Four-Step One-Pot Catalytic Asymmetric Synthesis of Polysubstituted Tricyclic Compounds: Lipase-Catalyzed Dynamic Kinetic Resolution Followed by an Intramolecular Diels-Alder Reaction

Article abstract of DOI:10.1055/a-1344-8713

Starting from readily available tertiary alcohols, four different reactions (a 1,3-migration of a hydroxy group, kinetic resolution, racemization, and an intramolecular Diels-Alder reaction) took place under co-catalysis by lipase and oxovanadium compounds in a one-pot process to produce polysubstituted tricyclic carbon frameworks in high yields and with high enantioselectivities. The key to the success of this process was the discovery that a silyl group attached to the terminal carbon of the vinyl moiety completely controls the direction of hydroxy group migration.

Full text of DOI:10.1055/a-1344-8713

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 822–828
letter
822
en
I. Tsuchimochi et al.
Letter
Synlett
Four-Step One-Pot Catalytic Asymmetric Synthesis of Polysubsti-
tuted Tricyclic Compounds: Lipase-Catalyzed Dynamic Kinetic
Resolution Followed by an Intramolecular Diels–Alder Reaction
Izuru Tsuchimochia,b
Shuhei Horia
lipase
O
X-O
O
O
&
H
R3
SiR2
oxovanadium
R3
Yasuo Takeuchib
Masahiro Egic
Tomo-o Satohd
Kyohei Kanomataa
Takashi Ikawaa
Shuji Akai*a
SiR2
3
3
OH
R1 R1
R1 R1
7 examples
up to 72% yield
up to 99% ee
racemate
1,3-migration
kinetic resolution
racemization
cyclization
One Pot
a Graduate School of Pharmaceutical Sciences, Osaka University,1-6, Yamada-
oka, Suita, Osaka 565-0871, Japan
akai@phs.osaka-u.ac.jp
b Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry,
and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka,
Kita-ku, Okayama 700-8530, Japan
c Graduate Division of Nutritional and Environmental Sciences, University of
Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
d School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suru-
ga-ku, Shizuoka 422-8526, Japan
Corresponding Author
Received: 07.12.2020
Accepted after revision: 04.01.2021
Published online: 04.01.2021
Chemoenzymatic dynamic kinetic resolution (DKR) is a
successful example of a multistep, multicatalysis, one-pot
asymmetric synthesis, in which enzymes such as lipases
conduct the kinetic resolution (KR) of racemic substrates,
while racemization catalysts generate a rapid equilibrium
between two enantiomers.2 A high compatibility between
these two different catalysts permits the efficient transfor-
mation of racemic secondary alcohols or amines into opti-
cally pure compounds in up to quantitative yields with
minimal material losses. Thus, transition-metal catalysts,
such as those based on Ru,3 Rh,4 Pd,5 and Fe,6 have been
found to catalyze racemization through a redox process,
and have been widely combined with lipases in DKR pro-
cesses. At the same time, we have independently developed
the DKR of allylic alcohols by combining oxovanadium com-
pounds with lipases.7 In particular, oxovanadium com-
pounds, unlike the aforementioned redox racemization cat-
alysts, catalyze both the racemization and the 1,3-migra-
tion of an allylic hydroxy group. These vanadium catalysts
generate a dynamic equilibrium between the two regioiso-
mers (±)-I and (±)-II (Scheme 1a) while lipase catalyzes the
chemo- and enantioselective esterification of (R)-I to
achieve the DKR.
DOI: 10.1055/a-1344-8713; Art ID: st-2020-u0622-l
Abstract Starting from readily available tertiary alcohols, four differ-
ent reactions (a 1,3-migration of a hydroxy group, kinetic resolution, ra-
cemization, and an intramolecular Diels–Alder reaction) took place un-
der co-catalysis by lipase and oxovanadium compounds in a one-pot
process to produce polysubstituted tricyclic carbon frameworks in high
yields and with high enantioselectivities. The key to the success of this
process was the discovery that a silyl group attached to the terminal
carbon of the vinyl moiety completely controls the direction of hydroxy
group migration
Key words allylic alcohols, asymmetric synthesis, Diels–Alder reac-
tion, dynamic kinetic resolution, lipase, one-pot reaction
Multistep one-pot processes represent a smart synthet-
ic concept that increases the overall efficiency of a prepara-
tion by decreasing the number of isolation and purification
steps in addition to allowing a reduction in the quantities of
organic solvents and reagents required for each step.1 Catal-
ysis plays a central role in realizing such one-pot processes,
because catalytic transformations can avoid the generation
of stoichiometric byproducts. Therefore, the combined use
of multiple catalysts, each of which conducts a different re-
action, in a single flask should further improve the overall
efficiency of a transformation. However, such multistep
multicatalyst one-pot syntheses tend to involve more-chal-
lenging criteria in relation to catalyst and reaction design.
In these DKR processes, the acyl groups introduced into
the alcoholic substrates are generally removed or replaced
by other substituents in subsequent transformations,8 and
only a few examples involving the use of these installed acyl
moieties have been reported.7e,f,9 Domino or one-pot se-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 822–828
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

823
I. Tsuchimochi et al.
Letter
Synlett
action followed by an IMDA reaction.11 In addition, Aso and
co-workers obtained an optically active alcohol 2 through a
lipase-catalyzed KR of (±)-2, and they synthesized optically
active 4 by using similar esterification and IMDA reac-
tions.12 These polycyclic compounds 4 are pivotal synthetic
intermediates for the enantioselective syntheses of such
bioactive molecules as forskolin and mevastatin. However,
the methods discussed above all employ relatively unstable
conjugated dienols 2 as key intermediates.
(a)
R2
OH
R3
R2
OCOR4
R3
OH
or
R2
R3
R1
R1
R1
( )-II
(R)-III
(
)-I
O=VX3
lipase
kinetic
resolution
lipase
acyl donor
acyl donor
R2
OH
R3
R2
X2
V
O=VX3
R3
HO
R1
R1
O
O
(R)-I
R2
R1
We report a challenging one-pot DKR/IMDA that uses a
combination of lipase and oxovanadium catalysts, and in
which more stable tertiary alcohols (±)-6 are used as syn-
thetic equivalents of (±)-2 to produce products 4 in their
optically active form through four different reactions: a 1,3-
hydroxy migration from (±)-6 to give (±)-2, the enantiose-
lective esterification of (±)-2, the racemization of 2, and the
IMDA reaction of optically active 3 (Scheme 1c). This strate-
gy is expected to be beneficial due to the ready availability
of (±)-6 through the 1,2-addition of a vinyl anion to enones
5, some of which are commercially available, and also be-
cause it addresses the issue of instability of alcohols 2.13
To check the feasibility of this concept, we studied the
1,3-migration of (±)-6a [obtained from cyclohex-2-en-1-
one (5a)] by using our original racemization catalyst V-
MPS4, in which oxovanadium species are covalently bound
to the inner surface of mesoporous silica (MPS) with a pore
size of 4 nm.7c,d However, trials with V-MPS4 (1 mol%) in
several solvents14 gave the desired dienol (±)-2a in relative-
ly low yields of 32–48%, together with a mixture of the E-
and Z-isomers of primary alcohol 8a (≤8% yield) (Table 1,
entries 1–3). A more serious problem was that the total
yields of these three regioisomers (2a, 6a, and 8a) were low
(≤68%), indicating significant decomposition of the alcohols
occurred under the migration conditions. We therefore ex-
amined the same reaction by using a less reactive oxovana-
dium compound, O=V(OSiPh3)37a (10 mol%) and, fortunately,
obtained 2a in higher yields in acetone (63%) or dichloro-
methane (68%) (entries 4 and 6). In particular, dichloro-
methane was found to be the most suitable solvent, with no
loss of the alcohols being observed; however, the yield of 8a
also increased.
(R)-II
R3
R2
OH
R3
A
R2
R1
HO
R1
racemization &
1,3-migration
R3
(S)-I
(S)-II
(b)
Z
Z
Z
X
O
*
O
R2
R2
*
Y
R2
*
*
*
intramolecular
Diels–Alder
esterification
R1
1 X = O
R1
R1
(IMDA) reaction
optically
active 4
optically
active 3
reduction
2 X = OH, H
(c) Concept of this work
O
R2
Y
O
7
(S)-2
lipase
O=VX3
M
O
O=VX3
(R)-2
6
R1
R1
OH
racemization &
1,3-migration
5
(
)-6
7
enantioselective
esterification
lipase
One-Pot
IMDA
optically
active 4
optically active
3
Scheme 1 (a) Lipase/oxovanadium co-catalyzed DKR of racemic allyl
alcohols (I and II). (b) Approaches for constructing optically active poly-
substituted tricyclic compounds 4. (c) Lipase/oxovanadium co-cata-
lyzed one-pot DKR/IMDA of tert-alcohols (±)-6 for constructing optically
active 4.
With these results in hand, we conducted preliminary
trials of the one-pot DKR/IMDA of (±)-6a in dichlorometh-
ane. A mixture of (±)-6a, functionalized acyl donor 7A, the
commercially available immobilized lipase Candida antarc-
tica lipase B (CAL-B), O=V(OSiPh3)3, and 4Å molecular sieves
(MS 4Å)15 was stirred in dichloromethane at 35 °C for two
days to give the tricyclic product 4aA (92% ee) as a single
diastereomer, albeit in a low yield of 34%. The main reason
for this low yield was the formation of a mixture of (E)- and
(Z)-9a in a 36% combined yield, derived from the undesired
migration product 8a (Scheme 2).
quential reactions that utilize the acyl moiety for construc-
tion of a carbon framework can amplify the synthetic effi-
ciency of the DKR. On this basis, we applied the aforemen-
tioned lipase/Ru co-catalyzed DKR of (±)-2 with acylating
reagents each bearing a dienophile moiety. More specifical-
ly, the DKR of (±)-2 provided optically active esters 3, which
underwent an intramolecular Diels–Alder (IMDA) reaction
to form optically active tricyclic molecules 4 (Scheme 1b).10
In these reactions, ketones 1 (~10% yield) were obtained as
byproducts of the in situ racemization. In their related
work, Corey et al. prepared optically active allylic alcohols 2
by enantioselective reduction of dienones 1, and they syn-
thesized similar compounds 4 through an esterification re-
To improve the yield of 4aA, we considered using the
tertiary allyl alcohol (±)-6b, bearing a silyl group at the
alkene terminal and we expected that the catalytic equilib-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 822–828

824
I. Tsuchimochi et al.
Letter
Synlett
Table 1 Oxovanadium-Catalyzed Isomerization of 6a
OH
oxovanadium
compound
solvent (0.1 M)
35 °C
OH
OH
( )-6a
( )-2a
8a
Entry
Oxovanadium compound (mol%)
Solvent
Time (min)
Yielda (%)
2a
8a
6a
1
2
3
4
5
6
V-MPS4 (1)
acetone
MeCN
40
40
40
30
30
30
32
48
39
63
18
68
3
8
4
33
V-MPS4 (1)
10
V-MPS4 (1)
CH2Cl2
acetone
MeCN
trace
trace
trace
8
O=V(OSiPh3)3 (10)
O=V(OSiPh3)3 (10)
O=V(OSiPh3)3 (10)
16
4
CH2Cl2
24
a Determined by gas-chromatographic analysis of the crude product.
rium between 6b, 2b, and 8b would be pushed in the direc-
tion of 2b due to the steric and electronic effects of the silyl
group. In fact, computational studies suggested that the rel-
ative stability of 2 compared with that of 8 should increase
upon the introduction of a silyl group [see the Supporting
Information (SI) for further details]. We also expected that
2b, which presents the lowest steric hindrance, would react
exclusively with lipase so that an equilibrium between 2b
and 8b would favor the formation of 2b, thereby leading to
the complete transformation of all alcohols into a single
product. As expected, the reaction of (±)-6b [prepared from
5a and 2-(trimethylsilyl)vinyllithium] in the presence of
O=V(OSiPh3)3 (10 mol%) in dichloromethane afforded (±)-2b
in >90% yield (Scheme 3).13 Similar good results were ob-
tained in acetone and acetonitrile (Scheme 3).
Subsequently, the CAL-B-catalyzed KR of (±)-2b was ex-
amined by using 7A at 35 °C in dichloromethane. Even with
its bulky trimethylsilyl group, (±)-2b underwent enantiose-
lective esterification to form a mixture of ester (R)-3bA, cy-
clic product 4bA, and (S)-2b, with almost 50% conversion
after two hours. To achieve complete conversion of 3bA into
4bA, toluene was added to the reaction solution, and the
mixture was stirred at 80 °C for further two hours. The
crude product mixture was found to contain only 4bA and
(S)-2b, both of which were optically pure. Thus, the KR pro-
ceeded with an extremely high enantioselectivity (E value16
>200) (Table 2, entry 1). Similarly, the KR was carried out by
using the same conditions and procedure in acetone, aceto-
nitrile, and 1,2-dichloroethane, and gave excellent enantio-
selectivities (entries 2–4) (see the SI for additional results).
O
CO2Et
7A (2 equiv)
EtO
O
C. antarctica lipase B (0.6 g/mmol)
O=V(OSiPh3)3 (10 mol%)
OH
MS 4Å, CH2Cl2, 35 °C, 2 d
(
)-6a
O
O
OH
O
O
H
CO2Et
CO2Et
7A, lipase
7A, lipase
(
)-2a
4aA
34%, 92% ee
3a
OV(OSiPh3)3
(
)-6a
single diastereomer
O
CO2Et
O
OH
8a
9a, 36%, dr = 4:3
Scheme 2 Lipase/oxovanadium co-catalyzed one-pot DKR/IMDA of (±)-6a.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 822–828

825
I. Tsuchimochi et al.
Letter
Synlett
Overall, our results indicated that silylated alcohol 6b can
serve as an alternative substrate for the one-pot DKR/IMDA
process.
complete the DKR, while the IMDA proceeded in parallel to
give 4bA. Optimization of the conditions was carried out by
varying the quantities of 7A, CAL-B, and V-MPS4, as well as
the concentration of 6b, the reaction temperature, the sol-
vent, and the reaction time (see the SI for further details).
One of the best procedures was as follows. (±)-6b was ini-
tially treated with 7A (2 equiv), CAL-B (0.6 g/mmol), and
O=V(OSiPh3)3 (10 mol%) in dichloromethane (0.05 M of 6b)
at 35 °C for two hours, then V-MPS4 (2 mol%) was added
and the resulting mixture was stirred at 35 °C for two days
to obtain 4bA as a single diastereomer (93% ee) in a 72% iso-
lated yield (Method I) (Scheme 4).17 This method was then
applied to (±)-6c bearing a tert-butyl(dimethyl)silyl group
to afford 4cA (98% ee) in 70% yield. Another acyl donor 7B,
bearing a sulfonyl group was also suitable for this one-pot
DKR/IMDA, giving 4bB and 4cB. In these cases, esterifica-
tion with 7B proceeded more slowly than the correspond-
A racemization study of the optically active secondary
alcohol 2b provided further insights into its DKR. The reac-
tion of (S)-2b (99% ee) with O=V(OSiPh3)3 (10 mol%) in ei-
ther dichloromethane or acetone at 35 °C for six hours
caused neither racemization nor decomposition (Table 3,
entries 1 and 2). In contrast, the racemization proceeded in
dichloromethane in the presence of only 0.2 mol% V-MPS4,
with no decomposition of 2b being observed (entry 3). Sim-
ilarly, racemization proceeded in 1,2-dichloroethane (DCE)
(entry 6), but was unsuccessful in both acetone and aceto-
nitrile (entries 5 and 6). Therefore, the use of V-MPS4 in ei-
ther dichloromethane or DCE was considered suitable for
the DKR, whereas that of O=V(OSiPh3)3 was suitable for the
migration of 6b to yield 2b.
After these studies, the one-pot DKR/IMDA was investi-
gated by treatment of (±)-6b with 7A in the presence of
CAL-B, O=V(OSiPh3)3, and MS4Å in dichloromethane, fol-
lowed by the addition of V-MPS4. Under these conditions,
the migration and enantioselective esterification proceeded
to give (R)-3bA and (S)-2b, whereas the subsequent addi-
tion of V-MPS4 promoted the racemization of (S)-2b to
Table 3 Oxovanadium-Catalyzed Racemization of Optically Pure (S)-2b
OH
OH
oxovanadium
compound
solvent
SiMe3
SiMe3
35 °C, 6 h
(S)-2b, 99% ee
2b
Entry Oxovanadium
compound (mol%)
Solvent
2b
Table 2 CAL-B-Catalyzed Kinetic Resolution of (±)-2b followed by IMDA
Yielda (%)
eeb (%)
Entry
Solvent
Conversiona (%) ee (%)
E value16
1
2
3
4
5
6
O=V(OSiPh3)3 (10)
O=V(OSiPh3)3 (10)
V-MPS4 (0.2)
CH2Cl2
acetone
CH2Cl2
acetone
MeCN
DCE
100
84
95
80
84
70
97
99
37
99
99
49
4bb
(S)-2bc
1
2
3
4
CH2Cl2
acetone
MeCN
DCE
50
50
51
50
98
99
97
96
99
99
99
94
>200
>200
>200
175
V-MPS4 (0.2)
V-MPS4 (0.2)
V-MPS4 (0.2)
a Calculated16 based on the optical purities of 4bA and (S)-2b.
a Determined by HPLC analysis of the crude product.
b Determined by HPLC analysis on a chiral column (CHIRALCEL OD-3).
b Determined by HPLC analysis on a Daicel CHIRALPAK AD-3 column.
c Determined by HPLC analysis on a Daicel CHIRALCEL OD-3 column.
O=V(OSiPh3)3
(10 mol%)
Li
SiMe3
SiMe3
O
solvent (0.1 M)
35 °C, 4 h
OH
(
)-6b
5a
O
CO2Et
O
7A
(2.0 equiv)
EtO
O
O
OH
H
CO2Et
SiMe3
CAL-B (0.6 g/mmol)
+ (S)-2b
solvent
35 °C, 2 h
toluene
80 °C, 2 h
SiMe3
4bA
(
)-2b
see Table 2
85% yield (in acetone)
91% yield (in CH2Cl2)
81% yield (in MeCN)
O
O
OH
CO2Et
SiMe3
SiMe3
(R)-3bA
(
)-8b
Scheme 3 Oxovanadium-catalyzed isomerization of (±)-6b into (±)-2b and CAL-B-catalyzed kinetic resolution followed by IMDA.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 822–828

826
I. Tsuchimochi et al.
Letter
Synlett
ing reaction with 7A, and higher yields of the products, 4bB
(70% yield, 99% ee) and 4cB (60% yield, 99% ee), were ob-
tained by a stepwise addition of V-MPS4 (Method II) (see
the SI for details). Moreover, 6d, which contains two methyl
groups, gave optically pure 4dA (99% ee) in 44% yield. In ad-
dition, 6e, bearing a seven-membered ring, could also be
used in this reaction, giving 4eA (96% ee) in 51% yield. In
contrast, 6f, which contains a five-membered ring, provid-
ed two diastereomers, 4fA and 4fA′, with an optical purity
of 38% ee and a total yield of 78% (for determination of the
stereochemistry of all products, see the SI).13 Further opti-
mization is therefore required to improve the yields, optical
purities, and diastereoselectivities of 4dA, 4eA, and 4fA.
In summary, we have developed a one-pot synthesis of
optically active (or, in some cases, optically pure) polysub-
stituted tricyclic skeletons in good-to-high overall yields
from readily available tertiary alcohols. This one-pot trans-
formation involves four different steps: an oxovanadium-
catalyzed 1,3-migration of the hydroxy group, a racemiza-
tion, a lipase-catalyzed enantioselective esterification, and
an intramolecular Diels–Alder reaction. It was successfully
achieved by using a combination of lipase and an oxovana-
dium compound in a single environment. Another key to
the success of this process was the discovery of the effect of
the silyl group, which completely controls the direction of
hydroxy group migration. Because these tertiary alcohols
are readily available from cyclic enones, this work provides
a proof-of-concept for a two-step enantioselective assem-
bly of enones, vinyl anions, and acyl donors, and features
excellent pot (or step), atom, and redox economies for the
asymmetric synthesis of highly functionalized polycyclic
carbon skeletons that could serve as useful synthetic inter-
mediates for biologically important compounds such as me-
vastatin and forskolin. Studies into further transformations
of the products by using available functional groups, such
as the allylsilane moiety, to synthesize these molecules are
now underway in our laboratory, and the results will be re-
ported in due course. Because of the inherent enantioselec-
Method I
O
EWG
7 (2 equiv)
1)
RO
CAL-B (0.6 g/mmol)
O=V(OSiPh3)3 (10 mol%)
MS 4Å, CH2Cl2, 35 °C
O
O
H
EWG
2) V-MPS4 (2.0 mol%), 35 °C
( )n
(
SiR2
3
R1
Method II
SiR2
OH
( )n
3
R1
O
EWG
7 (3 equiv)
1)
)-6
4
RO
CAL-B (0.8 g/mmol)
O=V(OSiPh3)3 (10 mol%)
MS 4Å, CH2Cl2, 35 °C
2) V-MPS4 (0.7 mol%), 35 °C
O
O
CO2Et
7A
EtO
O
SiMe2(tBu)
OH
SiMe3
( )n
SiMe3
OH
OH
SO2Ph
6d
6c
6b: n = 1
6e: n = 2
6f: n = 0
F3CCH2O
7B
O
O
O
O
O
O
O
O
H
H
H
H
CO2Et
SO2Ph
SiMe3
SO2Ph
CO2Et
SiMe3
SiMe2(tBu)
SiMe2(tBu)
4bA
4cA
4bB
4cB
Method I
72% yield
93% ee
Method I
Method II
70% yield
99% ee
Method II
60% yield
99% ee
70% yield
98% ee
dr = >99:1
dr = >99:1
dr = >99:1
dr = >99:1
O
O
O
O
O
O
O
O
H
H
H
CO2Et
SiMe3
H
CO2Et
CO2Et
CO2Et
SiMe3
SiMe3
SiMe3
4fA
4fA'
4dA
4eA
Method II
44% yield
99% ee
dr = >99:1
Method II
51% yield
96% ee
dr = >99:1
Method I
78% yield
38% ee
dr = 2:1
Scheme 4 Lipase/oxovanadium co-catalyzed one-pot DKR/IMDA of (±)-6.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 822–828

827
I. Tsuchimochi et al.
Letter
Synlett
tivities of natural lipases, the stereochemistries of the prod-
ucts obtained in this study were antipodes of mevastatin
and forskolin. We are therefore also investigating the ma-
nipulation of natural lipases to create mutants for the pro-
duction of enantiomers of the resulting products.18,19
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Chem. Int. Ed. 2013, 52, 3654. (d) Sugiyama, K.; Oki, Y.;
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nol. 2014, 6, 5023. (e) Kawanishi, S.; Sugiyama, K.; Oki, Y.;
Ikawa, T.; Akai, S. Green Chem. 2017, 19, 411. (f) Sugiyama, K.;
Kawanishi, S.; Oki, Y.; Kamiya, M.; Hanada, R.; Egi, M.; Akai, S.
Bioorg. Med. Chem. 2018, 26, 1378. (g) Kawanishi, S.; Oki, S.;
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H.; Akai, S. Eur. J. Org. Chem. 2020, 1961. (i) Kühn, F.; Katsuragi,
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56, 2885.
(8) For an example, see: Warner, M. C.; Shevchenko, G. A.; Jouda, S.;
Bogár, K.; Bäckvall, J. E. Chem. Eur. J. 2013, 19, 13859.
(9) Koszelewski, D.; Borys, F.; Brodzka, A.; Ostaszewski, R. Eur. J.
Org. Chem. 2019, 2019, 1653.
(10) Akai, S.; Tanimoto, K.; Kita, Y. Angew. Chem. Int. Ed. 2004, 43,
1407.
(11) (a) Corey, E. J.; Da Silva Jardine, P.; Mohri, T. Tetrahedron Lett.
1988, 29, 6409. (b) Corey, E. J.; Da Silva Jardine, P.; Rohloff, J. C.
J. Am. Chem. Soc. 1988, 110, 3672. (c) Corey, E. J.; Da Silva Jar-
dine, P. Tetrahedron Lett. 1989, 30, 7297.
(12) Yamada, S.; Nagashima, S.; Takaoka, Y.; Torihara, S.; Tanaka, M.;
Suemune, H.; Aso, M. J. Chem. Soc., Perkin Trans. 1 1998, 1269.
(13) The conjugated dienol 2a is prone to decompose even when
stored under argon atmosphere in a refrigerator, whereas the
unconjugated alcohol 6a is stable and no decomposition was
observed during storage in a refrigerator for more than six
months. Similarly, the silylated dienols 2b and 2c decomposed
in a refrigerator, whereas the unconjugated alcohols 6b–f were
all stable.
Funding Information
This work was financially supported by the JSPS KAKENHI
[18HO4411 (Middle Molecular Strategy) and 18H02556] and the Plat-
form Project for Supporting Drug Discovery and Life Science Research
[Basis for Supporting Innovative Drug Discovery and Life Science Re-
search (BINDS)] from AMED under grant number JP20am0101084.
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Acknowledgment
We thank Taiyo Kagaku Co. Ltd., for providing mesoporous silica.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1344-8713.
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References and Notes
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(14) Because the lipase-catalyzed KR of (±)-2a proceeded with high
enantioselectivity in acetone, CH2Cl2, and acetonitrile in our
previous study,10 these solvents were chosen for a preliminary
study of the migration to find suitable conditions for the DKR.
(15) Although the results of KR of (±)-2a in CH2Cl2 fluctuated, we
found that the addition of MS4Å under the KR conditions dra-
matically improved their reproducibility. We are now investi-
gating the effect of MS4Å.
(16) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc.
1982, 104, 7294.
(17) Ethyl (2aS,3R,4S,8aR,8bS)-2-Oxo-4-(trimethylsilyl)-2a,3,4,6,7,
8,8a,8b-octahydro-2H-naphtho[1,8-bc]furan-3-carboxylate
(4bA); Typical Procedure (Method I in Scheme 4)
To a solution of (±)-6b (20 mg, 0.10 mmol) in CH2Cl2 (2.0 mL) at
rt were added 7A (43 mg, 0.20 mmol), MS4Å (40 mg), immobi-
lized CAL-B (60 mg) and O=V(OSiPh3)3 (8.9 mg, 0.010 mmol).
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 822–828

828
I. Tsuchimochi et al.
Letter
Synlett
The mixture was stirred at 35 °C for 2 h, and then V-MPS4 (10
mg, 0.0020 mmol) was added at the same temperature. The
mixture was stirred at 35 °C for 2 d then filtered through a
Celite pad, that was washed with Et2O. The combined filtrates
were concentrated under reduced pressure, and the residue was
(18) For some examples of the creation of (S)-selective mutants, see:
(a) Engström, K.; Vallin, M.; Syrén, P.-O.; Hult, K.; Bäckvall, J. E.
Org. Biomol. Chem. 2011, 9, 81. (b) Xia, B.; Xu, J.; Xiang, Z.; Cen,
Y.; Hu, Y.; Lin, X.; Wu, Q. ACS Catal. 2017, 7, 4542. (c) Zhang, Y.;
Zhu, Q.; Fei, Z.; Lin, X.; Xia, B.; Wu, Q. Eur. Polym. J. 2019, 119, 52.
(d) Cen, Y.; Li, D.; Xu, J.; Wu, Q.; Wu, Q.; Lin, X. Adv. Synth. Catal.
2019, 361, 126. (e) Xu, J.; Cen, Y.; Singh, W.; Fan, J.; Wu, L.; Lin,
X.; Zhou, J.; Huang, M.; Reetz, M. T.; Wu, Q. J. Am. Chem. Soc.
2019, 141, 7934.
(19) For esterases for enantioselective esterification of (S)-alcohols,
see: (a) Kim, M.-J.; Chung, Y. I.; Choi, Y. K.; Lee, H. K.; Kim, D.;
Park, J. J. Am. Chem. Soc. 2003, 125, 11494. (b) Borén, L.; Martín-
Matute, B.; Xu, Y.; Córdova, A.; Bäckvall, J. E. Chem. Eur. J. 2005,
12, 225. (c) Koul, S.; Koul, J. L.; Singh, B.; Kapoor, M.; Parshad, R.;
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2005, 16, 2575.
purified by column chromatography [silica gel, EtOAc–hexane
22
(1:10)] to give a colorless oil; yield: 24 mg (72%, 93% ee); []D
45.5 (c 1.0, CHCl3).
=
IR (neat): 1730, 1786 cm–1. 1H NMR (500 MHz, CDCl3):  = 5.32–
5.30 (m, 1 H), 4.65 (ddd, J = 4.5, 8.5, 13.0 Hz, 1 H), 4.22–4.10 (m,
2 H), 3.21–3.17 (m, 1 H), 3.12 (dd, J = 1.0, 4.0 Hz, 1 H), 2.31–2.23
(m, 3 H), 2.15 (d, J = 1.0 Hz, 1 H), 1.97–1.93 (m, 1 H), 1.91–1.89
(m, 1 H), 1.70–1.61 (m, 1 H), 1.43–1.33 (m, 1 H), 1.25 (t, J = 7.0
Hz, 3 H), 0.09 (s, 9 H). 13C NMR (125 MHz, CDCl3):  = 174.6,
173.5, 137.0, 121.1, 77.9, 61.3, 42.6, 37.4, 36.6, 30.6, 26.2, 24.3,
19.4, 14.2, –2.9. HRMS (EI): m/z [M+] calcd for C17H26O4Si:
322.1600; found: 322.1599
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 822–828