) analytical columns with cellulose-based sta-
tionary phase. The UV detection was performed at 215, 225, and
254 nm. Chemical purity of the obtained enantiomers was con-
trolled by comparing their 1H NMR spectra with that reported in
the literature. Derivatization with
a-methoxy-a-trifluoromethyl-
phenylacetic acid (MTPA) chloranhydride was carried out accord-
ing to the literature.13 The enantiomeric excess values were
determined from the 19F NMR spectra of the MTPA derivatives, or
from chiral HPLC analysis. Absolute configurations of the alcohols
obtained were determined by comparison of the specific rotation
with the literature values and were consistent with Kazlauskas’s
rule.7 The IR spectra were recorded on a Bruker Vertex 70 FTIR
spectrometer in KBr; the absorption values are given in cmꢀ1. Sub-
stance purity was checked on an Agilent 1100 LC/MSD SL (chemical
ionization) system to exceed 95%.
In our hands BCL gave good results with chroman-4-ol core ana-
logues such as homo-, thio-, and dioxothio- as well as chromanol
itself. Complications were found in the case of the substrates 1f
and especially 1d. In the last case, thiohomo modification of the
initial chroman-4-ol structure led to a significant drop in the reac-
tion conversion as well as the resolution. The saturated heterocycle
in chroman-4-ol defines the ‘medium’-substituent in the second-
ary alcohol structure when accommodated by the lipase binding
pocket, whereas the large substituent is the phenyl-ring. Both an
enlargement of the saturated cycle and substitution of the ring
oxygen with sulfur in 1d, led to complications in the enzyme-
binding.
4.2. General procedure for enzymatic resolution of alcohols
To
a solution of the racemic secondary alcohol (1 equiv,
0.29 mol) in TBME (800 ml per 1 mol of the alcohol; for 1e–f
4.5 l per 1 mol), lipase (1:10 or 2:3 by mass to the alcohol) and
vinyl-acetate (3 equiv) were added. The reaction was stirred
(either at room temperature of 23 °C or at 50 °C) until 50% con-
version was reached (1H NMR monitoring). The lipase was filtered
off and washed by the solvent twice. The filtrate was evaporated
and subjected to chromatographic separation on silica gel with
hexane–ethyl acetate gradient elution yielding (S)-1 alcohol and
(R)-2 ester.
3. Conclusion
In conclusion, we have reported a convenient procedure for
the enzymatic kinetic resolution of chroman-4-ol and its unsub-
stituted analogues. The resolution is based on a Burcholderia

566
O. V. Kucher et al. / Tetrahedron: Asymmetry 25 (2014) 563–567
4.3. Resolution details and characterization of (S)-1 alcohols
(4S)-Chroman-4-ol (S)-1a was obtained using the general pro-
4.5. Details and characterization of (R)-1 alcohols
(4R)-Chroman-4-ol (R)-1a. Yield; 43%. ½a D20
¼ þ65:5 (c 3.0,
ꢁ
cedure at 23 °C, reaction time: 14 h. Yield; 47%. ½a D20
ꢁ
¼ ꢀ56:0 (c
EtOH) for 95% ee {literature ½a D20
¼ þ70:2 (c 1.0, EtOH) for 99%
ꢁ
1.4, EtOH) for 94% ee {literature ½a D25
ꢁ
¼ ꢀ71:3 (c 0.5, EtOH) for
ee}.25
99% ee}.23
(5R)-2,3,4,5-Tetrahydro-1-benzoxepin-5-ol (R)-1b was re-crys-
(5S)-2,3,4,5-Tetrahydro-1-benzoxepin-5-ol (S)-1b was obtained
using the general procedure at 23 °C, reaction time: 14 h. Yield;
tallized from hexane. Yield; 43%. Mp = 73 °C. IR bands: 3465,
2956, 2867. ½a 2D0
¼ þ13:5 (c 1.0, EtOH) for 99% ee {literature
ꢁ
48%.
½
a 2D0
ꢁ
¼ ꢀ18:4 (c 0.7, CHCl3) for 99% ee {literature
½
a 2D5
ꢁ
¼ ꢀ15:5 (c 2.5, CHCl3) for the (S)-isomer}.18
½
a 2D5
ꢁ
¼ ꢀ15:5 (c 2.48, CHCl3)}.24
(4R)-Thiochroman-4-ol (R)-1c was re-crystallized from hexane.
(4S)-Thiochroman-4-ol (S)-1c was obtained using the general
Yield; 40%. ½a 2D0
¼ þ117:5 (c 1.2, CHCl3) for 95% ee {literature
ꢁ
procedure at 23 °C, reaction time: 14 h. Yield; 47%.
½
a 2D5
ꢁ
¼ þ143:0 (c 1.0, CHCl3) for 98% ee}.26
½
a 2D0
ꢁ
¼ ꢀ104:5 (c 1.5, CHCl3) for 95% ee {literature ½a D25
ꢁ
¼ ꢀ136:0
(5R)-2,3,4,5-Tetrahydro-1-benzothiepin-5-ol (R)-1d. Yield; 35%.
(c 1.0, CHCl3) for 99% ee}.17
Re-crystallized from hexane-chloroform (10:1). Mp = 39 °C. IR
(5S)-2,3,4,5-Tetrahydro-1-benzothiepin-5-ol
(S)-1d
was
bands: 3289, 2919, 2856 cmꢀ1. ½a D20
¼ þ83:5 (c 5.7, EtOH) for
ꢁ
obtained using the general procedure at 23 °C, reaction time:
85% ee.
14 h. Yield 41%. Re-crystallized from hexane-chloroform 10:1.
Otherwise the synthesis was performed as following. Acetate
(R)-2d (0.51 g, 2.3 mmol) obtained in Section 4.2 was dissolved
in TBME (4 ml). The lipase (1.5 g, 3:1 by mass to the acetate) and
phosphate buffer (4 ml, pH = 7.2, 50 mM KH2PO4) were then added
and the mixture was stirred for 60 h at 50 °C. The resulting mixture
contained 26% of the hydrolyzed product (1H NMR). The mixture
was then filtered from the solid lipase, the organic layer was sep-
arated, and the aqueous layer was extracted by TBME (3 ꢂ 5 ml).
The organic fractions were dried over sodium sulfate, the crude mix-
ture was concentrated in vacuo, and then separated on silica gel
(hexane—ethyl acetate gradient elution) to give 0.070 g (13%) of
½
a 2D0
ꢁ
¼ ꢀ91:3 (c 2.9, EtOH) for 85% ee.
The second resolution step was performed as follows; alcohol
(S)-1d (0.80 g, 4.4 mmol; ee = 85%) obtained in the general proce-
dure was dissolved in 7 ml of TBME (1.5 l per 1 mol of the alcohol).
Next, the lipase (0.80 g, 1:1 by mass to the alcohol) was added fol-
lowed by vinyl acetate (1.0 ml, 13.2 mmol, 3 equiv). The mixture
was stirred for 11 h at 40 °C at which point the desired conversion
was reached (1H NMR). The lipase was filtered off, washed twice,
and the resulting filtrate was concentrated under reduced pres-
sure, after which it was subjected to chromatographic separation
on silica gel (hexane—ethyl acetate gradient elution) to give
the desired alcohol (R)-1d with 95% ee. ½a D20
¼ þ97:8 (c 3.2, CHCl3).
ꢁ
0.71 g of (S)-1d (yield 88%). ½a D20
ꢁ
¼ ꢀ98:1 (c 3.2, CHCl3) for 99%
(4R)-1,1-Dioxo-3,4-dihydro-2H-thiochromen-4-ol (R)-1e was
re-crystallized from hexane—isopropanol (10:1). Mp = 91 °C.
ee. Mp = 42 °C. 1H NMR (CDCl3), d: 7.45–7.52 (2H, m), 7.31 (1H, t,
J = 7.3 Hz), 7.17 (1H, t, J = 7.0 Hz), 5.22 (1H, d, J = 9.1 Hz), 2.80–
2.95 (1H, br s), 2.75–2.81 (1H, m), 2.63 (1H, t, J = 9.4 Hz), 2.06–
2.22 (2H, m), 1.96–2.06 (1H, m), 1.76–1.88 (1H, m). 13C NMR
(CDCl3), d: 28.4 (CH2), 33.5 (CH2), 35.4 (CH2), 73.4 (CH), 125.8
(CH), 126.9 (CH), 128.2 (CH), 132.8 (C), 133.5 (CH), 148.3 (C). IR
bands: 3296, 2922.
Yield—34%. IR bands: 3455, 2977, 2924. ½a D20
¼ ꢀ7:0 (c 1.3, CHCl3)
ꢁ
for 94% ee {literature ½a D25
¼ þ5:1 (c 1.0, CHCl3) for 99% ee of the
ꢁ
(S)-isomer}.17
(5R)-1,1-Dioxo-2,3,4,5-tetrahydro-1-benzothiepin-5-ol (R)-1f
was re-crystallized from hexane–isopropanol (10:1). Yield—35%.
Mp = 146 °C. IR bands: 3496, 2925. ½a D20
¼ þ34:8 (c 1.4, CHCl3)
ꢁ
(4S)-1,1-Dioxo-3,4-dihydro-2H-thiochromen-4-ol (S)-1e was
for 90% ee.
obtained using the general procedure at 50 °C, reaction time:
96 h. Yield; 40%. ½a D20
ꢁ
¼ þ5:1 (c 1.41, CHCl3) for 95% ee {literature
References
½
a 2D5
ꢁ
¼ þ5:1 (c 1.0, CHCl3) for 99% ee}.17
1. Wohlgemuth, R. Curr. Opin. Microbiol. 2010, 13, 283–292.
(5S)-1,1-Dioxo-2,3,4,5-tetrahydro-1-benzothiepin-5-ol (S)-1f
2. Jaeger, K.-E.; Eggert, T. Curr. Opin. Biotechnol. 2002, 13, 390–397.
3. Ghanem, A.; Aboul-Enein, H. Y. Tetrahedron: Asymmetry 2004, 15, 3331–3351.
4. (a) Kim, H.; Choi, Y. K.; Lee, J.; Lee, E.; Park, J.; Kim, M.-J. Angew. Chem., Int. Ed.
2011, 50, 10944–10948; (b) Kim, C.; Lee, J.; Cho, J.; Oh, Y.; Choi, J. K.; Choi, E.;
Park, J.; Kim, M.-J. J. Org. Chem. 2013, 78, 2571–2578.
5. Kim, M.-J.; Ahn, Y.; Park, J. Curr. Opin. Biotechnol. 2002, 13, 578–587.
6. Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.; Kim, E. J.; Kim, M.-J.; Park, J. J. Org.
Chem. 2004, 69, 1972–1977.
7. (a) Jing, Q.; Kazlauskas, R. J. Chirality 2008, 20, 724–735; (b) Kazlauskas, R. J.;
Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656–2665.
8. For few recent examples with Burkholderia cepacia lipase, see: (a) Forró, E.;
Schönstein, L.; Fülöp, f. Tetrahedron: Asymmetry 2011, 22, 1255–1260; (b)
Kolodiazhna, O. O.; Kolodiazhna, A. O.; Kolodiazhnyi, O. i. Tetrahedron:
Asymmetry 2013, 24, 37–42; (c) Kołodziejska, R.; Górecki, M.; Frelek, J.;
was obtained using the general procedure at 50 °C, reaction time:
72 h. Yield; 45%. Mp = 148 °C. 1H NMR (DMSO-d6), d: 7.91 (1H, d,
J = 7.9 Hz), 7.88 (1H, d, J = 7.9 Hz), 7.73 (1H, t, J = 7.5 Hz), 7.50
(1H, t, J = 7.5 Hz), 5.73 (1H, s), 5.26 (1H, d, J = 10.3 Hz), 3.41 (1H,
d, J = 14.0 Hz), 3.19 (1H, t, J = 13.8 Hz), 2.22 (1H, q, J = 13.3 Hz),
2.13 (1H, d, J = 13.3 Hz), 2.01 (1H, d, J = 13.5 Hz), 1.55 (1H, q,
J = 12.2 Hz). 13C NMR (DMSO-d6), d: 22.7 (CH2), 37.1 (CH2), 54.2
(CH2), 69.4 (CH), 126.2 (CH), 127.0 (CH), 127.4 (CH), 134.2 (CH),
137.2 (C), 145.5 (C). IR bands: 3496, 2925, 2869. ½a D20
¼ ꢀ32:8 (c
ꢁ
1.4, CHCl3) for 99% ee.
´
Draminski, M. Tetrahedron: Asymmetry 2012, 23, 683–689; (d) Li, N.; Hu, S.-B.;
Feng, G.-Y. Biotechnol. Lett. 2012, 34, 153–158; (e) Wang, Z.-Y.; Bi, Y.-H.; Zong,
M.-H. Biotechnol. Bioprocess Eng. 2012, 17, 393–397; (f) Chen, Z. G.; Tan, R. X.;
Huang, M. Process Biochem. 2010, 45, 415–418.
4.4. General procedure for the hydrolysis of (R)-2 acetyl esters
9. Holland, H. L.; Manoharan, T. S.; Schweizer, F. Tetrahedron: Asymmetry 1991, 2,
335–338.
10. Majeric´, M.; Gelo-Pujuc´, M.; Šunjic´, V.; Lévai, A.; Sebök, P.; Timàr, T.
To a solution of the corresponding (R)-2 (1 equiv, 0.16 mol) in
methanol (300 ml), potassium carbonate (3 equiv) was added.
The mixture was stirred for 3 h at room temperature (23 °C). Next,
the mixture was filtered off and the filtrate was concentrated un-
der reduced pressure. Water (300 ml) was then added to the resi-
due and this was extracted by ethyl acetate (3 ꢂ 200 ml). The
organic layers were dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. Resulting crude material was purified
by either vacuum distillation for (R)-1a and (R)-1d, or re-crystalli-
zation to give pure (R)-1 alcohol.
Tetrahedron: Asymmetry 1995, 6, 937–944.
11. Ramadas, S.; Krupadanam, G. L. D. Tetrahedron: Asymmetry 1997, 8, 3059–3066.
12. For a recent example of an oxygen to sulfur substitution effect see: Xu, S.-Q.;
Yan, X.; Chen, Y.; Xia, P.; Qian, K.; Yu, D.; Xia, Y.; Yang, Z.-Y.; Morris-Natschke,
S. L.; Lee, K.-H. Bioorg. Med. Chem. 2010, 18, 7203–7211.
13. (a) Pietta, P. G. J. Nat. Prod. 2000, 63, 1035–1042; (b) Nijveldt, R. J.; van Nood, E.;
van Hoorn, D. E. C.; Boelens, P. G.; van Norren, K.; van Leeuwen, P. A. M. Am. J.
Clin. Nutr. 2001, 74, 418–425.
14. Birt, D. F.; Hendrich, S.; Wang, W. Pharmacol. Ther. 2001, 90, 157–177.
15. Saengchantara, S. T.; Wallace, T. W. Nat. Prod. Rep. 1986, 465–475.

O. V. Kucher et al. / Tetrahedron: Asymmetry 25 (2014) 563–567
567
16. (a) Lenta, B. N.; Tantangmo, F.; Devkota, K. P.; Wansi, J. D.; Chouna, J. R.; Soh, R.
C. F.; Neumann, B.; Stammler, H.-G.; Tsamo, E.; Sewald, N. J. Nat. Prod. 2009, 72,
2130–2134; (b) Tezuka, Y.; Morikawa, K.; Li, F.; Auw, L.; Awale, S.; Nobukawa,
T.; Kadota, S. J. Nat. Prod. 2011, 74, 102–105.
68, 7535–7537; (c) Yamada, T.; Higano, S.; Yano, T.; Yamashita, Y. Chem. Lett.
2009, 38, 40–41; (d) Klauck, M. I.; Patel, S. G.; Wiskur, S. L. J. Org. Chem. 2012,
77, 3570–3575.
23. Utsumi, N.; Tsutsumi, K.; Watanabe, M.; Murata, K.; Arai, N.; Kurono, N.;
Ohkuma, T. Heterocycles 2010, 80, 141–149.
17. Barlow, J. W.; Walsh, J. J. Eur. J. Med. Chem. 2010, 45, 25–37.
18. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
24. Kasai, M.; Herman, Y. J. Org. Chem. 1983, 48, 712–715.
25. Touge, T.; Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.; Saito, T.; Kayaki, Y.;
Ikariya, T. J. Am. Chem. Soc. 2011, 133, 14960–14963.
26. Zeror, S.; Collin, J.; Collin, J.; Fiaud, J.-C.; Youioueche, L. A. Adv. Synth. Catal.
2008, 350, 197–204.
19. Utz, R., Englert, H. C., Scholkens, B., Klaus, E. US Patent 5,194,442, A1, 1993.
20. Sheppard, C. I.; Taylor, J. L.; Wiskur, S. L. Org. Lett. 2011, 13, 3794–3797.
21. Traynelis, V. J.; Love, R. F. J. Org. Chem. 1961, 26, 2728–2733.
22. Selected examples: (a) Ursini, C. V.; Dias, G. H. M.; Rodrigues, A. R. J. Organomet.
Chem. 2005, 690, 3176–3186; (b) Mandal, S. K.; Sigman, M. S. J. Org. Chem. 2003,