Chemo-enzymatic synthesis of (R)-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate, a potential chiral building block for multicyclic terpenoids

Article abstract of DOI:10.1016/j.tetasy.2017.05.007

The chemo-enzymatic synthesis of (R)-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate, a potential chiral building block for polycyclic terpenoids containing a five–membered ring having isopropyl and angular methyl substituents, such as erinacin A and dolatriol, was achieved over 11 steps from ethyl 2-oxocyclopentane-1-carboxylate. The key synthetic precursor for this triflate was ethyl (1S,2R)-2-hydroxycyclopentanecarboxylate (>99% ee), which was prepared by a lipase-catalyzed enantioselective hydrolysis of the corresponding racemic acetate. The antipodal (S)-triflate is expected to be the synthetic intermediate for another group of terpenoids involving hamigeran B and stolonidiol. Enantiomerically pure (1R,2S)-hydroxyester (>99% ee) was prepared in high yield using the asymmetric reduction of the oxoester with commercially available carbonyl reductase, “Chiralscreen OH”-E001.

Full text of DOI:10.1016/j.tetasy.2017.05.007

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemo-enzymatic synthesis of (R)-5-hydroxymethyl-2-isopropyl-5-
methylcyclopent-1-en-1-yl trifluoromethylsulfonate, a potential
chiral building block for multicyclic terpenoids
⇑
⇑
Kazuaki Kuwata, Kengo Hanaya, Takeshi Sugai , Mitsuru Shoji
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemo-enzymatic synthesis of (R)-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl tri-
fluoromethylsulfonate, a potential chiral building block for polycyclic terpenoids containing a five–mem-
bered ring having isopropyl and angular methyl substituents, such as erinacin A and dolatriol, was
achieved over 11 steps from ethyl 2-oxocyclopentane-1-carboxylate. The key synthetic precursor for this
triflate was ethyl (1S,2R)-2-hydroxycyclopentanecarboxylate (>99% ee), which was prepared by a lipase-
catalyzed enantioselective hydrolysis of the corresponding racemic acetate. The antipodal (S)-triflate is
expected to be the synthetic intermediate for another group of terpenoids involving hamigeran B and
stolonidiol. Enantiomerically pure (1R,2S)-hydroxyester (>99% ee) was prepared in high yield using the
asymmetric reduction of the oxoester with commercially available carbonyl reductase, ‘‘ChiralscreenÒ
OH”-E001.
Received 10 April 2017
Revised 8 May 2017
Accepted 11 May 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
HO
O
O
O
Numerous polycyclic terpenoids with various bioactivities have
been isolated from Nature. Among them, compounds containing
five–membered rings with an isopropyl side chain and an angular
methyl group, which constitutes a quaternary stereogenic center,
are frequently observed (Fig. 1). Erinacin A, a cyathane diterpene,
was isolated from the mycelia of a fungus Hericium erinaceum as
a strong stimulator of nerve growth factor synthesis, 1 and dolatriol
was isolated from the sea slug Dolabella auricularia as a cytotoxic
component against P-388 leukemia cells.2 Other terpenoids with
an angular methyl group, but with an opposite stereochemistry
of the quaternary center located in the five–membered ring, were
also found. Hamigeran B was isolated from the poecilosclerid
sponge Hamigera tarangaensis as an antiviral component,3 and
stolonidiol was isolated from the soft coral Clavularia sp. as a cyto-
toxic component against P-388 leukemia cells.4
O
OH
OTf
HO
OH
OH
OH
dolatriol
CHO
(S)-1
erinacin A
O
O
O
OH
H
HO
H
H
O
O
Br
H
OH
hamigeran B
stolonidiol
(R)-piperitone 2
Figure 1. Polycyclic terpenoids containing a five–membered ring with an isopropyl
side chain and an angular methyl group and a known example of the building block
1 and its synthetic precursor 2.
With regards to the total synthesis of the above-mentioned nat-
ural products, the development of a synthetic method for the
building blocks with a five-membered ring and the correct alkyl
side chains is desirable. Vinyl triflate (S)-1, derived from (R)-piperi-
tone 2, was applied towards the total synthesis of hamigerans.5
However, highly enantiomerically pure (S)-1 was sometimes inac-
cessible due to the fluctuating enantiomeric purity of commercially
available 2.6
⇑
Corresponding authors at present address: Faculty of Pharmacy, Yokohama
University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan
(M.S.).
E-mail addresses: sugai-tk@pha.keio.ac.jp (T. Sugai), mitsu.shoji@hamayaku.ac.
jp (M. Shoji).
http://dx.doi.org/10.1016/j.tetasy.2017.05.007
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kuwata, K.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.007

2
K. Kuwata et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
CO2Et
O
CO2Et
Conversely, we have reported the preparation of chiral building
blocks 4 and ent-4, based on the whole-cell-catalyzed enantiofa-
1) Ac2O, pyridine
cially selective desymmetrization of 2,2-disubstituted cyclohex-
OAc
2) H2, Rh/C
THF
ane-1,3-dione
3
(Scheme 1).7 Both enantiomerically pure
8
(1R*,2S*)-( )-7b
85%
building blocks 4 and ent-4 were available from 3 by simply chang-
ing the yeast strain used. However, this synthesis was limited to
providing both enantiomers with a 5/6-fused ring structure.
Herein, we have designed and synthesized potential chiral building
blocks (R)-5 and (S)-5 for the synthesis of various types of natural
products containing five–membered rings via the biocatalytic reac-
tions (Scheme 2).
CO2Et
CO2Et
Pseudomonas sp.
lipase Amano AK
+
OH
OAc
pH 7.0
36 °C, 20 h
48% conv.
(1S,2R)-7a
38%, >99% ee
(1R,2S)-7b
49%
Scheme 3. Synthesis and kinetic resolution of ( )-7b.
O
O
With (1S,2R)-7a in hand, we embarked upon the synthesis of
(R)-5 (Scheme 4). According to the reported procedure,11 (1S,2R)-
7a was stereoselectively methylated to give (1S,2R)-6 in 85% yield
as a single diastereomer. Subsequently, the Dess–Martin oxidation
of the secondary alcohol afforded oxoester (S)-9. The sterically hin-
dered isopropyl group was introduced in a stepwise manner. The
aldol reaction between (S)-9 and acetaldehyde gave b-hydroxyke-
tones as a diastereoisomeric mixture. Mesylation of the resulting
secondary alcohol followed by b-elimination under basic condi-
tions furnished enone (1S,3E)-10 in 61% yield over three steps from
(S)-9. Subsequently, the 1,4-addition of lithium dimethylcuprate to
10 yielded the isopropyl group in (S)-11. The formation of the eno-
late and triflylation with Comins reagent12 afforded the corre-
sponding enol triflate. Finally, reduction of the ethoxycarbonyl
group with diisobutylaluminum hydride (DIBAL-H) furnished the
target molecule (R)-5 in 78% yield over two steps from (S)-11.
O
O
Lit.7
O
O
O
O
O
O
O
3
4
ent-4
Scheme 1. Our previous approach for six-membered ring-fused chiral building
blocks.
Our synthetic strategy was based on biocatalytic reactions
showing high selectivity and reproducibility; the retrosynthesis
of (R)-5 and (S)-5 is shown in Scheme 2. The isopropyl group and
enol triflate moiety would be installed into 6, whose quaternary
stereogenic center would be constructed via Fráter’s diastereose-
lective methylation8 of 7a. One enantiomer of 7a is accessible using
a
lipase-catalyzed enantioselective hydrolysis of its racemic
LDA, THF
acetate,9 which can be synthesized from ethyl 2-oxocyclopen-
tanecarboxylate 8. Conversely, another enantiomer of 7a would
be obtained using an enzyme-mediated direct asymmetric reduc-
tion of 8.
CO2Et
OH
CO2Et
OH
–50 °C
DMP, NaHCO3
CH2Cl2, 87%
then CH3I
–50 ~ –10 °C
85%
(1S,2R)-7a
(1S,2R)-6
1) LDA, CH3CHO
CO2Et
CO2Et
O
THF, –78 °C
2) MsCl, Et3N, CH2Cl2
R
CO2Et
O
OH
3) DBU, toluene
61% (3 steps)
cis-selective
reduction
and kinetic
resolution
OTf
(1S,3E)-10
(S)-9
OH
CO2Et
O
(1S,2R)-6 R = Me
(1S,2R)-7a R = H
(R)-5
1) LDA
CO2Et
Comins reagent
OH
(CH3)2CuLi
THF, –78 ~ –10 °C
R
or
CO2Et
8
OTf
OH
Et2O, –30 °C
95%
asymmetric
reduction
O
2) DIBAL-H
THF, –78 °C
78% (2 steps)
OTf
OH
(R)-5
(S)-11
(1R,2S)-6 R = Me
(1R,2S)-7a R = H
(S)-5
Scheme 4. Synthesis of (R)-5 from (1S,2R)-7a.
Scheme 2. Potential chiral building blocks (R)-5 and (S)-5 and their retrosyntheses
from 8.
In order to synthesize (S)-5, the preparation of the antipode of
the starting material (1R,2S)-7a was investigated using another
route. As shown in Scheme 3, we performed the kinetic resolution
of racemic 7b, and the unreacted recovery product was (1R,2S)-7b,
as the b-acetoxyester. Even if it has high ee, the hydrolysis might
cause partial isomerization to give a stereoisomeric mixture of
7a. Sakai et al. applied several lipases on racemic 7b, and the two
successful examples only exhibited the same enantiomeric prefer-
ence on (1S,2R)-7b.9a
2. Results and discussion
The preparation of (1S,2R)-7a is shown in Scheme 3. The forma-
tion of the enol acetate and the subsequent rhodium-catalyzed
hydrogenation10 predominantly yielded racemic cis-acetate 7b
with the trans-isomer in a 5:1 ratio. After chromatographic isola-
tion of cis-7b, the reported lipase-catalyzed hydrolysis occurred
in a reproducible manner. At 48% conversion, the desired (1S,2R)-
7a was isolated in 38% yield and with >99% ee.
We thus investigated an alternative method to obtain (1R,2S)-
7a, i.e., the direct asymmetric reduction of 8. Whole-cell bakers’
yeast-catalyzed reduction of 8 was reported to furnish (1R,2S)-7a
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K. Kuwata et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 1
Reduction of cyclic oxoester 8 with ‘‘ChiralscreenÒ OH.”
CO2Et
O
CO2Et
OH
CO2Et
OH
CO2Et
OH
CO2Et
OH
"Chiralscreen®
OH"
30 °C, 24 h
8
(1R,2S)-7a
(1S,2R)-7a
(1S,2S)-7a
(1R,2R)-7a
Entry
Enzyme No.
Conv. (%)a
Ratio of enantiomersa
(1R,2S)
(1S,2R)
1
2
3
4
5
6
7
E001
E007
E031
E039
E078
E087
E146
100
67
91
21
41
>99
73
>99
4
>99
>99
>99
0
27
0
96
0
100
37
0
0
a
Determined by 1H NMR and HPLC analyses. For further details, see Section 4.7.
as the major product.11,13 Although these procedures are estab-
lished, the bakers’ yeast-mediated reductions require a large quan-
tity of cell mass (5–10 times in dry cell weight over substrate),
which increases over 30 times by absorbing water during the reac-
tions. At the work-up stage, the tedious removal of them from the
incubation broth, prior to extraction with organic solvent, has been
problematic in the past. Moreover, several undesired components
from the autodigested cells can contaminate the desired products.
Recently, we have examined the substrate specificity, reactivity,
and selectivity of a commercially available carbonyl reductase
screening kit, ‘‘ChiralscreenÒ OH,” 14 on a variety of cyclic and acyc-
lic substrates.15 The commercial availabilities of carbonyl reduc-
tases in ‘‘ChiralscreenÒ OH” assured the large-scale preparation
of enantiomerically enriched forms of secondary alcohols. This sit-
uation prompted us to embark upon the reduction of 8 with ‘‘Chi-
ralscreenÒ OH.”
The results of the reduction using seven different types of car-
bonyl reductases in ‘‘ChiralscreenÒ OH.” are summarized in Table 1.
All enzymes exhibited almost exclusive cis-selectivity, based on the
1H NMR analyses. E001, E031, and E087 demonstrated excellent
reactivity and enantioselectivity. On the contrary, the reactivity
of E007, E039, E078, and E146 were relatively low. E007 showed
less enantiofacial selectivity, resulting in less than 50% ee. Among
the seven enzymes, only E039 produced the contrasting (1S,2R)–
isomer with high selectivity.
route would contribute to the synthesis of both enantiomers of
polycyclic terpenoids with a five-membered ring containing iso-
propyl and angular methyl substituents.
4. Experimental
4.1. General
IR spectra were measured as ATR on a Jeol FT-IR SPX60 spec-
trometer. 1H NMR spectra were measured in CDCl3 at 400 MHz
on a VARIAN 400-MR spectrometer or at 500 MHz on a VARIAN
500-MR spectrometer and 13C NMR spectra were measured in
CDCl3 at 100 MHz on a VARIAN 400-MR spectrometer or at
125 MHz on a VARIAN 500-MR spectrometer. Merck silica gel
60 N (spherical, neutral, 63–210 lm, 37565-84) from Kanto Chem-
ical Co. was used for column chromatography. HPLC data were
recorded on SHIMADZU SPD-M20A multi-channel detector. Optical
rotation values were recorded on a Jasco P-1010 polarimeter. ‘‘Chi-
ralscreenÒ OH” was purchased from Daicel Corp.
4.2. Ethyl (1S,2R)-2-hydroxy-1-methylcyclopentanecarboxylate
6
According to the reported procedure, (1S,2R)-7a was prepared
by the lipase AK-catalyzed hydrolysis of racemic 7b. The conver-
sion (48%) was estimated by the area of signals in 1H NMR spec-
trum of the crude mixture with the comparison of authentic
signals (CDCl3): d 5.42 (ddd, 1H, J = 8.5, 5.4, 2.9 Hz for 7b) and
4.43 (ddd, 1H, J = 4.1, 3.9, 3.9 Hz for 7a). The ee was confirmed by
HPLC analysis: [column, Daicel ChiralcelÒ OD-H, 0.46 cm  25 cm;
hexane/2-propanol = 98:2, flow rate 0.5 mL/min, detected at
210 nm], tR (min) = 16.8 for (1R,2S)-7a, 22.5 for (1S,2R)-7a. Even
under various analytical conditions, the ee of acetate (1R,2S)-7b
could not be determined due to the broadening of peaks, which
was caused by contaminant with intense UV absorption. Under
our analytical conditions, certain extent of b-elimination was
supposed.
We then proceeded to scale-up the reduction with ‘‘Chi-
ralscreenÒ OH”-E001, and the reaction proceeded without any
decrease of stereochemical purity, giving (1R,2S)-7a in 95% yield
and with >99% ee. Thus, the developed ‘‘ChiralcsreenÒ OH”-E001
mediated reduction showed; 1) compatible stereoselectivity com-
pared to that of bakers’ yeast; 2) enhanced (95%) isolated yield;
and 3) a simple workup and isolation procedure, as shown in Sec-
tion 4.8. This result means that the synthesis of (S)-5 could be
achieved according to the same route for (R)-5.
3. Conclusion
In conclusion, we have designed and synthesized 5. The key
precursor for (R)-5, i.e. (1S,2R)-7a, was prepared in 38% yield and
with >99% ee by a lipase-catalyzed enantioselective hydrolysis of
the corresponding racemic acetate, 7b. The asymmetric reduction
of ketone 8 with ‘‘ChiralscreenÒ OH”-E001 afforded (1R,2S)-7a in
95% yield and with >99% ee. Starting from (1S,2R)-7a, isopropyl
and methyl substituents were introduced in a stepwise site-selec-
tive and stereoselective manner to give (R)-5 in 33% overall yield
over a sequence as short as eight steps. The establishment of this
To a solution of lithium diisopropylamide (LDA, 8.11 mmol) in
tetrahydrofuran (THF, 12.5 mL) was added a solution of (1S,2R)-
7a (613 mg, 3.88 mmol) at À50 °C and the reaction temperature
was raised to À10 °C. The mixture was further stirred for 1 h at
À10 °C. The reaction was cooled to À50 °C and methyl iodide
(360 mL, 5.78 mmol) was added to the solution. The mixture was
warmed to À10 °C over 1 h and the reaction was quenched with
saturated NH4Cl aq. solution. The organic materials were extracted
with EtOAc three times, and the combined extract was washed
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4
K. Kuwata et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography with hexane/EtOAc (30:1–4:1) to furnish
oil. [a]
20 = +1.9 (c 1.22, CHCl3). 1H NMR (CDCl3, 500 MHz): d 1.23
D
(3H, t, J = 7.1 Hz), 1.35 (3H, s), 1.77 (1H, ddd, J = 13.5, 8.3, 6.4 Hz),
1.84 (3H, ddd, J = 7.4, 1.9, 1.7 Hz), 2.52 (1H, ddd, J = 13.5, 8.6,
5.2 Hz), 2.56–2.70 (2H, m), 4.15 (2H, q, J = 7.1 Hz), 6.74 (1H, ddq,
J = 7.4, 2.7, 2.7 Hz); 13C NMR (CDCl3, 125 MHz): d 14.0, 15.4, 19.8,
23.7, 32.7, 56.7, 61.3, 134.1, 137.2, 172.4, 202.8; IR mmax 2978,
2935, 1738, 1713, 1650, 1446, 1374, 1261, 1220, 1175,
(1S,2R)-6 (709 mg, 85%) as a colorless oil. [
a]
D
20 = À28.5 (c 1.19,
CHCl3) {lit.11
[
a]
24 = +27.8 (c 1.27, CHCl3) for (1R,2S)-6}. 1H NMR
D
(CDCl3, 500 MHz): d 1.19 (3H, s), 1.28 (3H, t, J = 7.3 Hz), 1.54–
1.60 (1H, m), 1.64–1.74 (2H, m), 1.81–1.90 (1H, m), 1.96–2.04
(1H, m), 2.22 (1H, ddd, J = 13.2, 10.0, 7.1 Hz), 3.08 (1H, dd, J = 4.6,
1.2 Hz), 3.97–4.00 (1H, m), 4.18 (2H, q, J = 7.3 Hz); 13C NMR (CDCl3,
125 MHz): d 14.1, 20.4, 22.3, 31.9, 33.1, 54.0, 60.6, 79.9, 177.2; IR
1084 cmÀ1
;
HRMS (ESI) [M+Na]+ calculated for C11H16NaO3:
219.0997, found: 219.1018.
m
max 3445, 2965, 1712, 1264. Its 1H NMR and IR spectra were iden-
4.5. Ethyl (S)-3-isopropyl-1-methyl-2-oxocyclopentanecarbo-
xylate 11
tical with those reported previously.11
4.3. Ethyl (S)-2-methyl-2-oxocyclopentanecarboxylate 9
To a suspension of CuI (471 mg, 2.47 mmol) in Et2O (10 mL) was
added a solution of methyllithium (4.9 mL, 1.1 M in Et2O) at
À30 °C, and the resulting mixture was stirred at the same temper-
ature for 20 min. To the aforementioned solution of (CH3)2CuLi was
added a solution of (S)-10 (431 mg, 2.20 mmol) in Et2O (12 mL) at
À30 °C. After stirring for 1 h at that temperature, the reaction was
quenched with saturated NH4Cl aq. solution, and the organic mate-
rials were extracted with EtOAc three times. The combined extract
was washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography with hexane/EtOAc (40:1–20:1) to
To a solution of (1S,2R)-6 (591 mg, 3.43 mmol) in CH2Cl2
(30 mL) were added NaHCO3 (1.56 g, 18.5 mmol) and Dess-Martin
periodinane (2.19 g, 5.17 mmol) at 0 °C under an Ar atmosphere.
The mixture was stirred at room temperature for 2 h. Then the
reaction was quenched with a mixture of saturated NaHCO3 aq.
solution and saturated Na2S2O3 aq. solution. The organic materials
were extracted with EtOAc twice. The combined extract was
washed with brine, dried over Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by silica gel col-
umn chromatography with hexane/EtOAc (50:1–10:1) to furnish
furnish (S)-11 (442 mg, 95%) as a colorless oil. [a]
21 = +64.4 (c
D
(S)-9 (507 mg, 87%) as a colorless oil. [
a
]
D
21 = +13.9 (c 1.25, CHCl3).
1.18, CHCl3). 1H NMR (CDCl3, 500 MHz): d 0.82 (3H, d, J = 6.8 Hz),
1.00 (3H, d, J = 6.9 Hz), 1.22–1.25 (6H, m), 1.69 (1H, dddd,
J = 12.7, 11.3, 11.3, 7.1 Hz), 1.86 (1H, ddd, J = 12.9, 7.0, 2.6 Hz),
2.02–2.09 (1H, m), 2.17 (1H, dqq, J = 7.1, 6.9, 6.8 Hz), 2.33–2.41
(2H, m), 4.12–4.18 (2H, m); 13C NMR (CDCl3, 125 MHz): d 14.0,
18.3, 18.4, 21.0, 21.1, 27.1, 33.5, 55.5, 56.3, 61.2, 172.7, 216.1; IR
{lit.11
[
a]
D
24 = À15.9 (c 1.72, CHCl3) for (R)-9}. 1H NMR (CDCl3,
500 MHz): d 1.25 (3H, dd, J = 7.4, 7.4 Hz), 1.31 (3H, s), 1.83–1.97
(2H, m), 2.02–2.08 (1H, m), 2.28–2.35 (1H, m), 2.41–2.54 (2H,
m), 4.15 (1H, qd, J = 7.4, 3.2 Hz), 4.17 (1H, qd, J = 7.4, 3.2 Hz); 13C
NMR (CDCl3, 125 MHz): d 14.0, 19.4, 19.6, 36.2, 37.7, 55.9, 61.3,
172.4, 215.9; IR mmax 2976, 1748, 1728, 1267, 1153 cmÀ1. Its 1H
NMR and IR spectra were identical with those reported
previously.11
mmax 2960, 2873, 1747, 1728, 1466, 1372, 1266, 1172, 1152 cmÀ1
;
HRMS (ESI) [M+Na]+ calculated for C12H20NaO3: 235.1310, found:
235.1328.
4.4. Ethyl (2S,3E)-3-ethylidene-2-methyl-2-oxocyclopentane-
4.6. (R)-5-Hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-
carboxylate 10
1-yl trifluoromethylsulfonate 5
To a solution of LDA (3.42 mmol) in THF (10 mL) was added a
solution of (S)-9 (482 mg, 2.83 mmol) in THF (6 mL) at À78 °C.
After 1 h, to the reaction mixture was added acetaldehyde
To a solution of LDA (1.12 mmol) in THF (3.5 mL) was added a
solution of (S)-11 (183 mg, 0.861 mmol) at À78 °C with stirring.
After 1 h, to the mixture was added a solution of 2-[bis(trifluo-
romethylsulfonyl)amino]-5-chloropyridine (522 mg, 1.33 mmol)
in THF (2.0 mL) and the reaction mixture was gradually warmed
to room temperature over 3 h. The reaction was then quenched
with saturated NaHCO3 aq. solution. The organic materials were
extracted with EtOAc twice. The combined extract was washed
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was filtered through a pad of silica
gel with hexane/EtOAc (20:1) to give crude triflate. This was
employed for the next step without further purification.
(480
lL, 8.50 mmol) and the mixture was warmed to À30 °C over
1 h. The reaction was then quenched with saturated NH4Cl aq.
solution and the organic materials were extracted with EtOAc
three times. The combined extract was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was diluted with EtOAc and filtered through a pad of
silica gel. The combined filtrate and washings were concentrated
under reduced pressure to give a crude alcohol. This was employed
for the next reaction without further purification.
To a solution of the crude alcohol in CH2Cl2 (7 mL) were added
Et3N (530 lL, 3.82 mmol), methylsulfonyl chloride (223 lL,
To a solution of aforementioned triflate in THF (8 mL) was
added a solution of DIBAL-H in hexane (1.0 M, 1.8 mL) at À78 °C
with stirring and the reaction mixture was gradually warmed to
0 °C over 1 h. The reaction was quenched with saturated sodium/
potassium tartrate aq. solution and the organic materials were
extracted with EtOAc three times. The combined extract was
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel col-
umn chromatography with hexane/EtOAc (60:1–10:1) to furnish
2.86 mmol) and 4-(dimethylamino)pyridine (DMAP, 28 mg,
0.23 mmol). After stirring for 1 h at room temperature, the reaction
was quenched with phosphate buffer solution (pH 7.0, 0.1 M), and
the mixture was extracted with EtOAc twice. The combined extract
was washed with brine, dried over Na2SO4, filtered and concen-
trated under reduced pressure. The residue was diluted with
toluene (7 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,
343
lL, 2.28 mmol) was added to it, and the mixture was stirred
(R)-5 (204 mg, 78%) as a colorless oil. [a]
22 = +2.5 (c 1.24, CHCl3).
D
for 1 h at room temperature. The mixture was diluted with H2O
and the organic materials were extracted with EtOAc three times.
The combined extract was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography with hexane/
EtOAc (30:1–10:1) to furnish (S)-10 (315 mg, 61%) as a colorless
1H NMR (CDCl3, 500 MHz): d 1.04 (3H, d, J = 6.6 Hz), 1.05 (3H, d,
J = 6.8 Hz), 1.06 (3H, s), 1.70 (1H, ddd, J = 12.8, 9.2, 6.1 Hz), 2.20
(1H, ddd, J = 12.8, 9.0, 4.1 Hz), 2.27 (1H, ddd, J = 15.9, 9.2, 4.1 Hz),
2.38 (1H, ddd, J = 15.9, 9.0, 6.1 Hz), 2.88 (2H, qq, J = 6.8, 6.6 Hz),
3.32 (1H, d, J = 12.3 Hz), 3.59 (1H, d, J = 12.3 Hz); 13C NMR (CDCl3,
125 MHz): d 20.3, 20.5, 20.9, 24.2, 25.9, 31.6, 49.1, 67.4, 118.5
Please cite this article in press as: Kuwata, K.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.007

K. Kuwata et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
(1C, q, J = 319.6 Hz), 141.7 (2C); IR mmax 3402, 2966, 2936, 2874,
1458, 1405, 1209, 1140, 1048, 1027, 889, 849 cmÀ1
ddd, J = 10.0, 7.8, 4.1 Hz), 4.18 (2H, q, J = 7.1 Hz), 4.43 (1H, ddd,
J = 4.1, 3.9, 3.9 Hz); 13C NMR (CDCl3, 125 MHz): d 14.2, 22.0, 26.4,
33.9, 49.5, 60.6, 73.7, 175.0; IR mmax 3447, 2958, 2876, 1714,
1190 cmÀ1. Its NMR spectra were identical with those reported
previously for (1S,2R)-7a.9b
.
4.7. Examination of ‘‘ChiralscreenÒ OH” on the reduction of 8
A mixture of carbonyl reductase, formate or glucose dehydroge-
nase, oxidoreductive coenzyme such as NADH or NADPH, and buf-
fer ingredient was dissolved in each vial with purified water (1 mL)
involved in ‘‘ChiralscreenÒ OH” (E001, E007, E031, E039, E078,
E087, and E146). Ketone 8 (10 mg) was added to each vial. The
mixture was stirred at 30 °C for 24 h. After extractive workup,
the conversion and diastereomeric ratio were estimated by 1H
NMR spectra with the comparison of authentic signals (CDCl3): d
3.15 (dd, 1H, J = 9.1, 8.8 Hz, for 8), 4.43 [ddd, 1H, J = 4.1, 3.9,
3.9 Hz, for (1R⁄,2S⁄)-7a], and 4.37 [ddd, 1H, J = 6.6, 6.6, 6.6 Hz, for
(1R⁄,2R⁄)-7a]. The ratio between (1S,2R)- and (1R,2S)-isomer was
determined by HPLC analysis as described in section 4.2.
Acknowledgements
We thank Amano Enzyme Inc. for generous gift of lipase AK.
This work was supported by JSPS KAKENHI (JP 16J01810) for K.
K. and by Platform for Drug Discovery, Informatics, and Structural
Life Science (16am0101054j0005), and those supports were grate-
fully acknowledged with thanks.
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The organic materials were then extracted with EtOAc three
times. The combined extract was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure to give
(1R,2S)-7a (259 mg, 95%) as a colorless oil. [a]
22 = +15.1 (c 1.11,
D
CHCl3) {lit.9b
[a
]
D
24 = À14.1 (c 1.11, CHCl3) for (1S,2R)-7a}. Its ee
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(>99%) was confirmed by HPLC analysis as described in section
4.2. 1H NMR (CDCl3, 500 MHz): d 1.28 (3H, t, J = 7.1 Hz), 1.60–
1.68 (2H, m), 1.76–1.82 (2H, m), 1.88–2.06 (3H, m), 2.67 (1H,
Please cite this article in press as: Kuwata, K.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.007