Catalytic Hydrogenolysis of Enantioenriched Donor–Acceptor Cyclopropanes Using H2 and Palladium on Charcoal

Article abstract of DOI:10.1002/ejoc.201700345

The hydrogenolysis of enantioenriched donor–acceptor (D–A) cyclopropanes using H₂ (1 atm) and a catalytic amount of palladium on charcoal gave trans-α-alkoxycarbonyl-β-benzyl-γ-lactones or β-substituted γ-aryl-α,α-diesters with high enantiomeric excess. The reaction was also used as a key step in the asymmetric total synthesis of yatein with high ee and excellent dr. This demonstrates the utility of this new protocol for the asymmetric synthesis of trans-α,β-disubstituted γ-butyrolactones. D–A cyclopropanes containing electron-withdrawing groups at the β-position were not susceptible to hydrogenolysis under these conditions. The reductive ring-opening of a D–A cyclopropane using D₂ instead of H₂ generated the corresponding monodeuterated product.

Full text of DOI:10.1002/ejoc.201700345

A Journal of
Accepted Article
Title: Catalytic hydrogenolysis of enantioenriched donor-acceptor
cyclopropanes using H2 and Palladium on charcoal
Authors: Yoshitomo Sone, Yumi Kimura, Ryotaro Ota, Junki Ito,
Yoshinori Nishii, and Takehito Mochizuki
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700345
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700345
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10.1002/ejoc.201700345
European Journal of Organic Chemistry
FULL PAPER
Catalytic hydrogenolysis of enantioenriched donor-acceptor
cyclopropanes using H2 and Palladium on charcoal
Yoshitomo Sone, Yumi Kimura, Ryotaro Ota, Takehito Mochizuki, Junki Ito and Yoshinori Nishii*[a]
This paper is dedicated to Prof. Dennis P. Curran in celebration of his recovery and 64th birthday.
Abstract: The hydrogenolysis of enantioenriched donor-acceptor
(D-A) cyclopropanes using H2 (1 atm) and a catalytic amount of
Palladium on charcoal afforded trans-α-alkoxycarbonyl-β-benzyl
lactones or γ-aryl-β-substituted diesters with high enantiomeric
excess. The present reaction was also successfully employed as a
key step in the asymmetric total synthesis of yatein with high ee and
excellent dr, thus demonstrating the utility of this new protocol for the
asymmetric synthesis of trans-α,β-disubstituted γ-butyrolactones. D-
A cyclopropanes containing electron-withdrawing groups at the β-
position were not susceptible to hydrogenolysis under these
conditions. The reductive ring-opening of a D-A cyclopropane using
D2 instead of H2 generated the corresponding mono-deuterated
product.
the hydrogenolysis of alkyl- and acetyl-substituted D-A
cyclopropanes (eq. 4).6e To the best of our knowledge, even the
hydrogenolysis of representative D-A cyclopropanes of the type
2-arylcyclopropane-1,1-dicarboxylic diester has not yet been
reported. Herein, we report the hydrogenolysis of D–A
cyclopropanes, including enantioenriched bicyclic lactones 1 and
arylcyclopropanedicarboxylic diesters 3, using H2 (1 atm) and a
catalytic amount of Palladium on charcoal (Pd-C).
A: Acceptor, D: Donor
!
a
b
H2
(1)
OH
OH
c
Ph
D
cat. Pd(OH)2
TfOH, MeOH
D
OH
Ph OH
major
!
CN
O
O
H2
a
A
D
c
(2)
HO
CN
b
cat. Pd-C
AcOEt
O
Introduction
A
NC
!
c
NC
R
Cyclopropanes represent an important class of organic
compounds due to their synthetic utility and their widespread
occurrence in nature.1,2 In addition, the rigid conformation of
cyclopropanes as the smallest conceivable [C3] ring compound
can be exploited in stereo-controlled syntheses. Especially
H2
a
R
b
D
(3)
(4)
O
Raney-Ni
THF
N
N
R
R
!
H
c
donor–acceptor
(D–A)
cyclopropanes
have
attracted
H
O
b
O
H2 (high pressure)
cat. Pd-C
considerable attention due to recent synthetic developments.2d-
O
a
D
h,3
O
A
During our synthetic studies on the transformation of
O
O
OH
cyclopropanes,4 we have recently reported a Cu-catalyzed oxy-
homo-Michael reaction,4h and a Cu-catalyzed 1,5-addition4i of
Grignard reagents to enantioenriched donor-acceptor (D-A)
cyclopropanes. According to the Walsh model5 for
cyclopropanes, their single bonds resemble π-bonds. Although
the hydrogenolysis of several types of cyclopropanes using H2 (1
atm) in combination with heterogeneous Pd or Ni catalysts has
been studied,6 the background information for the
hydrogenolysis of cyclopropanes present in the scientific
literature is not sufficient to establish comprehensive guidelines
for the regioselectivity of the bond cleavage (Fig. 1). For
example, phenyl-substituted acceptor-less cyclopropanes were
cleaved at bond a (eq. 1).6c In the case of D-A cyclopropanes
such as arylcycanocyclopropanes, the ring-opening if the
cyclopropanes occurs at bond a, i.e., the bond between the
donor and the acceptor group (eq. 2 and 3).6d,f However, bond a
between the donor and acceptor group was not cleaved during
BnO
H
O
H
O
Fig. 1. Examples for the hydrogenolysis of cyclopropanes that contain donor
(D) and/or acceptor (A) groups.
O
O
RO2C
H2
RO2C
O
O
!
cat. Pd-C
61–97%
H
Ar
Ar
major
1a–h
2a–h
(93-98%ee)
(93-98%ee)
RO2C
CO2R
H2
RO2C
Ar
CO2R
!
cat. Pd-C
0–95%
R
Ar
3a–f
(95%ee)
R
4a–f
(95%ee)
[a]
Y. Sone, S. Takada, J. Ito, Prof. Y. Nishii
Department of Applied Chemistry, Faculty of Textile Science and
Technology
Shinshu University
Scheme 1. Hydrogenolysis of D–A cyclopropanes 1 and 3 using H2/Pd-C.
Tokida 3-25-1, Ueda, Nagano, Japan 386-8567
E-mail: nishii@shinshu-u.ac.jp
[b]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700345
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
Following our previous study,4h we initially prepared bicyclic
lactones 1. Treatment of bicyclic lactone 1a with H2 from a
balloon (1 atm) in the presence of Pd-C in THF at room
temperature resulted in reductive ring-opening and afforded
optically active trans-α,β-disubstituted lactone 2a as the major
isomer (61%), whereby the inseparable cis-α,β-disubstituted
lactone 2’a was obtained as the minor product (Table 1, entry 1).
Similar reactions in AcOEt also immediately furnished a 91:9
mixture of 2a and 2’a in good yield (entries 2 an 3), and the yield
of 2a and 2’a was slightly increased at T = 0 ˚C (entry 3). In
methanol, the yield of the mixture of 2a and 2’a was also
increased (entry 4). The scope of aryl groups on the substrates
was investigated under mild reaction conditions (AcOEt; T = 0
˚C). The hydrogenolysis of 1a–1d, which contain electron-
donating aryl groups such as alkoxyphenyl groups, afforded the
corresponding ring-opened lactones 2b–2d and 2’b–2’d in high
yield (entries 5–7).
MeO
MeO
MeO
MeO
MeO
BnO
O
O
DMP
F
BMP
MDP
OMe
TMP
O2N
MeO2C
NP
FP
MCP
Fig. 2. Abbreviations for the aryl groups in Tables 1 and 2, as well as in
Schemes 2 and 3.
The relative stereostructure of the major product 2c (trans-
isomer) was determined by a comparison of its spectra with
previously reported data.7 In a similar fashion, 2a, 2b, and 2d–
2h were also assigned as the trans-isomers after comparison of
their NMR spectra with that of 2c. It should be noted that 1e,
which contains a benzyloxy methoxy phenyl (BMP) group, was
selectively hydrolyzed at 0 ˚C in 1 h, whereby the benzyl group
of BMP remained intact, to furnish a 95:5 mixture of 2e and 2’e
in high yield (entry 8). However, when the same reaction was
carried out at room temperature for 12 h, a debenzylation of
BMP occurred together with the ring-opening, which afforded a
95:5 mixture of 2ee and 2’ee in high yield (entry 9). The
hydrogenolysis of 1f–h, which bear electron-withdrawing aryl
groups, also furnished the corresponding ring-opened lactones
2f–h and 2’f–h in good to high yields (entries 10–12). Notably,
the reductive ring-opening of 4-fluorophenyl-substituted 1f and
4-methoxycarbonylphenyl substrate 1g proceeded in very high
yield (entries 10 and 11). The hydrogenolysis of 4-nitrophenyl-
substituted 1h induced a ring-opening in 75% yield, whereby a
reduction of the nitro group was not observed (entry 12). When
the same reaction was carried out at room temperature in MeOH
for 18 h, a reduction of the nitro group occurred in addition to the
ring-opening, which afforded 4hh in high yield (entry 13).
Table 1. Catalytic hydrogenolysis of bicyclolactone 1a–h using H2/Pd-C.
O
O
O
MeO2C
+
MeO2C
H2 (1atm)
MeO2C
Ar
O
O
O
Pd-C (5 mol%)
Solvent
cis
2'a–h
trans
H
H
Ar
Ar
1a–h
2a–h
(93-98% ee)
(93-98% ee)
2/2' = 91/9-95/5
Ent-
ry
1a
Ar
Solvent
T
(˚C)
2 + 2’
Yield
(%)b
drc
2/2’
1
1a
Ph
THF
rt
rt
0
rt
0
0
0
0
rt
0
0
0
rt
2a + 2’a
61
65
78
78
93
87
94
90
80
96
97
75
94
91/9
91/9
91/9
91/9
93/7
93/7
92/8
93/7
91/9
92/8
95/5
92/8
92/8
2
AcOEt
3
4
MeOH
AcOEt
AcOEt
AcOEt
AcOEt
5
1b
1c
1d
1e
DMP
TMP
MDP
BMP
2b + 2’b
2c + 2’c
2d + 2’d
2e + 2’e
2ee + 2’eed
2f + 2’f
Subsequently, we examined the catalytic hydrogenolysis of
monocyclic D–A cyclopropanes 3 using H2/Pd-C (Table 2). The
hydrogenolysis of the simple D–A cyclopropyldicarboxylic diester
3a at 0 ˚C in AcOEt provided the corresponding acyclic product
6
7
(4a) in 95% yield after 0.5
h
(entry 1), whereas
8
cyclopropylcarboxylic monoester 3b afforded 4b in low yield
under similar conditions (entry 2). This result suggests that the
presence of two geminal carbonyl substituents accelerates the
hydrogenolysis of the cyclopropyl ring. However, prolonging the
reaction time (t = 1.5 h) increased the yield of 3b to 90%. D–A
cyclopropanes 3c and 3d, which bear electron-withdrawing
formyl or ester groups at the β-position and an electron-donating
3,4-dimethoxyphenyl group at the β’-position, were not
susceptible to ring scission and 90% of 3c and 3d were
recovered (entries 3 and 4). Therefore, the electron-withdrawing
groups at the β-position should eliminate the reactivity toward
hydrogenolysis. Especially electron-withdrawing groups at the β-
position lead to a depletion of electron density in the HOMO of
the Walsh orbitals, which contains an antibonding component at
9
10
11
12
13
1f
FP
AcOEt
AcOEt
AcOEt
MeOH
1g
1h
MCP
NP
2g + 2’g
2h + 2’h
2hh + 2’hh
[a] Enantioenriched substrates 1a–c (95% ee), 1d (93% ee), 1e–f (94% ee),
and 1h (94% ee) were used; [b] isolated yield; [c] determined by 1H-NMR
spectroscopy; [d] T = rt, t = 23 h; debenzylation of OBn afford a phenolic OH
group together with the ring-opening.
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10.1002/ejoc.201700345
European Journal of Organic Chemistry
FULL PAPER
the bond to be opened. D–A cyclopropane 3e, which contains an
electron-deficient olefin, underwent hydrogenation of the olefin
moiety prior to the ring-opening of the cyclopropane under
similar conditions (entry 5). Increasing the reaction time (t = 18
The utility of this hydrogenolysis in total synthesis was
demonstrated by the asymmetric total synthesis of yatein (5)
from lactones 2d and 2’d, which proceeded in 93% ee (Scheme
2). Specifically, the benzylation of a 93:7 mixture of 2d and 2’d
under basic conditions, followed by decarboxylation using LiCl in
DMSO at 150 ˚C, furnished (-)-yatein (5) in 65% yield (over 2
steps) with 93% ee and excellent trans-selectivity (98:2). The
spectral data of 5 were in good accordance with those reported
previously.8 We assumed that the tautomerization from the enol-
(E) to the keto-form (5) furnished the thermodynamically favored
trans-product 5 with excellent dr (Scheme 3). In the literature, a
similar decarboxylation using LiCl in DMF generated similar
lignan lactones as a 85:15 mixture of the trans- and cis-
isomers.7 Therefore, Bouyssi and Balme et. al. treated the
mixture of trans and cis isomers with DBU in CH2Cl2 to enrich
the trans-isomer (19:1).7a In our case, the decarboxylation at 150
˚C in DMSO provided the trans-product with excellent trans-
selectivity (98:2).
h) resulted in
a
ring-opening hydrogenolysis and
a
hydrogenation of the olefin moiety to afford 4’e in 85% yield
(entry 6).
Table 2. Catalytic hydrogenolysis of D-A cyclopropanes 3a–d using H2/Pd-C.
RO2C
Ar
CO2R
R
MeO2C
Ar
CO2Me
H2 (1 atm)
Pd-C (5 mol%)
R
4a–f
3a–f
Entr
y
Yield
a (%)
Substrates
Products
MeO2C
Ph
CO2Me
4a
MeO2C
CO2Me
O
H
1
2
95c
O
H
H
3a
Ph
Ar2
MeO2C
keto
Ar1 = MDP
Ar2 = TMP
O
CO2Me
O
CO2Me
13c
90d
H
Ar1
Ph
Ph
3b
4b
5
keto
2d and 2'd
Ar1
MeO2C
DMP
CO2Me
O
Thermodynamically
favored
MeO2C
CO2Me
O
0d
3
4
5
0b,d
K2CO3
DMP
3c
4c
MeO2C
DMP
CO2Me
CO2Me
MeO2C
CO2Me
CO2Me
K+
OH
O-
0d
O
DMP
3d
4d
Ar2
O
MeO
MeO2C
CO2Me
(95% ee)
MeO2C
CO2Me
(95% ee)
O
H
33c,e
CO2Et
CO2Et
enol
DMP
DMP
H
Ar1
Ar1
3e
4''e
A
D
MeO2C
DMP
CO2Me
(95% ee)
MeO2C
DMP
CO2Me
(95% ee)
Nucleophilic
attack from
less hindered side
6
85f
Ar2
Br
Protonation
CO2Et
CO2Et
3e
4'e
MeO2C
Ar2
O
OLi
[a] Isolated yield; [b] Pd(OH)2-C was used instead of Pd-C; [c] t = 0.5 h; [d] t =
1.5 h; [e] 62% of 3e was recovered; [f] t = 18 h.
Ar2
Decarboxylation
with LiCl
O
O
H
Ar1
H
Ar1
enol
B
C
Kinetically
favored
O
O
H
H
H
H
MeO2C
MeO
MeO
1) K2CO3
TMP Br
O
O
2)
LiCl, 150 ˚C
MeO
O
Scheme 3. Highly trans-selective synthetic pathway to yatein (5).
65% (2 steps)
DMSO
(93% ee)
(93% ee)
O
O
Yatein (5)
trans/cis = 98/2
2d and 2'd
trans/cis = 93/7
O
Scheme 2. Total synthesis of yatein (5c).
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10.1002/ejoc.201700345
European Journal of Organic Chemistry
FULL PAPER
O
Pd-C (12 mg, 5 mol%) was added to a solution of ester 1a (50 mg, 0.22
mmol) in AcOEt (1.1 mL) at 0 ˚C, followed by stirring at the same
temperature for 1 h under an atmosphere of H2 (1 atm, balloon). After
filtration, the filtrate was concentrated under reduced pressure, and the
thus obtained crude oil was purified by column chromatography (SiO2,
hexane/AcOEt = 2/1, v/v) to give a 91:9 mixture of 2a and 2’a (39 mg,
78%). 2a: colorless liquid; [α]26D = 34.4° (c 1.00, chloroform, l = 589 nm);
1H NMR (400 MHz, CDCl3) δ 2.79-2.89 (m, 2H), 3.35-3.25 (m, 2H), 3.69
(s, 3H), 4.01 (dd, J = 8.0, 9.1 Hz, 1H), 4.43 (dd, J = 7.0, 9.1 Hz, 1H),
7.14-7.34 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 38.2, 42.0, 52.2, 53.4,
71.8, 127.5, 129.2, 129.3, 137.3, 168.1, 172.1; IR (NaCl, neat) 2953,
1778, 1738, 1437, 1250, 1207, 1146, 1018, 702 cm-1, HRMS (APCI)
calcd for C13H14O4 (M+H)+ 233.0808 , found 233.0805 ; HPLC analysis:
95% ee [Daicel CHIRALPAK IC (25 cm) at 25 ˚C, flow rate = 1.0 mL/min,
solvent: hexane/ethanol = 2/1 (v/v), tR(racemic) = 10.2 min and 13.7 min,
tR(2a) = 9.6 min for the major and 12.9 min for the minor product].
Selected data for 2’a (minor product): 1H NMR (400 MHz, CDCl3) δ 2.63
(dd, J = 9.7, 13.9 Hz, 0.1H), 2.97 (dd, J = 6.1, 13.9 Hz, 0.1H), 3.07-3.20
(m, 0.1H), 3.61 (d, J = 8.7 Hz, 0.1H), 3.81 (s, 0.3H), 4.22-4.29 (m, 0.2H).
As the absolute configuration at the β-position does not change during
the hydrogenolysis, the ee values of 2a and 2'a were assigned on the
basis of the ee value of 1a (95% ee), which was obtained from the HPLC
analysis (see ESI).
O
O
H
H
H
MeO2C
D
MeO2C
D
D2
MeO2C
MDP
O
O
O
+
Pd-C
AcOEt
1h
H
2i
MDP
MDP
1d
85%
2'i
(93% ee)
(2i/2'i = 93/7, 93% ee)
Scheme 4. Ring-opening deuteration of bicyclic lactone 1d.
Treatment of bicyclolactone 1d with D2 in the presence of a
catalytic amount of Pd-C in AcOEt afforded deuterated lactone
2i in 85% yield (Scheme 4). The deuteration occurred only at the
benzylic position, and afforded a 93:7 mixture of 2i and 2’i, even
though trace amounts of deuteration at the α-position of the
ester were also observed.9a The hydrogen at the α-position of 2i
and 2’i might stem from H2O present in the charcoal of Pd-C
and/or the solvents.9 At this point, the reaction mechanism
remains ambiguous.
(αS,βR)-α-Methoxycarbonyl-β-(3,4-methylenedioxyphenyl)methyl-γ-
Conclusions
butyrolactone
(2d)
and
(αR,βR)-α-Methoxycarbonyl-β-(3,4-
methylenedioxyphenyl)methyl-γ-butyrolactone (2’d)
In conclusion, we established a synthetic protocol for the highly
regioselective reductive ring-opening of enantioenriched D–A
cyclopropanedicarboxylic diesters using H2 (1 atm) and a
catalytic amount of Pd-C, which afforded the ring-opened
products in high ee. The synthetic utility of the present reaction
was demonstrated by the asymmetric total synthesis of yatein
with high ee (93% ee) and excellent dr (98:2). The present
reaction can also be used as a new protocol for the asymmetric
synthesis of γ-substituted diesters and trans-α,β-disubstituted γ-
butyrolactones. In addition, a reaction of a D-A cyclopropane
with D2 in the presence of a catalytic amount of Pd-C afforded
the mono-deuterated ring-opened product. Mechanistic studies
are currently in progress in our laboratory. The results of the
present study thus provide insight into the reactivity and
regioselectivity of the reductive bond cleavage in D-A
cyclopropanes.
Following the procedure for the hydrogenolysis of 1a using AcOEt as the
solvent at 0 ˚C, the reaction of 1d (60 mg, 0.22 mmol) afforded a 92:8
mixture of 2d and 2’d (57 mg, 94%). 2d: colorless liquid; [α]26D = 8.5° (c
1.00, chloroform, l = 589 nm); 1H NMR (400 MHz, CDCl3) δ 2.68-2.82
(m, 2H), 3.23 (m, 1H), 3.32 (d, J = 8.7 Hz, 1H), 3.74 (s, 3H), 3.99 (dd, J =
9.0, 7.7 Hz, 1H), 4.42 (dd, J = 9.0, 7.2 Hz, 1H), 5.95 (s, 2H), 6.60 (dd, J =
7.9, 1.7 Hz, 1H), 6.64 (d, J = 1.7 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H); 13C
NMR (101 MHz, CDCl3) δ 37.9, 42.1, 52.1, 71.8, 101.5, 108.9, 109.4,
122.3, 131.0, 147.1, 148.4, 168.1, 172.0; IR (NaCl, neat) 2955, 2909,
1778, 1738, 1504, 1491, 1445, 1242, 1148, 1038, 1018, 928, 812 cm-1;
HRMS (APCI) calcd for C14H14O6 (M+H)+ 277.0707, found 277.0715;
HPLC analysis: 93% ee [Daicel CHIRALPAK IC (25 cm) at 25 ˚C, flow
rate = 0.8 mL/min, solvent: hexane/ethanol = 2/1 (v/v), tR(2d) = 14.4 min
for the minor and 19.9 min for major product]. Selected data for 2’d
(minor product): 1H NMR (400 MHz, CDCl3) δ 2.55 (dd, J = 9.8, 14.0 Hz,
0.09H), 2.88 (dd, J = 6.2, 14.0 Hz, 0.09H), 3.00-3.12, (m, 0.09H), 3.59 (d,
J = 8.7 Hz, 0.09H), 3.81 (s, 0.27H), 4.20-4.30 (m, 0.18H). As the absolute
configuration at the β -position does not change during the
hydrogenolysis, the ee values of 2d and 2'd were assigned on the basis
of the ee value of 1d (93% ee), which was obtained from the HPLC
analysis (see ESI).
Experimental Section
A summary of the preparative procedures, hydrolyses, asymmetric total
synthesis of yatein, and the determination of ee values is shown in
Scheme 5, and details are described in the ESI.
Total synthesis of yatein from a 92:8 mixture of 2d and 2’d.
A DMF (1 mL) solution of 2d was added to a suspension of K2CO3 in
Preparation of bicyclic D–A cyclopropanes 1a-h.
DMF (1.0 mL) at
0 ˚C. Subsequently, a DMF solution of 3,4,5-
trimethoxybenzyl bromide (394 mg, 1.5 mmol) was added at 0 ˚C, and
stirring at room temperature was continued for 3 h. Aqueous HCl (1 M,
10 mL) was added to the reaction mixture, which was then extracted with
AcOEt (ca. 5 x 10 mL). The organic phase was separated, washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The thus obtained crude oil was purified by column
chromatography (SiO2, hexane/AcOEt = 2/1, v/v) to give the product pre-
5 (422 mg, 91%). Then, LiCl (39 mg, 0.92 mmol) was added to a solution
of pre-5 (422 mg, 0.92mmol) in DMSO (0.92 mL). This mixture was
Bicyclolactones 1a-1h were prepared according to previous reports.4f,h,i
For the details of the synthesis of 1a, 1c, 1d, and 1f, as well as their
characterization, see the Supporting Information of these reports.
Typical procedure for the catalytic hydrogenolysis of 1a to afford a
91:9 mixture of 2a and 2’a.
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10.1002/ejoc.201700345
European Journal of Organic Chemistry
FULL PAPER
stirred for 1 h at 150 ˚C, before water (20 mL) was added. Then, the
mixture was extracted with AcOEt (ca. 3 x 10 mL), the organic phase was
washed with brine, dried over, Na2SO4, filtered, and concentrated under
reduced pressure. The thus obtained crude oil was purified by column
chromatography (SiO2, hexane/AcOEt = 3/2, v/v) to furnish (-)-yatein (5)
(262 mg, 72%). 5: colorless liquid; [α]21D = -24.7° (c 1.00, chloroform, l =
589 nm); 1H NMR (400 MHz, CDCl3) δ 2.43-2.66 (m, 4H), 2.85-2.97 (m,
2H), 3.83 (s, 3H), 3.83 (s, 6H), 3.85-3.91 (m, 1H), 4.18 (dd, J = 7.2, 9.1
Hz, 1H), 5.92-5.95 (m, 2H), 6.36 (s, 2H), 6.45-6.49 (m, 2H), 6.70 (d, J =
7.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 178.9, 153.7, 148.3, 146.8,
137.3, 133.8, 132.0, 121.9, 109.2, 108.7, 106.7, 101.5, 71.6, 61.3, 56.5,
46.9, 41.4, 38.7, 35.7; IR (NaCl, neat) 2938, 1778, 1771, 1591, 1504,
1489, 1456, 1346, 1128, 1038, 1011, 926, 733 cm-1; HRMS (APCI) calcd
for C22H24O7 (M+H)+ 401.1595, found 401.1593. As the absolute
configuration at the β -position does not change during the
transformations from 2d to 5d, the ee values of 5d were assigned on the
basis of the ee value of 2d (93% ee). The spectral data of 5d were in
good accordance with reported data.8
Pd-catalyzed deuteration of bicyclolactone 1d.
Following the procedure for the hydrogenolysis of 1a at 0 ˚C in AcOEt,
the reaction of 1d (20 mg, 72 µmol) under an atmosphere of D2 instead
of H2 afforded a 93:7 mixture of 2i and 2’i (17 mg, 85%). 2i: colorless
liquid; 1H NMR (400 MHz, CDCl3) δ 2.76 (d, J = 6.9 Hz, 1H), 3.17-3.27
(m, 1H), 3.32 (d, J = 8.8 Hz, 1H), 3.74 (s, 3H), 3.99 (dd, J = 7.8, 9.0 Hz,
1H), 4.42 (dd, J = 7.4, 9.0 Hz, 1H), 5.95 (s, 2H), 6.60 (dd, J = 1.7, 7.9 Hz,
1H), 6.64 (d, J = 1.7, 1H), 6.75 (d, J = 7.9 Hz, 1H); (APCI) calcd for
C14H13DO6 (M+H)+ 280.0926, found 280.0914. Selected data for 2’i
(minor product): 1H NMR (400 MHz, CDCl3) δ 2.86 (d, J = 6.2 Hz,
0.09H), 3.00-3.10, (m, 0.09H), 3.59 (d, J = 8.8 Hz, 0.09H), 3.81 (s,
0.27H), 4.20-4.30 (m, 0.18H). Mono-deuteration was observed based on
a comparison of the 1H-NMR spectra of 2d and 2i. As the absolute
configuration at the β -position does not change during the
hydrogenolysis, the ee value of 2i was tentatively assigned based on that
of 3e (93% ee).
O
O
1) NaBH4,
MeOH,
THF
Ph
Ph
OTMS
O
O
cat.
OMe
O
O
O
N
MeO
+
MeO2C
+
MeO2C
H
8
MeO2C
Ar
MeO
Ar
OMe
CHO
O
H2
Br
6
!
O
O
!
!
2,6-lutidine
CH2Cl2
2) TsOH,
CHCl3
Pd-C
CHO
7a–h
cis
2'a–h
trans
H
H
Ar
Ar
1a–h
9a–h
2a–h
Ar
2/2' = 91/9–95/5
2'a
2a (Ar = Ph) 95% ee
1a (Ar = Ph) 95% ee (known: ref. 4h)
9a (Ar = Ph) 95% ee (known: ref. 4h)
2'b
2'c
2'd
2b (Ar = DMP) 95% ee
2c (Ar = TMP) 95% ee
2d (Ar = MDP) 93% ee
1b (Ar = DMP) 95% ee (by HPLC)
1c (Ar = TMP) 95% ee (known: ref. 1f)
1d (Ar = MDP) 93% ee (known: ref. 4h)
9b (Ar = DMP) 95% ee (= 3c)
MeO
MeO
9c (Ar = TMP) 95% ee (known: ref. 1h)
9d (Ar = MDP) 93% ee (known: ref. 4h)
2'e
2'f
2e (Ar = BMP) 94% ee
2f (Ar = FP) 94% ee
2g (Ar = MCP) 98% ee
2h (Ar = NP) 94% ee
1e (Ar = BMP) 94% ee (by HPLC)
1f (Ar = FP) 94% ee (known: ref. 4h)
1g (Ar = MCP) 98% ee (by HPLC)
9e (Ar = BMP) 94% ee
DMP
9f (Ar = FP) 94% ee (known)
9g (Ar = MCP) 98% ee
MeO
MeO
2'g
2'h
1h (Ar = NP) 94% ee
(Based on the known ee value of 9h,
that of 1h was tentatively assigned.)
9h (Ar = NP) 94% ee (known: ref. 9)
OMe
TMP
As the absolute configuration at the
!-position does not change during
the hydrogenolysis, the ee values
of 2a-h and 2'a-h were tentatively
assigned on the basis of the ee
values of 1a-h.
O
O
MeO
O2N
NP
MeO2C
BnO
F
MDP
MCP
FP
BMP
1d (93% ee)
2d and 2'd
(93% ee)
9b (= 3c) (95% ee)
HWE reaction
D2
MeO2C
Ph
CO2Me
Pd-C
1) Oxidation
2) Methylation
1) K2CO3
Br
3a
O
TMP
O
MeO2C
MeO2C
D
LiCl,
150 ˚C
O
O
2)
O
O
H2
+
O
Pd-C
O
D
MeO
DMP
OMe
CO2Me
MeO
DMP
OMe
cis
trans
H
H
2i
O
MDP
MDP
2'i
H
MeO2C
Ph
CO2Me
(93% ee) 2i/2'i = 93/7
TMP
3d
CO2Et
O
3e (95% ee)
4a
Mono-deuteration was observed
based on a comparison of 1H-NMR
spectrum of 2d with that of 2i.
H
MDP
CO2Me
H2
H2
Yatein (5c)
(93% ee)
Pd-C
Ph
3b
The spectral data of 5c are consistent
with previously reported one.
H2
Pd-C
CO2Me
4b
MeO2C
DMP
CO2Me
MeO2C
DMP
CO2Me
CO2Et
4''e (95% ee)
CO2Et
4'e (95% ee)
Ph
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10.1002/ejoc.201700345
European Journal of Organic Chemistry
FULL PAPER
Scheme 5. Summary of the experimental work of this study including typical procedures (for details, see ESI).
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Daniliuc, A. Studer, Org. Lett. 2016, 18, 5576; t) J. Sabbatani, N.
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Acknowledgements
This research was partially supported by the Grants-in-Aid for
Scientific Research on Basic Areas (A) “15H01789”, (B)
“26288089”, and (C) “15K05420” from the Japan Society for the
Promotion of Science (JSPS).
Keywords: hydrogenolysis • deuteration • donor-acceptor
cyclopropane • cyclopropane ring opening • enantiomeric excess
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10.1002/ejoc.201700345
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
The hydrogenolysis of
Key Topic* Hydrogenolysis of
cyclopropanes, Asymmetric
synthesis
O
enantioenriched donor-acceptor (D-A)
cyclopropanes 1 or 3 using 1 atm of
H2 and a catalytic amount of
Palladium on charcoal afforded trans-
α-alkoxycarbonyl-β-benzyl lactones 2
or γ-aryl-β-substituted-α,α-diesters 4
O
RO2C
H2
RO2C
O
O
!
Yoshitomo Sone, Yumi Kimura, Ryotaro
Ota, Takehito Mochizuki, Junki Ito and
Yoshinori Nishii*
Pd-C
61–97%
H
Ar
Ar
major
1a–h
2a–h
(93-98% ee)
(93-98% ee)
with high enantiomeric excess. This
reaction was also successfully
employed as a key step in the
Page No. – Page No.
H2
RO2C
CO2R
R
RO2C
Ar
CO2R
!
Pd-C
0–95%
Catalytic hydrogenolysis of
enantioenriched donor-acceptor
cyclopropanes using H2 and
Palladium on charcoal
Ar
R
asymmetric total synthesis of yatein.
3a–f
(95% ee)
4a–f
(95% ee)
*one or two words that highlight the emphasis of the paper or the field of the study
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