Desymmetrization of meso-methylenecyclopropanes by a palladium-catalyzed asymmetric ring-opening bis(alkoxycarbonylation) reaction

Article abstract of DOI:10.1016/j.tetasy.2014.05.007

Desymmetrization of various meso-methylenecyclopropanes was accomplished by a palladium-catalyzed asymmetric ring-opening bis(alkoxycarbonylation) reaction employing a chiral bioxazoline ligand. The reaction proceeded smoothly in the presence of copper(I) triflate under carbon monoxide and oxygen at ambient pressure to give the corresponding optically active α-methyleneglutarates with up to 60% ee. Desymmetrization of protected meso-(3-methylenecyclopropane- 1,2-diyl)dimethanols was also carried out to give enantioenriched highly oxygen-functionalized α-methyleneglutarates.

Full text of DOI:10.1016/j.tetasy.2014.05.007

Tetrahedron: Asymmetry 25 (2014) 936–943
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Desymmetrization of meso-methylenecyclopropanes
by a palladium-catalyzed asymmetric ring-opening
bis(alkoxycarbonylation) reaction
⇑
Yasushi Yonezawa, Tomoki Furuya, Takahiro Aratani, Shuhei Fijinami, Katsuhiko Inomata, Yutaka Ukaji
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Desymmetrization of various meso-methylenecyclopropanes was accomplished by a palladium-catalyzed
asymmetric ring-opening bis(alkoxycarbonylation) reaction employing a chiral bioxazoline ligand. The
reaction proceeded smoothly in the presence of copper(I) triflate under carbon monoxide and oxygen
Received 5 March 2014
Accepted 14 May 2014
Available online 23 June 2014
at ambient pressure to give the corresponding optically active
ee. Desymmetrization of protected meso-(3-methylenecyclopropane-1,2-diyl)dimethanols was also car-
ried out to give enantioenriched highly oxygen-functionalized -methyleneglutarates.
Ó 2014 Elsevier Ltd. All rights reserved.
a-methyleneglutarates with up to 60%
a
1. Introduction
palladium-catalyzed ring-opening bis(alkoxycarbonylation) reac-
tion in the presence of a chiral bioxazoline ligand.9
Desymmetrization of meso-compounds has become a common
strategy in asymmetric synthesis since it allows the formation of
multiple stereogenic centers in one symmetry-breaking operation.
Among the desymmetrization techniques, methods which involve
the formation of new CAC bonds are relatively useful for the syn-
thesis of optically active natural products or biologically active
substances.1,2
2. Results and discussion
We initially performed the asymmetric bis(alkoxycarbonyla-
tion) reaction of 7-methylenebicyclo[4.1.0]heptane 1 in the pres-
ence of 0.02 equiv of PdCl2 and 0.5 equiv of CuOTf(C6H6)0.5 under
carbon monoxide and oxygen (ca. 1:1 v/v) at ambient pressure in
MeOH/THF using (S,S)-isopropyl-substituted bioxazoline 3A as a
chiral ligand.9–11 The reaction proceeded very slowly to give
methyl (1R,2S)-2-(3-methoxy-3-oxoprop-1-en-2-yl)cyclohexane-
carboxylate 2 in 58% yield. The enantiomeric excess of the obtained
Carbonylation is an important reaction in organic synthesis as it
provides an efficient means of making
a variety of useful
homologated carbonyl compounds.3 We have developed selective
mono- and bis(alkoxycarbonylation) reactions of terminal
olefins catalyzed by palladium in the presence of copper salts
under a mixture of carbon monoxide and oxygen at ambient
pressure.4 We have also taken an interest in utilizing
cyclopropanes as three carbon units for the preparation of
glutarates via the direct introduction of two carbonyl groups
and have developed the ring-opening reaction of methylenecyclo-
a-methyleneglutarate 2 was determined to be 37% ee by HPLC
analysis (Table 1, entry 1). The effect of various substituents at
the 4- and 40-positions of the bioxazoline ligand 3 was subse-
quently investigated. As shown in Table 1, the use of the isobu-
tyl-substituted ligand 3B resulted in enhanced stereoselectivity
(entry 2), while desymmetrization using the benzyl-substituted
bioxazoline ligand 3C proceeded with a further improved enanti-
oselectivity of 60% ee (entry 3).12 The use of the 1- and 2-naphthyl-
methyl substituted ligands 3D and 3E, however, did not improve
the selectivity (entries 5 and 6), while the bulky tert-butyl-substi-
tuted ligand 3F was less effective (entry 7). In addition, the phenyl-
substituted ligand 3G resulted in a reverse stereodifferentiation
(entry 8), while the other types of oxazoline ligands 4–6 gave poor
enantiomeric excesses (entries 9–11). When the amount of
CuOTf(C6H6)0.5 was reduced, the chemical yield and enantiomeric
excesses were slightly decreased (entry 4).
propanes to afford the corresponding
a
-methyleneglutarates.5 In
order to prepare optically active glutaric acid derivatives, the
asymmetric ring-opening bis(alkoxycarbonylation) reaction of
methylenecyclopropanes could be effective.6–8 Herein we report
the desymmetrization of meso-methylenecyclopropanes by
a
⇑
Corresponding author. Tel.: +81 762645700; fax: +81 762645742.
E-mail address: ukaji@staff.kanazawa-u.ac.jp (Y. Ukaji).
http://dx.doi.org/10.1016/j.tetasy.2014.05.007
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

Y. Yonezawa et al. / Tetrahedron: Asymmetry 25 (2014) 936–943
937
PdCl2 (0.02 equiv)
CuOTf(C6H6)0.5 (0.5 equiv)
Table 1
Optimization of the reaction
O
O
PdCl2 (0.02 equiv)
(0.04 equiv)
Ph
CuOTf(C6H6)0.5 (0.5 equiv)
ligand (0.04 equiv)
H
H
H
H
H
H
H
N
N
Ph
ð2Þ
3C
CO2Me
CO2Me
(2
(1R)
)
S
CO2Me
CO2Me
CO/O2 (ca. 1/1)
MeOH/THF (1/1)
rt, t h
CO/O2 (ca. 1/1)
MeOH/THF (1/1)
60 °C, 47 h
H
2
9
10
5%, 45% ee
Entry
Ligand
t (h)
Yield (%)
eea (%)
Next, in order to synthesize optically active oxygen-functionalized
glutarate derivatives,13 meso-methylene cyclopropanes 11 with alk-
oxymethyl groups at the 1- and 2-positions were used as substrates.
The desymmetrization reaction of the (benzyloxy)methyl-substi-
tuted methylene cyclopropane 11a using the bioxazoline ligand
(S,S)-3C proceeded to afford the ring-opened product 12a in 70%
yield, although unfortunately the enantiomeric excess was poor
(Table 2, entry 1). Employing the 1-naphthylmethyl-substituted
ligand 3D gave very little improvement in the stereoselectivity of
the reaction (entry 2), while the use of the phenyl-substituted biox-
azoline ligand 3G resulted in a reversal of the stereoselection in
addition to continued low enantioselectivity (entry 3). When a ste-
rically bulky triphenylmethyl group was introduced in place of the
benzyl group on 11a, desymmetrization proceeded more efficiently
1
2
3A
3B
3C
3C
3D
3E
3F
3G
4
41
49
60
59
37
37
47
72
44
41
43
58
65
53
50
54
57
47
62
56
60
59
37
51
60
56
50
43c
8
3
4b
5
6
7
8
9
10
11
ꢀ45d
7
7
6
5
6
a
b
c
Enantioselectivities were determined by HPLC analysis (DAICEL CHIRALPAK IA).
The amount of CuOTf(C6H6)0.5 was 0.01 equiv.
This reaction was carried out by using (R,R)-3E as the ligand to give mainly
(1S,2R)-2.
d
This reaction was carried out by using (R,R)-3G as the ligand to give mainly
(1R,2S)-2.
to give the oxygen-functionalized
a-methyleneglutarate 12b with
42% ee (entry 4). The triphenylsilyl ether 11c gave slightly improved
enatioselectivity (entry 5) and when the tert-butyldiphenylsily
ether 11d was subjected to desymmetrization, the corresponding
product 12d was obtained with a selectivity of 51% ee (entries 6
and 7). When using phenyl bioxazoline ligand 3G, a reversal of
enantioselection was again observed (entry 8).
O
N
O
N
O
O
(S)
(S)
N
N
R
R
3A
3B
3C
3D
3E
: R = i-Pr
: R = i-Bu
: R = PhCH2
: R = 1-NapCH2
Ph
Ph
: R = 2-NapCH2
Table 2
Scope of the substrates
4
3F: R = t-Bu
3G: R = Ph
PdCl2 (0.02 equiv)
CuOTf(C6H6)0.5 (0.5 equiv)
O
N
O
N
(0.04 equiv)
O
O
N
O
(S)
( )
S
H
H
H
O
O
N
N
R
R
3
R'O
R'O
N
N
R'O
R'O
CO2Me
CO2Me
Ph
Ph
CO/O2 (ca. 1/1)
MeOH/THF (1/1)
5
6
Ph
Ph
H
rt, t h
11
12
Entry
R0
R 3
t (h)
Yield (%)
ee (%)
The asymmetric ring-opening reactions of the methylene cyclo-
propanes 7 and 9, with a fused 5- or 8-membered ring, were next
investigated using the benzyl-substituted bioxazoline ligand 3C.
The ring-opening reaction did not proceed at rt and, when the reac-
tion temperature was increased to 60 °C, a complex mixture of
products resulted (Eqs. 1 and 2). In the case of 9, the desired
ring-opening product 10 was obtained in only 5% yield with 45%
ee.
1
2
3
4
5
6
7
8
PhCH2
a
PhCH2 3C
1-NapCH2 3D
Ph 3G
PhCH2 3C
PhCH2 3C
PhCH2 3C
1-NapCH2 3D
Ph 3G
43
24
36
67
72
49
30
71
70
47
69
65
48
67
82
76
18a
22a
–28a,b
42a
Ph3C
Ph3Si
t-BuPh2Si
b
c
d
48c
51a
51a
–24a,b
a
Enantioselectivitiy was determined by HPLC analysis (DAICEL CHIRALPAK IA).
This reaction was carried out by using (R,R)-3G as a ligand to give mainly the
b
same enantiomer as that when using (S,S)-3C.
c
PdCl2 (0.02 equiv)
CuOTf(C6H6)0.5 (0.5 equiv)
Enantioselectivitiy was determined by HPLC analysis (DAICEL CHIRALPAK IC).
O
N
O
N
(0.04 equiv)
Ph
In order to establish the absolute configuration of 2, the com-
pound was converted into 14 as follows. Enantiomerically enriched
2 (60% ee) obtained by using (S,S)-benzyl-substituted bioxazoline
ligand (S,S)-3C was reduced into the corresponding diol 13 with
LiAlH4. The diol was subsequently transformed into the bis-
camphanic ester 14 by treatment with (1S)-camphanic chloride
H
H
H
H
Ph
3C
ð1Þ
CO2Me
CO2Me
CO/O2 (ca. 1/1)
MeOH/THF (1/1)
60 °C, 77 h
7
8
not obtained

938
Y. Yonezawa et al. / Tetrahedron: Asymmetry 25 (2014) 936–943
O
O
O
Cl
(2.4 eq)
O
O
H
H
H
Et3N (2.6 eq)
OH
O
LiAlH4 (3.5 eq)
DMAP (cat.)
CO2Me
CO2Me
( )
S
(2
)
S
O
O
(1R)
(R)
Et2O
OH
CH2Cl2, rt
75%
0 °C –rt
O
O
O
H
H
H
65%
2
13
14
Scheme 1. Conversion of 2 into 14.
and Et3N in the presence of a catalytic amount of 4-(N,N-dimethyl-
amino)pyridine (DMAP) (Scheme 1). Recrystallization gave the
diastereomerically pure compound 14 and the absolute stereo-
chemistry at each of its two stereogenic centers was determined
(Fig. 1) by X-ray crystallographic analysis. In this manner, the
absolute configuration of 2 obtained by using the (4S,40S)-benzyl-
substituted bioxazoline ligand (S,S)-3C was determined to be
(1R,2S). This assignment also demonstrated that the relative stereo-
chemistry of the two substituents on the cyclohexane ring of 2 was
cis. The absolute configuration of 10 was also tentatively assigned as
(1R,2S). In the case of products 12 shown in Table 2, the stereochem-
istries of the molecules were assumed to correspond to the same
configurational arrangements as the substituents of 2 as depicted
in Table 2, in which case the manner of the chiral induction is similar
to that which occurs in the bis(alkoxycarbonylation) reaction of 1
using (S,S)-3C.
Although the precise mechanism of the present reaction is still
unknown, one possible transition state during the desymmetriza-
tion of meso-methylenecyclopropane using the benzyl-substituted
ligand (S,S)-3C is shown in Schemes 2 and 3, based on the absolute
stereochemistry assigned above. The copper salt might work not
only as an oxidant, but also as a co-catalyst to generate Pd-CO2Me
species C as previously proposed,9b that is, CuOTf reacts with CO
and MeOH successively to give the CuCO2Me species, from which
the CO2Me group was transferred into palladium chloride to gener-
ate complex C with the chiral ligand 3C. Furthermore, CuOTf also
reacts with C to afford a cationic palladium intermediate D, in
which the olefin strongly coordinates to the palladium metal
(Scheme 2). The following carbopalladation proceeds from the anti
direction relative to the R substituents, to give a terminal palla-
dium intermediate E regioselectively avoiding steric congestion
with the olefin component (Scheme 3).14 Desymmetrization then
occurs due to differentiation of the ring cleavage reaction via either
path (a) or (b). In the transition state Tcis, the steric hindrance
between R and the palladium complex moiety prevents the cis-
elimination pathway from proceeding. During trans-elimination,
there is steric congestion between the benzyl group of the bioxaz-
oline ligand 3C and the cyclopropane moiety in the transition state
Tb and therefore the predominant enantiomer in the final product
may arise from cleavage reaction (a) via transition state Ta by a
trans-b-carbon elimination pathway.15 Subsequent to this, a sec-
ond alkoxycarbonylation can take place with retention of the car-
bon center to afford enantiomer A, which corresponds to product
(1R,2S)-2 obtained from the reaction of the cyclohexane-fused
methylenecyclopropane 1. The cause of the observed reversal of
enatiodifferentiation with the use of the phenyl-substituted ligand
3G is still not well understood.
Figure 1. X-ray crystal structure of compound 14.
CuOTf
CO
H
R
TfOH
MeOH
R
CuCO2Me
N
H
N
N
N
CuOTf
3C
Pd
Pd
PdCl2
OTf
CuCl
CuCl
MeO2C
MeO2C
Cl
H
C
R
D
R
H
Scheme 2. A proposed pathway toward the generation of a Pd-CO2Me species.

Y. Yonezawa et al. / Tetrahedron: Asymmetry 25 (2014) 936–943
939
R
H
N
N
CO2Me
Pd
H
H
cis-
(a)
N
N
R
R
elimination
(b)
(a)
MeO2C
Pd
(b)
E
H
Tcis
R
trans-elimination
H
H
O
O
O
N
O
N
Ph
Ph
N
N
R
H
H
Pd
Pd
H
MeO2C
(a)
H
Ph
Ph
(a)
R
(b)
(b)
R
H
MeO2C
Ta
Tb
R
H
(a)
(b)
H
H
H
H
R
Pd
R
R
R
CO2Me
CO2Me
CO2Me
R
R
Pd
Pd
H
H
H
H
H
H
R
R
R
R
CO2Me
CO2Me
CO2Me
CO2Me
A
B
enantiomer-
enantiomer-
Scheme 3. Proposed transition states.
gel 60 N spherical neutral (37563-84), and JAIGL-SIL (s-043-15)
were used for thin-layer chromatography (TLC), flash column chro-
matography, and recycle HPLC, respectively. Methylenecyclopro-
panes 1,16 7,16 9,16 and 11a17 were prepared by literature
procedures. Oxygen-functionalized methylenecyclopropanes 11b,
11c, and 11d were prepared from 3-(methylenecyclopropane-1,2-
diyl)dimethanol by the following procedures.
3. Conclusion
In conclusion, we have realized the desymmetrization of
meso-methylenecyclopropanes by a palladium-catalyzed asym-
metric ring-opening bis(alkoxycarbonylation) reaction to afford
optically active
asymmetric carbonylation method provides
a
-methyleneglutarates with up to 60% ee. This
a
useful starting
point for the synthesis of optically active oxygen-functionalized
substrates.
4.2. 1,2-Bis((trityloxy)methyl)-3-methylenecyclopropane 11b
4. Experimental
A
DMF (3 mL) solution of 3-(methylenecyclopropane-1,2-
diyl)dimethanol18 (572 mg, 5 mmol) was added to a mixture of
trityl chloride (3.07 g, 11 mmol) and 4-(dimethylamino)pyridine
(1.83 g, 15 mmol) in DMF (9 mL) at rt under a nitrogen atmo-
sphere, and the mixture was stirred overnight at rt. Trityl chloride
(1.12 g, 4 mmol) was then added to the reaction mixture, and the
solution was stirred overnight at 80 °C. This mixture was subse-
quently poured into a mixture of ice and water, and extracted with
Et2O, after which the combined extracts were washed with H2O
and brine, dried over Na2SO4, and evaporated under reduced pres-
sure. The residue was purified by recrystallization from toluene to
give the corresponding methylenecyclopropane 11b (2.00 g, 62%)
as a solid. Mp 158 °C (toluene). 1H NMR (CDCl3, 400 MHz):
d = 1.91–1.98 (m, 2H), 2.92–2.98 (m, 2H), 3.11–3.15 (m, 2H), 5.43
(t, J = 1.8 Hz, 2H), 7.17–7.21 (m, 18H), 7.31–7.37 (m, 12H); 13C
NMR (CDCl3, 100 MHz): d = 19.6, 62.5, 86.4, 104.2, 126.8, 127.7,
128.6, 136.6, 144.2; IR (KBr) 3056, 3031, 2973, 2922, 2872, 1595,
1491, 1446, 1385, 1208, 1179, 1157, 1047, 1028, 891, 764, 738,
706 cmꢀ1; elemental analysis calcd (%) for C44H38O2: C 88.26, H
6.40; found: C 87.96, H 6.47.
4.1. General method
1H NMR spectroscopy was performed in CDCl3 using a JEOL ECS
400 NMR (400 MHz) spectrometer. Chemical shifts (d) were deter-
mined relative to TMS (d = 0 ppm) as an internal standard. 13C NMR
spectroscopy was performed in CDCl3 on a JEOL ECS 400 NMR
(100 MHz) spectrometer and chemical shifts (d) were determined
relative to CDCl3 (d = 77.0 ppm) as an internal standard. IR spectra
were acquired on a JASCO FT/IR-230 spectrometer. Melting points
were determined on a micro-melting apparatus (Yanagimoto–Sei-
sakusho) and are uncorrected. Optical rotations were recorded on a
JASCO DIP-370 spectrometer. HPLC was performed using a chiral
column with JASCO PU980 plus JASCO UV970. X-ray crystallogra-
phy was carried out using Mo-K
a radiation. Elemental analysis
was performed on a Yanaco CHN Corder MT-5 elemental analyzer.
Mass spectra were obtained using JMS-700 and JMS-T100TD mass
spectrometers. All solvents were distilled prior to use and stored
over drying agents. Merck silica gel 60 PF254 (Art. 7749), Cica silica

940
Y. Yonezawa et al. / Tetrahedron: Asymmetry 25 (2014) 936–943
4.3. 1,2-Bis-((triphenylsilyloxy)methyl)-3-methylenecyclopro-
pane 11c
953, 795, 776, 740 cmꢀ1; HRMS (ESI-TOF): m/z calcd for C28H24N2-
O2Na: 443.1736 [M+Na]+; found: 443.1739.
4.6. (R,R)-4,40-Bis(2-naphthalenylmethyl)-4,40,5,50-tetrahydro-
To a suspension of NaH (60% dispersion in mineral oil, 310 mg,
7.8 mmol) in DMF (14 mL), 3-(methylenecyclopropane-1,2-
diyl)dimethanol (355 mg, 3.1 mmol) in DMF (3 mL) was added at
0 °C. After the evolution of hydrogen gas ceased, 4-(N,N-dimethyl-
amino)pyridine (17 mg, 0.13 mmol) and a DMF (3 mL) solution of
chlorotriphenylsilane (2.245 g, 7.6 mmol) were added, and the
reaction mixture was stirred at rt for 3 d. The reaction mixture
was poured into a mixture of ice and water, and the insoluble sub-
stance was filtered through a bed of Celite. The filtrate was
extracted with Et2O, and the combined extracts were washed by
H2O and brine, dried over Na2SO4, and condensed under reduced
pressure. The residue was purified by column chromatography
(SiO2, hexane/AcOEt = 3:1) to give 11c (1.745 g, 93%) as a solid.
Mp 129 °C (hexane/AcOEt). 1H NMR (CDCl3, 400 MHz): d = 1.94–
1.96 (m, 2H), 3.79–3.81 (m, 4H), 5.27 (t, 2H, J = 1.84 Hz), 7.26–
7.46 (m, 30H); 13C NMR (CDCl3, 100 MHz): d = 22.2, 62.3, 104.1,
127.8, 129.9, 135.2, 135.4, 136.0; IR (KBr) 3066, 3008, 2911,
2871, 1588, 1485, 1427, 1387, 1308, 1253, 1188, 1158, 1119,
997, 887, 806, 740, 713 cmꢀ1; elemental analysis calcd (%) for C42-
H38O2Si2: C 79.95, H 6.07; found: C 79.79, H 6.10.
2,20-bioxazole 3E
Mp 173 °C (hexane/AcOEt); [
a]
D
25 = ꢀ26 (c 0.3, CHCl3); 1H NMR
(CDCl3, 400 MHz): d = 2.85 (dd, J = 13.8, 9.2, Hz, 2H), 3.42 (dd,
J = 13.8, 4.6, Hz, 2H), 4.21 (t, J = 8.2 Hz, 2H), 4.37 (dd, J = 10.1,
8.2 Hz, 2H), 4.67–4.75 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.42–7.48
(m, 4H), 7.63 (s, 2H), 7.77–7.81 (m, 6H); 13C NMR (CDCl3,
100 MHz): d = 41.2, 68.1, 72.7, 125.6, 126.2, 127.3, 127.5, 127.6,
128.4, 132.3, 133.5, 134.6, 155.1; IR (KBr) 3055, 2897, 1613,
1508, 1479, 1363, 1135, 1084, 1054, 944, 901, 861, 822, 758,
735 cmꢀ1
;
HRMS (ESI-TOF): m/z calcd for C28H24N2O2Na:
443.1736 [M+Na]+; found: 443.1734.
4.7. A representative procedure for the asymmetric bis(alkoxy-
carbonylation) reaction of 1 (Table 1, entry 3)
Under an argon atmosphere, CuOTf(C6H6)0.5 (253 mg, 1.0 mmol)
was placed in a flask, and an MeOH (12 mL) solution of 7-methyle-
nebicyclo[4.1.0]heptane 1 (217 mg, 2.0 mmol) and a THF (12 mL)
solution of (S,S)-3C (26 mg, 0.08 mmol) were added. To the mix-
ture, PdCl2 (7.1 mg, 0.04 mmol) was added. The argon atmosphere
was replaced with CO/O2 (ca. 1:1, v/v), and the reaction mixture
was stirred for 60 h at rt. A saturated aq solution of NaHCO3 was
then added to the reaction mixture at rt, and the insoluble sub-
stance was filtered off. After the filtrate was extracted with AcOEt,
the combined extracts were washed with water and brine, dried
over Na2SO4, and condensed in vacuo. The residue was purified
by TLC on SiO2 (hexane/AcOEt = 7:1, v/v) to give 2 (237 mg, 53%)
with a selectivity of 60% ee.
4.4. 1,2-Bis-((tert-butyldiphenylsilyloxy)methyl)-3-methylene-
cyclopropane 11d
To a suspension of NaH (60% dispersion in mineral oil, 430 mg,
11 mmol) in THF (6 mL), 3-(methylenecyclopropane-1,2-
diyl)dimethanol (410 mg, 4 mmol) in THF (3 mL) was added at
0 °C. After the evolution of hydrogen gas ceased, tetrabutylammo-
nium iodide (66 mg, 0.2 mmol) and a THF (3 mL) solution of tert-
butylchlorodiphenylsilane (2.93 g, 11 mmol) were added, and the
reaction mixture was stirred at rt for 1 d. Water was then added,
and the insoluble substance was filtered through a bed of Celite.
The filtrate was extracted with Et2O, and the combined extracts
were washed by H2O and brine, dried over Na2SO4, and condensed
under reduced pressure. The residue was purified by column chro-
matography (SiO2, hexane/AcOEt = 5:1) to give 11d (1.89 g, 89%) as
an oil. 1H NMR (CDCl3, 400 MHz): d = 1.01 (s, 18H), 1.90–1.95 (m,
2H), 3.68 (ddd, J = 11.0, 6.9, 2.3 Hz, 2H), 3.73 (ddd, J = 11.0, 7.3,
2.3 Hz, 2H), 5.35 (dd, J = 2.3, 1.8 Hz, 2H), 7.30–7.36 (m, 8H), 7.36–
7.43 (m, 4H), 7.61–7.67 (m, 8H); 13C NMR (CDCl3, 100 MHz):
d = 19.1, 22.1, 26.8, 62.6, 103.8, 127.6, 129.49, 129.52, 133.7,
133.8, 135.5, 135.6, 136.6; IR (neat) 3070, 2958, 2930, 2857,
1589, 1472, 1427, 1389, 1112, 1074, 823, 739, 702 cmꢀ1; HRMS
(EI): m/z calcd for C38H46O2Si2: 590.30364 [M]+; found: 590.30370.
Ligands (S,S)-3D and (R,R)-3E were prepared by literature pro-
cedures10a,19 described for the synthesis of other bioxazoline
ligands starting from (S)-2-amino-3-(1-naphthalenyl)-1-propanol
and (R)-2-amino-3-(2-naphthaleny)-1-propanol,20 respectively.
In a similar manner, glutaric acid dimethyl esters 10, and 12,
were prepared from the corresponding methylenecyclopropanes
9, and 11, respectively.
4.8. (1R,2S)-Methyl 2-(3-methoxy-3-oxo-1-propen-2-yl)cyclo-
hexanecarboxylate 2
Compound 2 (237 mg, 53%) was obtained as an oil. [
a]
25 = ꢀ49
D
(c 0.6, EtOH). The ee was determined to be 60% by HPLC (DAICEL
CHIRALPAK IAꢁ2, hexane/AcOEt = 50:1, 0.5 mL/min, 220 nm,
major 54 min and minor 50 min); 1H NMR (CDCl3, 400 MHz):
d = 1.29–1.43 (m, 1H), 1.49–1.61 (m, 2H), 1.59–1.73 (m, 2H),
1.81–1.90 (m, 1H), 1.91–2.04 (m, 2H), 2.75–2.84 (m, 1H), 3.04–
3.09 (m, 1H), 3.55 (s, 3H), 3.77 (s, 3H), 5.58 (s, 1H), 6.23 (s, 1H);
13C NMR (CDCl3, 100 MHz) d = 21.6, 25.68, 25.72, 28.3, 39.4, 42.6,
50.7, 51.8, 124.8, 142.7, 167.5, 174.4; IR (neat) 2949, 2859, 1735,
1720, 1628, 1437, 1281, 1247, 1194, 1165, 1143, 1030, 995, 949,
937, 819 cmꢀ1; HRMS (EI): m/z calcd for C12H18O4: 226.12051
[M]+; found: 226.12062.
4.5. (S,S)-4,40-Bis(1-naphthalenylmethyl)-4,40,5,50-tetrahydro-
2,20-bioxazole 3D
4.9. (1R,2S)-Methyl 2-(3-methoxy-3-oxo-1-propen-2-yl)cyclooc-
tanecarboxylate 10
Mp 149 °C (hexane/AcOEt); [
a
]
25 = ꢀ5 (c 0.9, CHCl3); 1H NMR
D
9-Methylenebicyclo[6.1.0]nonane 9 (68 mg, 0.50 mmol) was
subjected to carbonylation using PdCl2 (1.8 mg, 0.01 mmol),
CuOTf(C6H6)0.5 (63 mg, 0.25 mmol), and ligand (S,S)-3C (7 mg,
0.02 mmol) in MeOH/THF (3 mL/3 mL) at 60 °C for 47 h. Compound
(CDCl3, 400 MHz): d = 3.00 (dd, J = 14.2, 10.1 Hz, 2H), 3.88 (dd,
J = 14.2, 4.1 Hz, 2H), 4.289 (d, 2H, J = 8.2 Hz), 4.294 (d, 2H,
J = 9.2 Hz), 4.77–4.85 (m, 2H), 7.34 (d, J = 6.9 Hz, 2H), 7.41 (dd,
J = 8.2, 6.9 Hz, 2H), 7.48–7.57 (m, 4H), 7.76 (d, J = 7.8 Hz, 2H),
7.86 (d, J = 8.2 Hz, 2H), 8.09 (d, J = 8.2 Hz, 2H); 13C NMR (CDCl3,
100 MHz): d = 38.5, 67.2, 73.1, 123.4, 125.4, 125.8, 126.3, 126.8,
127.7, 128.9, 131.7, 133.1, 133.9, 155.2; IR (KBr) 3045, 2953,
2885, 1613, 1508, 1472, 1395, 1308, 1228, 1131, 1093, 1075,
10 (6 mg, 5%) was obtained as an oil. [
a]
25 = ꢀ11 (c 0.1, EtOH). The
D
ee was determined to be 45% by HPLC (DAICEL CHIRALPAK IAꢁ2,
hexane/EtOH = 400:1, 0.5 mL/min, 220 nm, major 42 min and
minor 38 min); 1H NMR (CDCl3, 400 MHz): d = 1.51–1.71 (m, 7H),

Y. Yonezawa et al. / Tetrahedron: Asymmetry 25 (2014) 936–943
941
1.71–1.84 (m, 2H), 1.84–1.93 (m, 2H), 1.93–2.05 (m, 1H), 2.82–2.90
(m, 1H), 3.32 (ddd, J = 11.5, 3.6, 3.2 Hz, 1H), 3.57 (s, 3H), 3.76 (s,
3H), 5.57 (s, 1H), 6.25 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d = 25.5, 26.4, 26.7, 26.9, 28.2, 29.4, 37.4, 46.0, 51.1, 52.0, 124.8,
143.7, 167.8, 175.5; IR (neat) 2922, 2851, 1725, 1685, 1627,
1436, 1268, 1192, 1168 cmꢀ1; HRMS (EI): m/z calcd for C14H22O4:
254.15181 [M]+; found: 254.15194.
3.91 (dd, J = 10.1, 8.7 Hz, 1H), 5.39 (s, 1H), 6.13 (s, 1H), 7.33–7.45
(m, 18H), 7.52–7.56 (m, 10H), 7.63–7.65 (m, 2H); 13C NMR (CDCl3,
100 MHz): d = 42.7, 48.8, 51.4, 51.7, 63.9, 64.4, 127.8, 128.0,
129.96, 130.01, 133.7, 135.3, 135.4, 137.9, 166.8, 173.9; IR (KBr)
3068, 2946, 2867, 1740, 1721, 1703, 1622, 1588, 1485, 1428, 1382,
1333, 1255, 1119, 996, 835, 741, 714 cmꢀ1; elemental analysis calcd
(%) for C46H44O6Si2: C, 73.76; H, 5.92; found: C, 73.57; H, 6.03.
4.10. (2S,3S)-Dimethyl 2,3-bis((benzyloxy)methyl)-4-methyl-
4.13. (2S,3S)-Dimethyl 2,3-bis((tert-butyldiphenylsilyloxy)-
enepentanedioate 12a
methyl)-4-methylenepentanedioate 12d
1,2-Bis((benzyloxy)methyl)-3-methylenecyclopropane
11a
1,2-Bis((tert-butyldiphenylsilyloxy)methyl)-3-methylenecyclo-
propane 11d (296 mg, 0.50 mmol) was subjected to carbonylation
using PdCl2 (1.9 mg, 0.01 mmol), CuOTf(C6H6)0.5 (61 mg,
0.24 mmol), and ligand (S,S)-3D (9 mg, 0.02 mmol) in MeOH/THF
(3 mL/3 mL) at rt for 30 h. Compound 12d (289 mg, 82%) was
(148 mg, 0.50 mmol) was subjected to carbonylation using PdCl2
(1.8 mg, 0.01 mmol), CuOTf(C6H6)0.5 (65 mg, 0.26 mmol), and
ligand (R,R)-3G (6 mg, 0.02 mmol) in MeOH/THF (3 mL/3 mL) at
rt for 36 h. Compound 12a (142 mg, 69%) was obtained as an oil.
[
a]
25 = +6 (c 1.3, EtOH). The ee was determined to be 28% by HPLC
obtained as an oil. [a]
25 = +3 (c 1.9, EtOH). The ee was determined
D
D
(DAICEL CHIRALPAK IAꢁ2, hexane/EtOH = 100:1, 0.5 mL/min,
254 nm, major 82 min and minor 88 min); 1H NMR (CDCl3,
400 MHz): d = 3.14 (ddd, J = 10.1, 8.7, 4.6 Hz, 1H), 3.28 (dt,
J = 10.1, 6.4 Hz, 1H), 3.49 (dd, J = 9.6, 4.6 Hz, 1H), 3.52–3.64 (m,
3H), 3.62 (s, 3H), 3.69 (s, 3H), 4.41 (d, J = 12.4 Hz, 2H), 4.45 (d,
J = 12.4 Hz, 1H), 4.47 (d, J = 12.4 Hz, 1H), 5.68 (s, 1H), 6.29 (s, 1H),
7.22–7.35 (m, 10H); 13C NMR (CDCl3, 100 MHz) d = 41.7, 47.1,
51.7, 51.9, 70.0, 71.1, 72.8, 72.9, 127.46, 127.49, 127.52 127.6,
127.8, 128.3, 129.6, 137.9, 138.1, 138.4, 166.8, 174.0; IR (neat)
2951, 2863, 1738, 1719, 1626, 1454, 1436, 1363, 1270, 1197,
1156, 1100, 1028, 739, 699 cmꢀ1; HRMS (EI): m/z calcd for
to be 51% by HPLC (DAICEL CHIRALPAK IAꢁ2, hexane/
EtOH = 100:1, 0.5 mL/min, 254 nm, major 17 min and minor
19 min); 1H NMR (CDCl3, 400 MHz): d = 0.99 (s, 18H), 3.08 (ddd,
J = 11.0, 8.7, 4.1 Hz, 1H), 3.16 (ddd, J = 11.0, 6.4, 4.1 Hz, 1H), 3.59
(dd, J = 10.5, 4.1 Hz, 1H), 3.65 (dd, J = 10.0, 4.1 Hz, 1H), 3.68 (dd,
J = 10.5, 6.4 Hz, 1H), 3.61 (s, 3H), 3.62 (s, 3H), 3.82 (dd, J = 10.0,
8.7 Hz, 1H), 5.39 (s, 1H), 6.18 (s, 1H), 7.31–7.44 (m, 12H), 7.54–
7.64 (m, 8H); 13C NMR (CDCl3, 100 MHz): d = 19.0, 19.1, 26.5,
26.6, 42.5, 48.4, 51.4, 51.7, 63.9, 64.2, 127.5, 127.6, 129.49,
129.55, 129.64, 133.1, 133.2, 135.39, 135.45, 135.50, 138.0, 166.7,
174.1; IR (neat) 3071, 3049, 2931, 2857, 1736, 1720, 1624, 1472,
1428, 1252, 1194, 1154, 1111, 822, 741, 702 cmꢀ1; HRMS (EI):
m/z calcd for C42H52O6Si2: 708.33025 [M]+; found: 708.33076.
C
24H28O6: 412.18859 [M]+; found: 412.18843.
4.11. (3S,4S)-Dimethyl 2-methylene-3,4-bis((trityloxy)methyl)-
pentanedioate 12b
4.14. Methyl 7-(2-methoxy-2-oxoethyl)bicyclo[4.1.0]heptane-7-
carboxylate 1511
1,2-Bis((trityloxy)methyl)-3-methylenecyclopropane
11b
(299 mg, 0.50 mmol) was subjected to carbonylation using PdCl2
(1.8 mg, 0.01 mmol), CuOTf(C6H6)0.5 (65 mg, 0.25 mmol), and
ligand (S,S)-3C (7 mg, 0.02 mmol) in MeOH/THF (3 mL/3 mL) at rt
for 67 h. Compound 12b (234 mg, 65%) was obtained as a solid.
7-Methylenebicyclo[4.1.0]heptane 1 (106 mg, 0.98 mmol) was
subjected to carbonylation using PdCl2 (3.6 mg, 0.02 mmol), and
CuOTf(C6H6)0.5 (127 mg, 0.50 mmol) in MeOH/THF (6 mL/6 mL) at
rt for 36 h. Compound 2 (87 mg, 39%) and compound 15 (44 mg,
20%) were obtained. Compound 15: an oil; 1H NMR (CDCl3,
400 MHz): d = 1.16–1.51 (m, 6H), 1.71–1.78 (m, 2H), 1.90–2.05
(m, 2H), 2.67 (s, 2H), 3.62 (s, 3H), 3.71 (s, 3H); 13C NMR (CDCl3,
100 MHz): d = 18.6, 21.5, 22.7, 27.5, 30.6, 51.7, 51.9, 172.5, 175.4;
IR (neat) 2969, 2931, 2857, 1758, 1723, 1672, 1435, 1411, 1359,
1309, 1276, 1200, 1172, 1131, 1068, 1043, 1012, 930, 879, 848,
780, 697 cmꢀ1; HRMS (EI): m/z calcd for C12H18O4: 226.12051
[M]+; found: 226.12040.
[a]
25 = +5 (c 0.5, EtOH). The ee was determined to be 42% by HPLC
D
(DAICEL CHIRALPAK IA, hexane/EtOH = 50:1, 0.5 mL/min, 254 nm,
major 28 min and minor 31 min); mp 146 °C (recrystallized from
CHCl3/Hexane); 1H NMR (CDCl3, 400 MHz): d 2.98–3.06 (m, 1H),
3.06–3.12 (m, 2H), 3.12–3.26 (m, 3H), 3.55 (s, 3H), 3.57 (s, 3H),
5.35 (s, 1H), 6.09 (s, 1H), 7.18–7.25 (m, 18H), 7.30–7.35 (m,
12H); 13C NMR (CDCl3, 100 MHz): d = 41.4, 46.8, 51.4, 51.6, 63.3,
64.1, 86.5, 126.8, 126.9, 127.55, 127.59, 128.5, 128.6, 143.7,
166.6, 173.9; IR (KBr) 3056, 3022, 2949, 2877, 1741, 1725, 1626,
1597, 1491, 1448, 1325, 1224, 1193, 1153, 1078, 764, 747,
706 cmꢀ1; HRMS (ESI-TOF): m/z calcd for C48H44O6Na: 739.3036
[M+Na]+; found: 739.3038.
4.15. (1S,4R)-2-((1S,2R)-2-((((1S,4R)-4,7,7-Trimethyl-3-oxo-2-
oxabicyclo[2.2.1]heptane-1-carbonyl)oxy)methyl)cyclohexyl)-
allyl 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-car-
boxylate 14
4.12. (3S,4S)-Dimethyl 2-methylene-3,4-bis((triphenylsilyloxy)-
methyl)pentanedioate 12c
To a suspension of LiAlH4 (65 mg, 1.75 mmol) in Et2O (5 mL) was
added dropwise an Et2O (3 mL) solution of 2 (113 mg, 0.50 mmol,
60% ee) at 0 °C under an N2 atmosphere. The resulting mixture
was gradually warmed to rt and stirred overnight at rt, and then
treated with a saturated aq Na2SO4 solution (0.5 mL). The insoluble
substance was filtered through a bed of Celite, followed by washing
with AcOEt, and the filtrate was concentrated in vacuo. Separation
of the residue by column chromatography (hexane/AcOEt = 1:1, v/
v) afforded the corresponding diol 13 (51 mg, 65%) as an oil. A CH2-
Cl2 (3 mL) solution of (S)-camphanic chloride (171 mg, 0.79 mmol)
was added to a mixture of diol 13 (51 mg, 0.33 mmol), triethyl-
amine (0.12 mL, 0.86 mmol), and 4-(dimethylamino)pyridine
1,2-Bis((triphenylsilyloxy)methyl)-3-methylenecyclopropane
11c (252 mg, 0.4 mmol) was subjected to carbonylation using PdCl2
(1.4 mg, 0.008 mmol), CuOTf(C6H6)0.5 (60 mg, 0.2 mmol), and ligand
(S,S)-3C (5.1 mg, 0.016 mmol) in MeOH/THF (2 mL/2 mL) at rt for
72 h. 12c (145 mg, 48%) was obtained as a solid. [a]
25 = +6 (c 1.5,
D
CHCl3). The ee was determined to be 48% by HPLC (DAICEL CHIR-
ALPAK IC, hexane/EtOH = 100:1, 0.5 mL/min, 254 nm, major
13.5 min and minor 15.4 min); mp 124 °C (AcOEt/hexane); 1H
NMR (CDCl3, 400 MHz): d = 3.07 (ddd, J = 10.6, 8.7, 4.6 Hz, 1H),
3.17–3.22 (m, 1H), 3.43 (s, 3H), 3.53 (s, 3H), 3.75–3.82 (m, 3H),

942
Y. Yonezawa et al. / Tetrahedron: Asymmetry 25 (2014) 936–943
3606; (c) Mizutani, T.; Ukaji, Y.; Inomata, K. Bull. Chem. Soc. Jpn. 2003, 76, 1251–
1256.
5. Aratani, T.; Ukaji, Y.; Inomata, K. Chem. Lett. 2009, 38, 46–47.
6. For examples of catalytic asymmetric desymmetrizations of meso-
methylenecyclopropanes; see Refs. 2b,f,g,7b.
(5 mg, 0.03 mmol) in CH2Cl2 (3 mL) at rt under a nitrogen atmo-
sphere and the mixture was stirred overnight at rt. The reaction
was quenched by the addition of an aqueous solution of 1 M HCl
aq (1.5 mL), and the mixture was subsequently extracted with
AcOEt. The combined extracts were washed by H2O and brine, dried
over Na2SO4, and condensed under reduced pressure. The residue
was purified by TLC on SiO2 (hexane/AcOEt = 3:2) to give the corre-
sponding ester (131 mg, 75%) as a mixture of diastereomers as a
solid. Recrystallization (Et2O/hexane) gave more diastereomerically
pure ester (66 mg). The substrate obtained was further separated
by recycle HPLC (hexane/AcOEt = 3:1) to give almost diastereomer-
ically pure product (20 mg). Diastereomerically pure 14 was
7. The
palladium-catalyzed
ring-opening
copolymerization
of
methylenecyclopropanes with CO was recently reported: (a) Kim, S.;
Takeuchi, D.; Osakada, K. J. Am. Chem. Soc. 2002, 124, 762–763; (b) Takeuchi,
D.; Yasuda, A.; Okada, T.; Kuwabara, J.; Osakada, K.; Tomooka, K. Helv. Chim.
Acta 2006, 89, 1574–1588; (c) Takeuchi, D.; Okada, T.; Kuwabara, J.; Osakada, K.
Macromol. Chem. Phys. 2006, 207, 1546–1555.
8. For reviews on asymmetric carbonylations, see: (a) Nozaki, K. J. Polym. Sci., Part
A: Polym. Chem. 2004, 42, 215–221; (b) Godard, C.; Muñoz, B. K.; Ruiz, A.;
Claver, C. Dalton Trans. 2008, 853–860; (c) Gual, A.; Godard, C.; Castillón, S.;
Claver, C. Tetrahedron: Asymmetry 2010, 21, 1135–1146; (d) Godard, C.; Ruiz,
A.; Diéguez, M.; Pàmies, O.; Claver, C. Asymmetric Carbonylations. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed., 3rd ed.; John Wiley & Sons: New Jersey,
2010; pp 799–838; (e) Nozaki, K. Optically Active Polyketones. In Polymeric
Chiral Catalyst Design and Chiral Polymer Synthesis; Itsuno, S., Ed.; John Wiley &
Sons: Hoboken, 2011; pp 407–422; (f) Perandones, B. F.; Godard, C.; Claver, C.
Top. Curr. Chem. 2013, 342, 79–116; Recent examples of asymmetric
carbonylations; (g) Tsujihara, T.; Shinohara, T.; Takenaka, K.; Takizawa, S.;
Onitsuka, K.; Hatanaka, M.; Sasai, H. J. Org. Chem. 2009, 74, 9274–9279; (h)
Bajracharya, G. B.; Koranne, P. S.; Tsujihara, T.; Takizawa, S.; Onitsuka, K.; Sasai,
H. Synlett 2009, 310–314; (i) Konrad, T. M.; Fuentes, J. A.; Slawin, A. M. Z.;
Clarke, M. L. Angew. Chem., Int. Ed. 2010, 49, 9197–9200; (j) Nakamura, A.;
Kageyama, T.; Goto, H.; Carrow, B. P.; Ito, S.; Nozaki, K. J. Am. Chem. Soc. 2012,
134, 12366–12369; (k) Wang, X.; Buchwald, S. L. J. Org. Chem. 2013, 78, 3429–
3433; (l) Konrad, T. M.; Durrani, J. T.; Cobley, C. J.; Clarke, M. L. Chem. Commun.
2013, 3306–3308; (m) Wong, G. W.; Landis, C. R. Angew. Chem., Int. Ed. 2013, 52,
1564–1567; (n) Wang, Y.; Zhang, W.; Ma, S. J. Am. Chem. Soc. 2013, 135, 11517–
11520; (o) Kusakabe, T.; Takahashi, T.; Shen, R.; Ikeda, A.; Dhage, Y. D.; Kanno,
Y.; Inouye, Y.; Sasai, H.; Mochida, T.; Kato, K. Angew. Chem., Int. Ed. 2013, 52,
7845–7849. and references cited therein.
obtained by recrystallization from Et2O. [
a
]
D
25 = ꢀ11 (c 0.1, EtOH);
mp 135 °C (Et2O). 1H NMR (CDCl3, 400 MHz): d = 0.94 (s, 3H), 0.98
(s, 3H), 1.05 (s, 3H), 1.07 (s, 3H), 1.11 (s, 3H), 1.12 (s, 3H), 1.21–
1.73 (m, 8H), 1.80–2.09 (m, 6H), 2.26–2.36 (m, 2H), 2.36–2.49 (m,
2H), 4.15 (dd, J = 11.0, 4.6 Hz, 1H), 4.24 (dd, J = 11.0, 9.2 Hz, 1H),
4.70 (d, J = 13.3 Hz, 1H), 4.84 (d, J = 13.3 Hz, 1H), 4.97 (s, 1H), 5.20
(s, 1H); 13C NMR (CDCl3, 100 MHz): d = 9.7, 16.7, 20.5, 25.2, 25.9,
27.6, 28.9, 30.5, 30.6, 34.3, 41.1, 54.1, 54.2, 54.7, 54.8, 63.66,
63.74, 67.2, 91.08, 91.13, 113.7, 144.9, 167.2, 167.6, 178.17,
178.25; IR (KBr) 2968, 2933, 2857, 1795, 1751, 1718, 1649, 1453,
1399, 1359, 1348, 1332, 1314, 1271, 1227, 1166, 1106, 1064, 995,
928, 913 cmꢀ1
553.2777 [M+Na]+; found: 553.2779. Crystal data: C30H42O8, FW.
530.66, monoclinic, P21, a = 11.049(2), b = 10.876(2),
c = 12.586(2) Å, b = 114.556(4)°, Z = 2.
V = 1375.7(5) Å3,
Dcalcd = 1.281 g/cm3. R = 0.057 (Rw = 0.069) for 5515 reflections with
I > 3.00 (I) and 344 variable parameters. CCDC-985876 14 contains
; HRMS (ESI-TOF): m/z calcd for C30H42O8Na:
9. We have already reported on an asymmetric bis(alkoxycarbonylation) reaction
of terminal and internal alkenes using chiral bioxazoline ligands, see: (a) Ukaji,
Y.; Miyamoto, M.; Mikuni, M.; Takeuchi, S.; Inomata, K. Bull. Chem. Soc. Jpn.
1996, 69, 735–742; (b) Takeuchi, S.; Ukaji, Y.; Inomata, K. Bull. Chem. Soc. Jpn.
2001, 74, 955–958; (c) Aratani, T.; Tahara, K.; Takeuchi, S.; Ukaji, Y.; Inomata, K.
Chem. Lett. 2007, 36, 1328–1329; (d) Aratani, T.; Tahara, K.; Takeuchi, S.;
Kitamura, S.; Murai, M.; Fujinami, S.; Inomata, K.; Ukaji, Y. Bull. Chem. Soc. Jpn.
2012, 85, 1225–1232.
r
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
10. For recent reports of palladium catalyzed asymmetric reactions using
bioxazoline ligands, see (a) Denmark, S. E.; Stavenger, R. A.; Faucher, A.-M.;
Edwards, J. P. J. Org. Chem. 1997, 62, 3375–3389; (b) Gsponer, A.; Milani, B.;
Consiglio, G. Helv. Chim. Acta 2002, 85, 4074–4078; (c) Perch, N. S.; Kisanga, P.;
Widenhoefer, R. A. Organometallics 2000, 19, 2541–2545; (d) Carfagna, C.;
Gatti, G.; Mosca, L.; Paoli, P.; Guerri, A. Chem. Eur. J. 2005, 11, 3268–3278; (e)
Kawamura, Y.; Kawano, Y.; Matsuda, T.; Ishitobi, Y.; Hosokawa, T. J. Org. Chem.
2009, 74, 3048–3053.
Acknowledgements
The present work was financially supported in part by a Grant-
in-Aid for Scientific Research on Priority Areas ‘Advanced Molecu-
lar Transformations of Carbon Resources’ from The Ministry of
Education, Culture, Sports, Science, and Technology (MEXT) Japan
and a Grant-in-Aid for Scientific Research from Japan Society for
the Promotion of Science (JSPS).
11. It was found that the bis(alkoxycarbonylation) reaction of 1 without chiral
ligand 3C afforded not only
2 (39%), but also a considerable amount of
succinate 15 (20%) (see Section 4).
H
CO2Me
CO2Me
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Gotor, V. Chem. Rev. 2011, 111, PR110–PR180; (h) Díaz de Villegas, M. D.;
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Víu, M. P. Chem. Eur. J. 2012, 18, 13920–13935.
PdCl2
H
(0.02 equiv)
CuOTf(C6H6)0.5
(0.5 equiv)
2
H
H
39%
H
CO/O2
(ca. 1/1)
MeOH/THF
(1/1)
CO2Me
CO2Me
1
rt, 36 h
H
15
2. For recent examples of catalytic asymmetric desymmetrization and related
reactions, see: (a) Matsuda, T.; Shigeno, M.; Makino, M.; Murakami, M. Org. Lett.
2006, 8, 3379–3381; (b) Ohmura, T.; Taniguchi, H.; Kondo, Y.; Suginome, M. J.
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Suginome, M. J. Am. Chem. Soc. 2012, 134, 11092–11095; (g) Obame, G.;
Brémond, P.; Pannecouque, C.; Audran, G. Synthesis 2013, 45, 2612–2618.
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Springer: Berlin, 2006; (c) Brennführer, A.; Neumann, H.; Beller, M.
ChemCatChem 2009, 1, 28–41.
20%
12. In this reaction, 1511 was not isolated after the purification procedure.
13. Examples of biologically active oxygen-functionalized
a-alkylidene-b,c-
oxygen-functionalized glutarates: (a) Velten, R.; Klostermeyer, D.; Steffan, B.;
Steglich, W.; Kuschel, A.; Anke, T. J. Antibiot. 1994, 47, 1017–1024; (b) McPhail,
K.; Davies-Coleman, M. T. Tetrahedron 1997, 53, 4655–4660; (c) Chai, X.-Y.;
Sun, J.-F.; Tang, L.-Y.; Yang, X.-W.; Li, Y.-Q.; Huang, H.; Zhou, X.-F.; Yang, B.; Liu,
Y. Chem. Pharm. Bull. 2010, 58, 1391–1394; (d) Tan, J.-J.; Tan, J.-M.; Tan, C.-H.;
Qu, S.-J.; Zhu, D.-Y. Nat. Prod. Res. 2012, 26, 1213–1217; (e) Valente, S.; Xu, Z.;
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Kirsch, G. Eur. J. Org. Chem. 2013, 2869–2877.
14. In the bis(alkoxycarbonylation) reaction in the absence of bioxazoline ligand
3C, carbopalladation by chiral ligand-free palladium catalyst might proceed in
a non-regioselective manner to give both the terminal intermediate F and the
internal palladium intermediate G which produced succinate 1511 by the
4. (a) Inomata, K.; Toda, S.; Kinoshita, H. Chem. Lett. 1990, 1567–1570; (b) Toda,
S.; Miyamoto, M.; Kinoshita, H.; Inomata, K. Bull. Chem. Soc. Jpn. 1991, 64, 3600–

Y. Yonezawa et al. / Tetrahedron: Asymmetry 25 (2014) 936–943
943
second alkoxycarbonylation. To the contrary, the palladium coordinated by
bioxazoline ligand 3C might be bulky enough to afford the terminal palladium
intermediate E, regioselectively.
15. At present, an alternative pathway via cleavage of the proximal cyclopropane
CAC bond through oxidative addition to a methylenecyclopropane21 cannot be
ruled out.
16. Arora, S.; Binger, P. Synthesis 1974, 6, 801–803.
17. Ogata, K.; Shimada, D.; Fukuzawa, S.-I. Chem. Eur. J. 2012, 18, 6142–6146.
18. Taniguchi, H.; Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 11298–
11299.
19. (a) Müller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. Helv. Chim. Acta 1991, 74, 232–
240; (b) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem. Soc.
2004, 126, 15195–15201.
H
H
CO2Me
PdX
PdX
CO2Me
H
H
G
F
20. Blay, G.; Incerti, C.; Muñoz, M. C.; Pedro, J. R. Eur. J. Org. Chem. 2013, 1696–
1705.
21. (a) Suginome, M.; Matsuda, T.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 11015–11016;
(b) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002, 344, 111–129.
15
2