Catalytic asymmetric cyclopropanation of alkenes with diazoesters in protic and biphasic media

Article abstract of DOI:10.1016/S0957-4166(03)00168-X

As a C₂ symmetric hydrophilic chiral ligand, a series of 2,6-bis(oxazolinyl)-pyridines (pyboxs) bearing a hydroxyalkyl group on the oxazoline ring has been synthesized from readily available amino acid derivatives. Catalytic asymmetric intermolecular cyclopropanation of electron rich terminal alkenes with diazoesters in the presence of hydrophilic pybox ligand, pybox-hm and Ru(II) complex proceeded smoothly in protic or biphasic media to give the corresponding cyclopropanation products in 97:3 to 99:1 trans/cis ratios and 90 to 97% ee. In the case of the intramolecular cyclopropanation reaction of trans-cinnamyl diazoester using Ru(II)(pybox-he) complex in biphasic medium gave the corresponding cyclopropane ring fused lactone in 52% ee. Steric tuning of the chiral environment of pybox ligands was simply achieved by using a weak interaction between the solvent and the hydroxyl groups of the chiral ligand. The solubility of the new hydrophilic pybox and Ru(II) complexes in protic solvents is dramatically increased; hence, the efficiency of these catalysts enhanced the rate of cyclopropanation. Furthermore, the active catalyst in the water phase can be re-used several times for the cyclopropanation reaction.

Full text of DOI:10.1016/S0957-4166(03)00168-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 855–865
Catalytic asymmetric cyclopropanation of alkenes with
diazoesters in protic and biphasic media
Seiji Iwasa,* Shinji Tsushima, Kohei Nishiyama, Yasunori Tsuchiya, Futoshi Takezawa and
Hisao Nishiyama*,†
School of Materials Science, Toyohashi University of Technology, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan
Received 13 January 2003; accepted 7 February 2003
Abstract—As a C2 symmetric hydrophilic chiral ligand, a series of 2,6-bis(oxazolinyl)-pyridines (pyboxs) bearing a hydroxyalkyl
group on the oxazoline ring has been synthesized from readily available amino acid derivatives. Catalytic asymmetric intermolecular
cyclopropanation of electron rich terminal alkenes with diazoesters in the presence of hydrophilic pybox ligand, pybox-hm and Ru(II)
complex proceeded smoothly in protic or biphasic media to give the corresponding cyclopropanation products in 97:3 to 99:1 trans/cis
ratios and 90 to 97% ee. In the case of the intramolecular cyclopropanation reaction of trans-cinnamyl diazoester using
Ru(II)(pybox-he) complex in biphasic medium gave the corresponding cyclopropane ring fused lactone in 52% ee. Steric tuning
of the chiral environment of pybox ligands was simply achieved by using a weak interaction between the solvent and the hydroxyl
groups of the chiral ligand. The solubility of the new hydrophilic pybox and Ru(II) complexes in protic solvents is dramatically
increased; hence, the efficiency of these catalysts enhanced the rate of cyclopropanation. Furthermore, the active catalyst in the
water phase can be re-used several times for the cyclopropanation reaction. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
group moieties and their application for catalytic asym-
metric cyclopropanation reactions of terminal electron
rich alkenes with a diazoester in protic and/or biphasic
media, whose non-halogenated solvent system with
environmental concerns complies with recent social
demands (Scheme 1).
The Nozaki research group reported the first catalytic
asymmetric cyclopropanation reaction in 1966.2 It is
considered that this is one of the most important papers
since they used chiral molecular catalysts to induce
chirality in an achiral organic molecule. After their
historical report, various chiral ligands and their combi-
nation with metals for providing optically active
organic compounds have been reported.3 Although
there are many examples of cyclopropanation reactions,
because of interests in both industry and academia, to
the best of our knowledge, there are no reports about
the use of protic and/or biphasic solvent systems for the
catalytic asymmetric cyclopropanation reaction.4 In
most cases the reaction has been carried out in halo-
genated and/or organic solvents such as CH2Cl2, 1,2-
dichloroethane, CHCl3, etc. We report here the design
and synthesis of pybox ligands containing hydroxy
2. Results and discussion
2.1. Synthesis of ligands
As for the synthesis of functionalized pybox, we
recently reported the synthesis of the hydrophilic
derivative of pybox, 2,6-bis(4-hydroxymethyloxa-
zolinyl)pyridine 1 (pybox-hm), having two hydroxy-
methyl groups as the symmetric chiral stems of the
oxazoline rings.5 Furthermore, 2,6-bis(hydroxyethylox-
azolinyl)pyridine 2a (pybox-he) and 2,6-bis(hydroxy-
Scheme 1. Catalytic asymmetric cyclopropanation.
* Corresponding authors. E-mail: iwasa@tutms.tut.ac.jp; hnishi@apchem.nagoya-u.ac.jp
† See Ref. 1
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00168-X

856
S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
benzyloxazolinyl)pyridine 2b (pybox-hbn) having sec-
ondary hydroxy groups were synthesized from an
hydroxy groups and Ru(II) was slightly unstable during
purification even at low temperature. Ru(pybox-
hm)(ethylene) and Ru(pybox-hbn)(ethylene) complexes
could not be isolated because of their instability. In
these cases, ethylene atmosphere can be applied to
prepare Ru(pybox)(ethylene) complex in situ. The com-
plexation with ethylene and its purification process is
sometimes useful for achieving good reactivity and
selectivity compared to the preparation of the catalyst
in situ.
L
-
threonine derivative and amino alcohol, respectively, as
in the synthesis of 1a (Fig. 1). The synthetic routes are
summarized in Schemes 2 and 3. Classical synthetic
methods for oxazoline ring formation as a key step can
be applied under careful attention for avoiding the side
reactions such as dehydration reaction and racemiza-
tion of stereogenic centers on side chains.6 1a, 2a, and
2b were obtained in 54, 51, and 59% total yields,
respectively, in four to five steps starting from 3, which
is commercially available.
2.3. Catalytic asymmetric cyclopropanation of styrene
with diazoesters
2.2. Synthesis of Ru(pybox) catalysts
There were no systems effective in aqueous media or
protic solvents related to the catalytic cyclopropanation
of alkenes and diazoacetates.8 However, we discovered
that the existence of a free hydroxy group on chiral
ligands does not interfere with the smooth running of
cyclopropanation for copper catalyzed reactions, for
example, in the case of bis(oxazoline) ligands.9,10 It had
also very recently been reported that although a small
The catalysts were synthesized from pybox ligands and
pre-catalyst, [RuCl2(p-cymene)]2, which can be isolated
as its ethylene complex.7 We isolated Ru(py-
box)(ethylene) complexes 13 and 14 for asymmetric
cyclopropanation reaction (Scheme 4) As for ethylene
complex 14, deprotection of the hydroxy groups gave
complicated mixtures. The complexes of pybox bearing
P
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Figure 1. Pybox ligands.
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S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
857
Scheme 3. Synthesis of pybox-hbn.
Scheme 4. Synthesis of Ru(pybox)(ethylene) complexes.
amount of water in the reaction solvent diminishes the
enantioselectivity of cyclopropanation with rhodium
catalysts, the unfavorable influence of water was
reduced by addition of an appropriate phosphite lig-
and.8 Accordingly, we were intrigued to examine the
catalysis with pybox-hm 1a and [RuCl2(p-cymene)]2.7
Firstly, we chose styrene as an terminal alkene and
pybox-hm 1a as a hydrophilic ligand to optimize the
reaction conditions for intermolecular catalytic cylo-
propanation in protic and biphasic media. The results
are summarized in Table 1.11 First, we tried aqueous
media for the cyclopropanation of styrene and (d)-men-
thyl diazoacetate 16a with pybox-hm 1a in the presence
of co-solvent THF or toluene (Scheme 5). The use of a
single organic solvent resulted in lower yields and lower
enantioselectivities (entries 1 and 2). Surprisingly, addi-
tion of water to both media in entries 1 and 2 dramat-
ically improved the enantioselectivities and slightly the
yields (entries 3 and 5). This phenomenon can be
simply accounted for by the increase of the solubility of
the active catalyst Ru(pybox-hm)Cl2(vacant or solvent)
derived from pybox-hm 1a and pre-catalyst [RuCl2(p-

858
S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
Table 1. Catalytic asymmetric cyclopropanation of styrene and menthyl diazoeaters 16a–d with chiral pybox-hm 1a and
[RuCl2(p-cymene)]2 in the presence of water or alcoholsa
Entry
Pybox
Diazoester
Initial solvent (mL)
Solvent of 16 (mL)
17t+17cb
% eec
17c
Yield (%)
Ratio
17t
1
2
3
4
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
1a
1a
1a
1a
1a
1a
1a
1b
1b
2a
2ae
16a
16a
16a
16b
16a
16a
16c
16d
16b
16b
16a
16a
16a
16a
16b
16a
16a
16a
16a
16b
16b
THF (3)
Toluene (3)
THF (2)+H2O (1)
THF (2)+H2O (1)
THF (3)
Toluene (3)
THF (3)
39
38
46
57
56
57
24
30
75
35
67
54
78
52
78
73
59
47
61
78
65
83:17
89:11
95:5
86:14
96:4
97:3
92:8
92:8
96:4
95:5
96:4
91:9
95:5
97:3
95:5
96:4
95:5
94:6
98:2
94:6
97:3
8
8
30
28
45
44
51
76
27
26
54
60
2
15
65
88
88
58
30
15
13
78
71
78
68
88
94
67
57
83
89
35
11
92
96
90
89
84
64
66
91
91
THF (3)
5
Toluene (2)+H2O (1)
Toluene (0.5)+H2O (0.5)
Toluene (0.5)+H2O (0.5)
Toluene (0.5)+H2O (0.5)
Toluene (0.5)+H2O (0.5)
Toluene (0.5)+H2O (0.5)
Toluene (1)+EtOH (1)
Toluene (1)+t-BuOH (1)
Toluene (1)+i-PrOH (1)
Toluene (1)+i-PrOH (1)
Toluene (1)+i-PrOH (1)
THF (1)+i-PrOH (1)
i-PrOH (2)
Toluene (3)
Toluene (1.5)
Toluene (1.5)
Toluene (1.5)
Toluene (1.5)
Toluene (1.5)
Toluene (3)
Toluene (3)
Toluene (3)
Toluene (3)
Toluene (3)
THF (3)
i-PrOH (3)
Toluene (3)
Toluene (3)
Toluene (3)
Toluene (3)
6d
7d
8d
9d
10d
11
12
13
14f
15
16
17
18
19
20
21
Toluene (2)
Toluene (1)+i-PrOH (1)
Toluene (1)+i-PrOH (1)
Toluene (1)+i-PrOH (1)
a Styrene (10 mmol), diazoacetate (2.0 mmol), pybox (0.14 mmol), [RuCl2(p-cymene)]2 (0.05 mmol), 40°C. A solution of diazoacetate in 1.5–3.0
mL of the same solvent was slowly added by syringe for 6–8 h to the mixture of styrene and the catalyst in the initial solvent.
b Isolated yield, ratios by 1H NMR.
c % ee determined by reported method, see Ref. 7a. Absolute configuration: 17t for entries 1–8 and 11–19, (1S,2S); for entries 9, 10, 20 and 21,
(1R,2R); 17c for entries 3–8, 11 and 13–19, (1S,2R); for entries 1, 2, 9, 10, 12, 20 and 21, (1R,2S).
d Half scale for entry 1: styrene (5 mmol), diazoacetate (1.0 mmol), catalyst 5 mol%, for 4 h.
e Ethylene complex was used.
f 30°C. The cyclopropanation did not proceed at 20°C.
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reaction and the selectivities. The influence of sub-
stituents on the diazoesters was also examined. Steri-
cally hindered diazoesters gave higher stereoselectivities
in toluene/water phase. (d)-Menthyl ester was better
matching to the (R,R)-absolute configuration of pybox,
which ought to give higher enantioselectivity according
to our previous work (entries 3 and 6–8).7b The use of
pybox-he 2a and Ru(pybox-he)(ethylene) complex 13
gave moderate enantioselectivities (entries 9–10).
cymene)]2. When the catalytic asymmetric cyclopropa-
nation was carried out in toluene/water biphasic media,
the product gave a enantioselectivity of 94% (entry 6).
Into the two-phase system of water and organic solvent
(initial ratio=1:2), a solution of the diazoacetate 16a
was slowly added under vigorous stirring to give the
desired cyclopropanes 17 in moderate yields with higher
enantioselectivity (88% for 17t, entries 3 and 5). The
organic layer was extracted with degassed (or absolute)
diethyl ether and concentrated to give the products. In
this aqueous system, addition of phase-transfer reagents
such as (n-Bu4N)(HSO4) (10 mol% of 16a) into the
system of entry 5 resulted in no improvement in the
On the other hand, when alcohols such as ethanol,
isopropyl alcohol, and tert-butyl alcohol in place of
water were adopted to provide a homogeneous protic

S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
859
medium, isopropyl alcohol resulted in the best enan-
tioselectivities, up to 96% ee for trans-17t and 88% ee
for cis-17c at 30°C (entries 11–13 and 14). (l)-Menthyl
diazoacetate 16b showed a decrease of ee to 90% for the
trans-product (entry 15), because of the unmatched
steric pair toward (R,R)-absolute configuration of the
ligand. Use of pure isopropyl alcohol gave moderate
ees (entry 17). We have thus found that the choice of
alcohol solvents apparently influences the enantioselec-
tivity. Although at present we cannot define clearly the
origin of the stereochemical outcomes for protic sol-
vents, we believe that weak interactions between the
solvent and chiral ligands such as hydrogen bonding is
the most important factor in protic and biphasic sol-
was reported by us as an excellent chiral ligand for
1,3-dipolar cycloaddition reactions gave 64–66% ee for
trans (entries 18 and 19).12
2.4. Catalytic asymmetric cyclopropanation of vinyl
ethers with diazoester
Next, we applied our protic conditions to various more
electron rich terminal alkenes such as vinyl ethers to
afford functionalized chiral cyclopropane rings. The
results are summarized in Table 2. For all of the
substrates, the cyclopropanation reactions were carried
out smoothly in biphasic media with high stereoselectiv-
ities to give b-functionalized chiral cyclopropane com-
pounds (entries 1–7). In the case of tert-butyl vinyl
ether, the reactivity and trans/cis ratio was found to be
low (entry 8). Electron deficient alkenes such as vinyl
acetate could not reacted with the diazoester under
same reaction condition because of electronic reasons
(entry 9).
vent systems. With pybox-he 2a synthesized from (L)-
threonine, the enantioselectivities with the ruthenium
catalyst were found to be moderate by using (l)-men-
thyl diazoacetate 16b at 40°C: 83% ee for trans and 54%
ee for cis, in 96:4 trans: cis ratio (entry 9). In toluene/i-
PrOH the enantioselectivities increased to 91% for trans
and 78% ee for cis, in 94:6 trans:cis ratio. (entry 20). In
comparison, classic pybox-ipr 2c with similar bulkiness
to 2a was found in toluene/i-PrOH media to give 93%
ee for trans and 90% ee for cis, in 97:3 trans/cis ratio
(84% yield). Pybox-he 2a thus proved to be inferior to
pybox-ipr 2c. Furthermore, pybox-tbdmsom 1b which
2.5. Intramolecular version
We examined briefly an intramolecular version for cata-
lytic asymmetric cyclopropanation using trans-cin-
namyl diazoester 26 in the presence of Ru(II)(pybox)
Table 2. Catalytic asymmetric cyclopropanation of various electron rich terminal alkenes and d-menthyl diazoeaters 16a with
chiral pybox-hm 1a and [RuCl2(p-cymene)]2 in the presence of watera
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Entry
Alkene
Time (h)
trans+cisb
Ratio
% eec trans
Yield (%)
1
2
3
4
5
6
7
8
9
15a
15b
15c
15d
15e
15f
15g
15h
15i
18
22
19
22
23
29
23
18
33
17 (62)
18 (82)
19 (70)
20 (55)
21 (58)
22 (56)
23 (57)
24 (24)
NDe
98:2
97:3
96:4
97:3
99:1
94:6
95:5
74:26
–
97
96
92
94
94
97
94
90d
–
a Alkene (5 mmol), diazoacetate (1.0 mmol), pybox-hm 1a (0.07 mmol), [RuCl2(p-cymene)]2 (0.025 mmol), 40°C. A solution of diazoacetate in 1.5
mL of the same solvent was slowly added by syringe for 9 h to the mixture of alkene and the catalyst in the initial solvent.
b Isolated yield, ratios by 1H NMR.
c % ee determined by chiral GC. Absolute configuration: for all products 17–24, (1S,2S).
d 82 % ee for cis isomer.
e The cyclopropanation did not proceed.

860
S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
catalyst in a single organic and biphasic media. The
solvent effects are summarized in Table 3. To our
surprise, the reactivities of pybox catalysts were differ-
ent from the intermolecular versions. Ru(pybox-hm)Cl2
catalyst gave relatively low enantioselectivity for trans
(entries 1–3). Interestingly, Ru(pybox-he)Cl2 catalyst
gave an enantioselectivity of 52% for the corresponding
cyclopropane ring fused lactone (entry 6). Bulky sub-
stituents of the hydroxy groups on the oxazoline rings
in pybox ligand seems to be increase the enantioselec-
tivity for intramolecular cyclopropanation reactions
(entries 10–12) (Scheme 6).
catalyst was soluble in the water phase. As the active
species remained in the aqueous phase, the second run
was carried out by addition of styrene and diazoacetate
to give a similar result (entry 2 in Table 4). We repeated
the same reaction using the same water phase. During
the fourth cycle, the yield and selectivitiy were dramati-
cally decreased. These results suggested that some
active intermediate such as a ruthenium carbenoid was
extracted into the organic phase or the catalyst was
destroyed by dissolved oxygen. We are now investigat-
ing further the optimization and recycling of the
catalyst.
Table 3. Catalytic asymmetric intramolecular cyclopropa-
nation reaction of trans cinnamyl diazoester 26 in protic
mediaa
Table 4. Re-use of the water phase for catalytic asymmet-
ric cyclopropanation reactiona
Run
Time (h)
trans+cisb
% eec trans
Entry
Pybox
Solvent
Yield (%)b
% eec trans
Yield (%)
Ratio
1
2
3
4
5
6
7
8
1a
1a
1a
2a
2a
2a
2b
2b
2b
12
12
12
CH2Cl2
Toluene
Toluene+H2O 77
CH2Cl2
Toluene
Toluene+H2O 70
CH2Cl2
Toluene
Toluene+H2O
CH2Cl2
Toluene
72
68
5
10
13
16
39
52
–
25
–
68
77
48
1
2
3
4
18
22
42
72
62
55
33
13
98:2
98:2
96:4
83:17
97
97
89
42
82
63
51
30
9
63
86
a Styrene (5 mmol), diazoacetate (1.0 mmol), pybox-hm 1a (0.07
mmol), [RuCl2(p-cymene)]2 (0.025 mmol), 40°C. A solution of
diazoacetate in 1.5 mL of the same solvent was slowly added by
syringe for 9 h to the mixture of styrene and the catalyst in toluene.
Then the organic phase was removed and the water phase was used
for next cycles.
9
10
11
12
Toluene+H2O 33
b Isolated yield, ratios by 1H NMR.
a 25 (0.3 mmol), catalyst 5 mol%, 40°C. A solution of 26 in 1.5 mL of
c The ee was determined by chiral GC.
toluene was slowly added by syringe for 6 h to the catalyst in the
solvent.
b Isolated yield.
c % ee determined by reported method, see Ref. 7a. Absolute configu-
ration: for entries 1–3, 8 and 10–12, (1R,5S). for entries 4–6,
(1S,5R).
3. Conclusion
One of the recent social demands for organic synthesis
and catalysis, with environmental concerns in mind, has
been for the reactions to be carried out in non-halo-
genated solvents or in aqueous and protic media.5 We
therefore had expectations of developing a new process
in aqueous media for asymmetric catalytic cyclopropan-
ation using our water-soluble Ru(pybox-hm) catalyst.
The hydroxymethyl derivative of pybox can provide
excellent stereoselectivities for cyclopropanations of
electron rich terminal alkenes, compared to the hydroxy-
ethyl or isopropyl derivatives, in moderate yields in
aqueous and protic media. We hypothesize that appro-
priate solvation of water or alcohols around the
hydroxy group causes a more favorable chiral environ-
ment around the active site for the cyclopropanation.
Work is now under way on applications to other cata-
lytic reactions performed in aqueous media.
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Scheme 6. Catalytic asymmetric intramolecular cyclopropa-
nation reaction in protic media.
2.6. On the re-use of the water phase containing active
catalyst
When the catalyst was dissolved in the protic or bipha-
sic media, the protic phase was immediately colorlized
to dark purple while toluene phase was almost color-
less. It could easily be seen from the dark-violet color-
ing of the bottom phase that most of the catalyst was
dissolved in the aqueous phase. As the reaction pro-
ceeded, the toluene phase was slightly colorlized to pale
red. This phenomenon suggested the ruthenium com-
plex or the intermediate was slightly soluble in the
organic phase during the reaction even though the
4. Experimental
4.1. General
All reactions were carried out under a nitrogen atmo-
sphere. Common solvents were purified before use.
THF (anhydrous), Et2O (anhydrous), toluene and
CH2Cl2 (anhydrous) are commercially available from

S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
861
Kanto Chemical Co. Ltd., and were used without fur-
ther purification. All reagents were reagent grade and
purified when necessary. Reactions were monitored by
TLC using 250 mm Merck (Art. 5715) precoated silica
gel. Flash column chromatography was performed over
Merck (Art. 7734) silica gel. Melting points were mea-
sured on a Thomas Hoover melting point apparatus
100 mL of dichloromethane and stirred at rt for 5 min.
Then tert-butyldimethylsilylchloride (4.60 g, 30.5
mmol) was added in one portion. After the reaction
mixture was stirred at rt for 3.5 h, the solution was
evaporated under reduce pressure. Purification by silica
gel chromatography (AcOEt/n-Hex=1:2) gave 7.50 g
(12.0 mmol, yield 97.5%) of bis-amide ester 6 as a
colorless oil. IR (NaCl); 3418, 2929, 2856, 1746, 1682,
1568, 1519, 1471, 1445, 1377, 1361, 1321, 1257, 1210,
1
and are uncorrected. H and 13C NMR spectra were
recorded on Varian Mercury-300 spectrometer. 1H
NMR chemical shifts are reported as l values(ppm)
relative to internal tetramethylsilane and splitting pat-
terns are designated as: s=singlet, d=doublet, t=
triplet, q=quartet, m=multiplet, br=broad. Coupling
constants are given in Hz. IR spectra were recorded
with JASCO FT/IR-230 spectrometer and are reported
in reciprocal centimeter (cm−1). Elemental analyses were
performed with Yanagimoto MT-3 CHN corder. Opti-
cal rotations were measured on JASCO DIP-140 polar-
imeter at the sodium D line (1 mL sample cell).
1
1173, 1093 cm−1. H NMR (300 MHz, CDCl3); l 0.06
(s, 6H), 0.08 (s, 6H), 0.91 (s, 18H), 1.25 (d, J=6.3 Hz,
6H), 3.76 (s, 6H), 4.51 (ddq, J=6.3, 6.3, 3.0 Hz, 2H),
4.83 (dd, J=9.1, 3.0 Hz, 2H), 8.04 (t, J=8.0 Hz, 1H),
8.20 (d, J=8.8 Hz, 2H), 8.36 (d, J=8.0 Hz, 2H). 13C
NMR (75.0 MHz, CDCl3); l −5.0, −4.4, 18.0, 20.6,
52.4, 58.5, 69.1, 125.7, 138.9, 149.0, 164.1, 170.5. Anal.
calcd for C29H51N3O8Si2: C, 55.65; H, 8.21; N, 6.71.
Found: C, 55.53; H, 8.23; N, 6.57.
4.2.1.3. Bis-amide alcohol 7. Lithium borohydride
(0.61 g, 25.6 mmol) was placed in a 200 mL, three
necked round bottomed flask equipped with a magnetic
stirring bar, nitrogen inlet tube and 100 mL dropwise
funnel. The flask was degassed with vacuum pump, and
flushed with nitrogen gas. The flask was charged with
40 mL of dry tetrahydrofuran and cooled to 0°C. 8.00
g (12.8 mmol) of bis-amide ester 6 in tetrahydrofuran
(35 mL) was added dropwise over 20 min. After the
reaction mixture was stirred at 0°C–rt for 6 h, 3 mL of
water was added the reaction mixture and extracted
with dichloromethane (100 mL×3). The combined
organic layer was dried over anhydrous sodium sulfate
and concentrated by rotary evaporator. The crude was
purified by column chromatography (AcOEt/n-Hex=
2:1) to yield 5.45 g (9.56 mmol, yield 74.8%) of bis-
amide alcohol 7 as a colorless oil. IR (NaCl); 3408,
3055, 2929, 2844, 2857, 2360, 1667, 1593, 1570, 1524,
1471, 1444, 1376, 1361, 1258, 1216, 1171, 1098, 1005
Chiral ligands, pybox-hm 1a were synthesized according
to the literature. Starting styrene derivatives are com-
mercially available. The absolute stereochemistry of
cyclopropanation product 17t, 17c, 18–25 and 27 was
determined by chiral GPLC.
4.2. Synthesis of pybox ligands
4.2.1. Synthesis of pybox-he 2a
4.2.1.1. Bis-amide ester 5.
L-Threonine methyl ester
hydrochloride 4 (5.00 g, 29.5 mmol) was placed in a 200
mL, three necked round bottomed flask equipped with
a magnetic stirring bar, nitrogen inlet tube and 100 mL
addition funnel. The flask was degassed with vacuum
pump, and flushed with nitrogen gas. The flask was
charged with 45 mL of chloroform. The solution was
stirred and cooled to 0°C. Triethylamine (10.0 mL, 72.1
mmol) was added dropwise to the solution. After stir-
ring for 5 min, 2,6-pyrizine dicarboxylic acid chloride 3
(3.00 g, 14.7 mmol) in chloroform (20 mL) was added
dropwise to the solution. When the adding was
finished, the reaction mixture was stirred at rt for 12 h.
Then CHCl3 was removed on rotary evaporator. Purifi-
cation by silica gel chromatography (AcOEt/MeOH=
20:1) gave 4.88 g (12.3 mmol, yield 91.8%) of amide
ester 5 as a white solid. Mp 127–128°C. IR (NaCl);
3384, 2977, 1745, 1673, 1531, 1439, 1356, 1273, 1175,
1
cm−1. H NMR (400 MHz, CDCl3); l 0.05 (s, 6H), 0.08
(s, 6H), 0.94 (s, 18H), 1.22 (d, J=6.2 Hz, 6H), 3.16
(brs, 2H), 5.83 (dd, J=4.9, 4.6 Hz, 4H), 4.02 (ddt,
J=8.6, 4.6, 2.2 Hz, 2H), 4.29 (dq, J=6.2, 2.2 Hz, 2H),
7.96 (d, J=8.6 Hz, 2H), 8.03 (t, J=7.9 Hz, 1H), 8.35
(d, J=7.9 Hz, 2H). 13C NMR (75.0 MHz, CDCl3); l
−4.8, −4.3, 18.0, 20.8, 57.4, 63.2, 67.9, 125.5, 139.1,
149.0, 164.5.
1
1135, 1084, 1018 cm−1. H NMR (400 MHz, CDCl3); l
1.31 (d, J=6.4 Hz, 6H), 3.27 (brs, 2H), 3.80 (s, 6H),
4.51 (ddq, J=6.4, 6.2, 2.6 Hz, 2H), 4.77 (dd, J=9.0, 2.7
Hz, 2H), 8.01 (d, J=7.9 Hz, 2H), 8.78 (d, J=9.0 Hz,
2H). 13C NMR (75.0 MHz, CDCl3); l 20.4, 52.9, 68.4,
125.4, 139.2, 148.4, 164.1, 171.6. Anal. calcd for
C17H23N3O8·0.5H2O: C, 50.24; H, 5.95; N, 10.34.
Found: C, 50.17; H, 6.13; N, 10.24%.
4.2.1.4. Pybox-he 2a. Bis-amide alcohol 7 (2.00 g,
3.50 mmol), imidazol (1.67 g, 24.5 mmol) and triphenyl
phosphine (2.01 g, 7.7 mmol) were placed in a 50 mL,
round bottomed flask equipped with a magnetic stirring
bar and nitrogen inlet tube. The flask was degassed
with vacuum pump, and flushed with nitrogen gas. The
flask was charged with 15 mL of dry dichloromethane
and stirred at rt for 5 min. And then 4 mL of
carbontetrachloride was added at one portion. After
the reaction mixture was stirred at rt for 4.5 h, the
solvent was removed under reduce pressure. Then the
residue was washed with n-hexane (10 mL×3) and the
solution was concentrated and to yield 0.83 g (1.55
mmol, yield 44.3%) of 8 as a pale yellow oil which was
used in a next step without further purification.
4.2.1.2. Bis-amide ester 6. 2,6-Bis[(1%-(S)-carbo-
methoxy-2%-(R)-hydroxy)propyl carbamoyl]pyridine 5
(4.85 g, 12.2 mmol) and imidazole (4.16 g, 85.4 mmol)
were placed in a 300 mL, round bottomed flask
equipped with a magnetic stirring bar and nitrogen inlet
tube. The flask was degassed with vacuum pump, and
flushed with nitrogen gas. The flask was charged with

862
S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
Compound 8 (0.80 g, 1.50 mmol) was placed in a 100
mL, round bottomed flask equipped with a magnetic
stirring bar and nitrogen inlet tube. The flask was
degassed with vacuum pump, and flushed with nitrogen
gas. The flask was charged with 18 mL of tetra-
hydrofuran and stirred at rt for 5 min. Then 4.2 mL
(4.2 mmol) of tetrabutylammoniumfluoride (DCM,
THF solution) was added slowly. After the mixture was
stirred at rt for 3 h, the solvent was removed on rotary
evaporator. Purification by silica gel chromatography
(AcOEt/MeOH=20:1). And then obtained solid was
washed small amount of water and to yield 0.46 g (1.50
mmol, yield 100%) of pybox-he 2a as a white solid. Mp
94–95°C. IR (NaCl); 3390, 2926, 1661, 1575, 1532,
1456, 1532, 1319, 1247, 1174, 1145, 1104 cm−1. 1H
NMR (400 MHz, CDCl3); l 1.30 (d, J=6.4 Hz, 6H),
2.70 (brs, 2H), 3.77 (dq, J=6.4, 3.5 Hz, 2H), 4.29 (ddd,
J=13.7, 12.2, 3.5 Hz, 4H), 4.59 (dd, J=13.7, 12.2 Hz,
2H), 7.91 (t, J=7.9 Hz, 1H), 8.15 (d, J=7.9 Hz, 2H).
13C NMR (75.0 MHz, CDCl3); l 19.5, 70.1, 70.4, 73.2,
126.1, 137.7, 146.5, 163.6. Anal. calcd for C15H19N3O4:
C, 55.72; H, 6.55; N, 13.00. Found: C, 55.48; H, 6.48;
N, 13.00%.
3.8 Hz, 2H), 3.88 (dd, J=11.7, 3.8 Hz, 2H), 3.47 (dd,
J=11.7, 4.8 Hz, 2H). 13C NMR (100 MHz, CDCl3); l
159.61, 156.88, 141.07, 131.90, 129.15, 126.34, 122.85,
122.52, 122.22, 122.00, 121.44, 118.00, 69.68, 68.85,
48.51, 37.36. Anal. calcd for C39H33Cl2N3O6: C, 65.92;
H, 4.68; N, 6.00. Found: C, 66.12; H, 4.81; N, 5.91%.
4.2.2.3. Pybox 12. Sodium hydride (0.29 g, 12.8
mmol) was added to a solution of dichlorodiamide
(3.50 g, 5.1 mmol) in tetrahydrofuran (40 mL) at 0°C
and stirred at 0°C–rt for 5 h. The solvent was removed
and purification by silica gel chromatography (AcOEt/
n-Hex=2:1) gave pybox 12 (2.64 g, 4.15 mmol, yield
81.4%) as a white solid. Mp 220–222°C IR;1724, 1647,
1582, 1452, 1279, 1127 cm−1. 1H NMR (400 MHz,
CDCl3); l 8.26 (d, J=7.9 Hz, 2H), 8.08 (dd, J=7.1, 1.3
Hz, 4H), 7.88 (t, J=7.9 Hz, 1H), 7.56–7.25 (m, 16H),
6.14 (d, J=6.2 Hz, 2H), 4.97 (ddd, J=10.1, 8.1, 6.2 Hz,
2H), 4.50 (dd, J=10.1, 9.0 Hz, 2H), 4.36 (dd, J=9.0,
8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3); l 166.86,
164.13, 148.34, 139.13, 136.41, 133.58, 130.10, 129.78,
129.46, 129.24, 128.68, 127.67, 125.25, 76.92, 76.11,
55.75, 44.61. Anal. calcd for C39H31N3O6: C, 73.46; H,
4.90; N, 6.59. Found: C, 73.55; H, 4.94; N, 6.63%.
4.2.2. Synthesis of pybox-hydroxy benzyl
4.2.2.1. Bis-amide alcohol 10. Triethylamine (4.5 mL,
35.1 mmol) was added dropwise to a solution of 2,6-
pyridinedicarboxylic acid (1.63 g, 8.00 mmol) in
dichloromethane (20 mL) at 0°C. The mixture was then
added to suspension of amino ester (4.34 g, 16.0 mmol)
in dichloromethane (50 mL) at 0°C and stirred for 3 h.
After warming to room temperature the reaction
medium was concentrated. Purification of the residue
by silica gel chromatography (AcOEt/n-Hex=3:1) gave
the bis-amide alcohol (4.19 g, 6.2 mmol, yield 77.8%) as
a white solid. Mp 109–111°C. IR; 3358, 3064, 2926,
2854, 1705, 1669, 1532, 1449, 1271, 1113, 1075 cm−1. 1H
NMR (400 MHz, CDCl3); l 9.00 (d, J=9.5 Hz, 2H),
8.02 (d, J=7.7 Hz, 2H), 7.87–7.38 (m, 20H), 7.26 (d,
J=7.7 Hz, 1H), 6.76 (d, J=10.1 Hz, 2H), 4.80 (ddddd,
J=12.1, 10.1, 6.8, 3.5, 2.6 Hz, 2H), 3.94 (dd, J=12.1,
2.6 Hz, 2H), 3.65 (dd, J=12.1, 3.5 Hz, 2H). 13C NMR
(100 MHz, CDCl3); l 168.0, 163.80, 147.66, 138.86,
136.47, 133.35, 129.41, 129.03, 128.86, 128.37, 127.79,
124.34, 75.78, 62.35, 57.01. Anal. calcd for C39H35N3O8:
C, 69.53; H, 5.24; N, 6.24. Found: C, 69.36; H, 5.46; N,
6.21%.
4.2.2.4. Pybox-hbn 2b. To 10% NaOH (20 mL) was
added 12 (2.64 g, 4.15 mmol) in methanol/tetra-
hydrofuran (15 mL/1 mL) in one portion. After stirring
20 min at rt, the solvent was evaporated under reduced
pressure. Purification of the residue by silica gel chro-
matography (AcOEt only) gave pybox-hbn (2b) (1.78 g,
4.14 mmol, yield 99.8%) as a white solid. Mp 85–87°C.
1
IR; 3336, 1732, 1650, 1580, 1246, 1112 cm−1. H NMR
(400 MHz, CDCl3); l 8.28 (d, J=7.9 Hz, 2H), 7.93 (t,
J=7.9 Hz, 4H), 7.44–7.26 (m, 10H), 4.66–4.57 (m, 4H),
4.36 (dd, J=9.5, 8.6 Hz, 2H), 4.22 (dd, J=8.6, 8.4 Hz,
2H). 13C NMR (100 MHz, CDCl3); l 163.99, 146.74,
139.83, 137.81, 129.00, 128.78, 127.32, 126.61, 77.85,
73.73, 70.40. Anal. calcd for C25H23N3O4·0.67H2O: C,
73.46; H, 4.90; N, 6.59. Found: C, 73.55; H, 4.94; N,
6.63%.
4.3. Synthesis of Ru(pybox-he)(ethylene) 13
A solution of pybox-he 2a (90mg, 29.5mmol) and
[RuCl2(p-cymene)]2 (90.3 mg, 14.8 mmol) in
dichloromethane (2 mL) was stirred at room tempera-
ture under ethylene atmosphere (1 atm) for 24 h. After
solvent was removed under reduced pressure, purifica-
tion of the residue by silica gel chromatography at 0°C
with acetone gave 13 (138.3 mg, 26.6 mmol, yield 90%)
as dark red solid. Mp 103–105°C. IR; 3388, 2972, 1699,
1569, 1492, 1402, 1251, 1209, 1104, 1001 cm−1. 1H
NMR (400 MHz, CDCl3); l 8.00 (s, 3H), 5.70–5.10 (m,
2H), 4.92 (dd, J=9.2, 2.4 Hz, 2H), 4.89 (dd, J=9.2, 3.3
Hz, 2H), 4.24 (ddd, J=8.4, 3.3, 2.4 Hz, 2H), 3.88 (dq,
J=6.4, 2.4 Hz, 2H), 3.60–3.57 (m, 2H), 1.23 (d, J=6.2
Hz, 6H). 13C NMR (100 MHz, CDCl3); l 166.02,
146.60, 134.25, 124.28, 76.51, 75.33, 70.80, 69.16, 18.95.
Anal. calcd for C15H26Cl2N3O4Ru: C, 40.40; H, 4.59;
N, 8.31. Found: C, 40.29; H, 4.69; N, 8.24%.
4.2.2.2. Bis-amide chloride 11. To a suspension of 10
(4.19 g, 6.22 mmol) in benzene (30 mL) was added
thionylchloride (5 mL, 66.7 mmol). The resulting mix-
ture was kept at reflux for 3 h. The solvent and excess
of thionylchloride were removed under reduced pres-
sure. The residue was washed with dichloromethane (20
mL×3) and concentrated. Purification of the residue by
silica gel chromatography (AcOEt/n-Hex=2:1) gave 11
(3.50 g, 5.1 mmol, yield 76.0%) as a white solid. Mp
88–90°C. IR; 3361, 1683, 1522, 1448, 1268, 1110, 1025
1
cm−1. H NMR (400 MHz, CDCl3); l 8.81 (d, J=8.8
Hz, 2H), 8.19 (d, J=7.9 Hz, 2H), 8.08 (dd, J=8.2, 1.1
Hz, 4H), 7.91 (t, J=7.9 Hz, 1H), 7.61–7.33 (m, 16H),
6.43 (d, J=9.0 Hz, 2H), 4.97 (dddd, J=11.7, 9.0, 4.8,

S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
863
4.4. Synthesis of 14
the mixture had been stirred for an additional 17 h, the
organic layer was extracted with diethylether (5 mL×4),
dried over sodium carbonate. Purification by silica gel
chromatography (AcOEt/n-Hex=1:20) gave a oily mix-
A solution of 12 (100 mg, 15.7 mmol) and [RuCl2(p-
cymene)]2 (49.1 mg, 7.85 mmol) in dichloromethane (2
mL) was stirred at rt under an ethylene atmosphere (1
atm) for 24 h. After solvent was removed under
reduced pressure, purification of the residue by silica gel
chromatography at 0°C with acetone gave ethylene
complex 14 (122.8 mg, 14.4 mmol, yield 92.0%) as dark
red solid. Mp 210–212°C. IR; 3060, 2358, 1724, 1585,
ture
L-menthyl-2-phenyl cyclopropane carboxylic acid
(195.3 mg, 0.65 mmol, Yield 65.0%, trans/cis ratio 97:3,
trans 91% ee, cis 71% ee).
Entry 6 in Table 3: To a solution of Ru(pybox-
he)(ethylene) (7.8 mg, 0.015 mmol, 5 mol%) in toluene
(1 mL)/H2O (1 mL) was added dropwise a solution of
trans-cinnamyl diazoacetate (60.7 mg, 0.3 mmol) in
toluene (1.5 mL) at 40°C for 6 h under an argon
atmosphere. After adding diazoacetate, stirred for 1 h.
The reaction mixture was concentrated and purified by
silica gel chromatography (AcOEt/n-Hex=1:5) gave 27
(26.1 mg, 0.21 mmol, yield 70%, 52% ee) as a white
solid. The enantiomeric purity was measured by GLC
(SPERCO, 30 m).
1492, 1450, 1401, 1313, 1068, 1024 cm−1. H NMR (400
1
MHz, CDCl3); l 8.20–8.18 (m, 4H), 7.79 (t, J=8.43 Hz,
1H), 7.68–7.21 (m, 18H), 6.58 (d, J=2.0 Hz, 2H),
5.95–5.92 (m, 2H), 5.20 (dd, J=9.2, 9.0 Hz, 2H), 5.04
(ddd, J=9.1, 9.0, 2.0 Hz, 2H), 4.87 (t, J=8.8 Hz, 2H).
13C NMR (100 MHz, CDCl3); l 166.77, 164.20, 134.21,
133.78,
133.46,
130.10.
Anal.
calcd
for
C42H38Cl2N3O6Ru: C, 69.53; H, 5.24; N, 6.24. Found:
C, 69.36; H, 5.46; N, 6.21%.
4.5. Catalytic asymmetric cyclopropanation of styrene
in biphasic media7b
4.5.1. 2-Phenyl-cyclopropanecarboxylic acid d-menthyl
ester(trans) 17. All of the reaction procedure in Table 2
was same as entry 6 in Table 1. 96% ee determined by
GLC (GL Sciences TC-WAX (30 M×0.25 mm): column
temperature 200°C, injector and detector temperature
230°C, detection FID, tR=25.8 (cis), 26.0 (cis), 29.4
(trans, major), 31.7 (trans, minor) min. [h]D=+227.0 (c
1.00, CH2Cl2, 23.9°C). White solid (mp=61.5–62.5°C).
IR (neat): 3031, 2953, 2868, 1721, 1604, 1497, 1457,
1404, 1330, 1266, 1183, 1082, 1032, 982, 937, 847, 755,
696 cm−1. 1H NMR (CDCl3, 300 MHz): l 0.77 (d,
J=6.9, 3H), 0.80–1.14 (m, 9H), 1.28 (ddd, J=8.4, 6.4,
4.5, 1H), 1.33–1.54 (m, 2H), 1.58 (ddd, J=9.1, 5.2, 4.5,
1H), 1.64–1.73 (m, 2H), 1.83–1.93 (m, 2H), 1.98–2.05
(m, 1H), 2.52 (ddd, J=9.1, 6.4, 4.2, 1H), 4.72 (ddd,
J=10.8, 10.8, 4.4, 1H), 7.10 (d, J=7.14, 2H), 7.20 (t,
J=7.42, 1H), 7.29 (dd, J=7.42, 7.14, 2H). 13C NMR
(CDCl3, 75 MHz): l 16.4, 17.1, 20.9, 22.1, 23.5, 24.4,
26.0, 26.3, 31.5, 34.3, 41.1, 47.2, 74.5, 126.3, 126.5,
128.5, 140.4, 173.0.
Entry 6 in Table 1: To a solution of pybox-hm 1a and
[RuCl2(p-cymene)]2 (15.3 mg, 0.05 mmol) in toluene
(0.5 mL) were stirred at rt under a nitrogen atmo-
sphere. After 30 min stirring water (0.5 mL) and styrene
(0.57 mL, 5.00 mmol) were added to the mixture and
stirring at rt for 30 min. To the mixture was added a
solution of
L-menthyldiazoacetate (224.3 mg, 1.00
mmol) in toluene (1.5 mL) through a microsyringe
pump over 4 h at 40°C. After the mixture had been
stirred for an additional 17 h, the organic layer was
extracted with diethylether (5 mL×4), dried over
Na2SO4. Purification by silica gel chromatography
(AcOEt/n-Hex=1:20) gave a oily mixture 17t and 17c
(234.3 mg, 0.78 mmol, yield 57.0%, trans/cis ratio 97:3,
trans 94% ee, cis 76% ee).
Entry 20 in Table 1: Pybox-he 2a (42.7 mg, 0.14 mmol)
and [RuCl2(p-cymene)]2 (30.6 mg, 0.05 mmol) in tolu-
ene (1 mL) were stirred at rt under a nitrogen atmo-
sphere. After 30 min stirring isopropanol (1 mL) and
styrene (1.14 mL, 10.0 mmol) were added to the mix-
ture and stirred at rt for 30 min. To the mixture was
4.5.2. 2-p-Tolyl-cyclopropanecarboxylic acid d-menthyl
ester(trans) 18. 96% ee determined by GLC (GL Sci-
ences TC-WAX (30 M×0.25 mm): column temperature
200°C, injector and detector temperature 230°C, detec-
tion FID, tR=31.2 (cis), 31.9 (cis), 40.7 (trans, major),
43.9 (trans, minor) min. [h]D=+221.9 (c 1.00, CH2Cl2,
24.3°C). White solid (mp=53.5–54.5°C). IR (neat):
2952, 2866, 1721, 1516, 1454, 1398, 1329, 1266, 1181,
added a solution of L-menthyldiazoacetate (448.6 mg,
1.00 mmol) in toluene (3 mL) through a microsyringe
pump over 8 h at 40°C. After the mixture had been
stirred for an additional 17 h, the organic layer was
extracted with diethylether (5 mL×4), dried over
Na2SO4. Purification by silica gel chromatography
(AcOEt/n-Hex=1:20) gave a oily mixture 17t and 17c
(466.0 mg, 1.55 mmol, yield 78.0%, trans/cis ratio 94:6,
trans 91% ee, cis 78% ee).
1
1033 cm−1. H NMR (CDCl3, 300 MHz): l 0.75–1.13
(m, 12H), 1.25 (ddd, J=8.4, 6.2, 4.4, 1H), 1.33–1.58 (m,
3H), 1.63–1.73 (m, 2H), 1.82–1.93 (m, 2H), 1.98–2.05
(m, 1H), 2.32 (s, 3H), 2.48 (ddd, J=9.3, 6.2, 4.0, 1H),
4.71 (ddd, J=10.9, 10.9, 4.5, 1H), 7.00 (d, J=8.0, 2H),
7.10 (d, J=8.0, 2H). 13C NMR (CDCl3, 75 MHz): l
16.4, 17.0, 20.9, 21.1, 22.1, 23.5, 24.3, 25.7, 26.3, 31.5,
34.4, 41.1, 47.2, 74.4, 126.2, 129.2, 136.1, 137.3, 173.1.
Anal. calcd for C21H30O2: C, 80.21; H, 9.62. Found: C,
80.23; H, 9.57%.
Entry 21 in Table 1: Ru(pybox-he)(ethylene) (25.2 mg,
0.05 mmol) in toluene (0.5 mL) was stirred at rt under
a nitrogen atmosphere. After 30 min stirring iso-
propanol (0.5 mL) and styrene (0.57 mL, 5.00 mmol)
were added to the mixture and stirred at rt for 30 min.
To the mixture was added a solution of
L
-menthyldia-
4.5.3. 2-(4-Methoxyphenyl)-cyclopropanecarboxylic acid
d-menthylester ester(trans) 19. 93% ee determined by
GLC (GL Sciences TC-WAX (30 M×0.25 mm): column
zoacetate (224.3 mg, 1.00 mmol) in toluene (1.5 mL)
through a micro syringe pump over 4 h at 30°C. After

864
S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
temperature 220°C, injector and detector temperature
250°C, detection FID, tR=34.8 (cis), 35.5 (cis), 46.6
(trans, major), 49.9 (trans, minor) min. [h]D=+236.2 (c
1.00, CH2Cl2, 24.2°C). Colorless oil. IR (neat): 2951,
2868, 1719, 1612, 1515, 1454, 1399, 1252, 1182, 1103,
0.76 (d, J=6.9, 3H), 0.80–1.12 (m, 12H), 1.17–1.30 (m,
2H), 1.31–1.59 (m, 6H), 1.62–1.75 (m, 3H), 1.82–1.99
(m, 2H), 3.49–3.54 (m, 2H), 3.56 (ddd, J=6.6, 4.5, 2.1,
1H), 4.66 (ddd, J=10.8, 10.8, 4.4, 1H). 13C NMR
(CDCl3, 75 MHz): l 13.9, 15.5, 16.6, 19.3, 20.8, 21.5,
22.1, 23.7, 26.6, 31.46, 31.48, 34.3, 41.1, 47.2, 60.7, 71.1,
74.3, 172.3. Anal. calcd for C18H32O3: C, 72.93; H,
10.88. Found: C, 72.92; H, 10.69%.
1
1036, 981, 939, 822 cm−1. H NMR (CDCl3, 300 MHz):
l 0.76–1.13 (m, 12H), 1.22 (ddd, J=8.5, 6.5, 4.5, 1H),
1.33–1.56 (m, 3H), 1.63–1.72 (m, 2H), 1.78–1.93 (m,
2H), 1.97–2.04 (m, 1H), 2.48 (ddd, J=9.2, 6.5, 4.1, 1H),
3.79 (s, 3H), 4.71 (td, J=10.8, 10.8, 4.4, 1H), 6.83 (d,
J=8.8, 2H), 7.03 (d, J=8.8, 2H). 13C NMR (CDCl3, 75
MHz): l 16.5, 16.8, 20.9, 22.1, 23.6, 24.1, 25.4, 26.3,
31.5, 34.4, 41.1, 47.2, 55.4, 74.4, 114.0, 127.5, 132.3,
158.4, 173.1. Anal. calcd for C21H30O3: C, 76.33; H,
9.15. Found: C, 76.44; H, 8.99%.
4.5.7. 2-Isobutoxy-cyclopropanecarboxylic acid d-men-
thylester ester(trans) 23. 94% ee determined by GLC
(GL Sciences TC-WAX (30 M×0.25 mm): column tem-
perature 145°C, injector and detector temperature
175°C, detection FID, tR=31.5 (trans, major), 33.0
(trans, minor), 48.8 (cis), 49.8 (cis) min. [h]D=+81.6 (c
1.00, CH2Cl2, 22.0°C). Colorless oil. IR (neat): 2954,
2871, 1721, 1451, 1380, 1324, 1259, 1219, 1171, 1098,
4.5.4. 2-(4-Chlorophenyl)-cyclopropanecarboxylic acid d-
menthylester ester(trans) 20. 93% ee determined by
GLC (GL Sciences TC-WAX (30 M×0.25 mm): column
temperature 200°C, injector and detector temperature
230°C, detection FID, tR=55.9 (cis), 56.7 (cis), 72.1
(trans, major), 78.1 (trans, minor) min. [h]D=+211.6 (c
1.00, CH2Cl2, 24.6°C). White solid (mp=97.0–98.0°C).
IR (KBr): 2952, 2868, 1716, 1491, 1453, 1405, 1326,
1
1049, 964, 870 cm−1. H NMR (CDCl3, 300 MHz): l
0.78 (d, J=6.9, 3H), 0.83–1.12 (m, 15H), 1.18–1.28 (m,
2H), 1.33–1.54 (m, 2H), 1.63–1.75 (m, 3H), 1.78–2.00
(m, 3H), 3.26 (dd, J=9.3, 6.7, 1H), 3.30 (dd, J=9.3,
6.7, 1H) or 3.26 (dd, J=11.7, 6.7, 1H), 3.30 (dd,
J=11.7, 6.7, 1H), 3.56 (ddd, J=4.3, 4.3, 2.1, 1H), 4.66
(ddd, J=10.8, 10.8, 4.4, 1H). 13C NMR (CDCl3, 75
MHz): l 15.6, 16.6, 19.3, 19.4, 20.8, 21.6, 22.1, 23.7,
26.6, 28.2, 31.5, 34.4, 41.1, 47.2, 60.9, 74.3, 78.2, 172.3.
Anal. calcd for C18H32O3: C, 72.93; H, 10.88. Found:
C, 72.95; H, 10.80%.
1
1192, 1094, 1039, 1004, 983, 937, 817, 740 cm−1. H
NMR (CDCl3, 300 MHz): l 0.75–1.13 (m, 12H), 1.24
(ddd, J=8.4, 6.4, 4.5, 1H), 1.33–1.54 (m, 2H), 1.58
(ddd, J=9.1, 5.3, 4.5, 1H), 1.64–1.73 (m, 2H), 1.82–
1.92 (m, 2H), 1.97–2.04 (m, 1H), 2.48 (ddd, J=9.1, 6.4,
4.2, 1H), 4.71 (ddd, J=10.8, 10.8, 4.4, 1H), 7.02 (d,
J=8.2, 2H), 7.25 (d, J=8.2, 2H). 13C NMR (CDCl3, 75
MHz): l 16.5, 17.0, 20.9, 22.1, 23.6, 24.5, 25.3, 26.4,
31.5, 34.3, 41.1, 47.2, 74.7, 127.7, 128.7, 132.2, 138.9,
172.7. Anal. calcd for C20H27ClO2: C, 71.73; H, 8.13.
Found: C, 71.55; H, 8.05%.
4.5.8. t-Butoxy-cyclopropanecarboxylic acid d-menthyl-
ester ester(trans) 24. 91% ee determined by GLC (Chi-
raldex B-DA (30 M×0.25 mm): column temperature
170°C, injector and detector temperature 200°C, detec-
tion FID, tR=20.3 (trans, minor), 23.2 (trans, major)
min. [h]D=+84.5 (c 1.00, CH2Cl2, 23.0°C). Colorless
oil. IR (neat): 2958, 2870, 1718, 1448, 1390, 1327, 1259,
1156, 1098, 1035, 951, 919, 856 cm−1. 1H NMR (CDCl3,
300 MHz): l 0.75 (d, J=7.2, 3H), 0.78–1.06 (m, 9H),
1.13 (ddd, J=9.4, 5.4, 4.5, 1H), 1.21–1.27 (m, 10H),
1.32–1.54 (m, 2H), 1.63–1.71 (m, 3H), 1.85–2.00 (m,
2H), 3.52 (ddd, J=7.0, 4.5, 2.3, 1H), 4.66 (ddd, J=
10.9, 10.9, 4.3, 1H). 13C NMR (CDCl3, 75 MHz): l
14.6, 16.2, 20.9, 22.1, 23.0, 23.3, 26.2, 28.0, 31.5, 34.3,
41.1, 47.1, 54.6, 74.3, 75.7, 172.5. Anal. calcd for
C18H32O3: C, 72.93; H, 10.88. Found: C, 73.13; H,
10.68%.
4.5.5. 2-(2-Chlorophenyl)-cyclopropanecarboxylic acid d-
menthylesterester 21. 93% ee determined by GLC (GL
Sciences TC-WAX (30 M×0.25 mm): column tempera-
ture 200°C, injector and detector temperature 230°C,
detection FID, tR=46.9 (cis), 49.3 (cis), 65.9 (trans,
major), 67.7 (trans, minor) min. [h]D=+126.0 (c 1.00,
CH2Cl2, 24.4°C). Colorless oil. IR (neat): 3065, 2952,
2867, 1721, 1446, 1400, 1326, 1268, 1183, 1091, 1046,
1
984, 944, 849, 753, 680 cm−1. H NMR (CDCl3, 300
MHz): l 0.77–1.14 (m, 12H), 1.32–1.76 (m, 7H), 1.93–
2.06 (m, 2H), 2.71 (ddd, J=8.9, 6.8, 4.3, 1H), 4.71
(ddd, J=10.8, 10.8, 4.4, 1H), 7.02–7.07 (m, 1H), 7.14–
7.22 (m, 2H), 7.34–7.40 (m, 1H). 13C NMR (CDCl3, 75
MHz): l 14.8, 16.4, 20.9, 22.1, 23.3, 23.4, 24.6, 26.2,
31.5, 34.4, 41.1, 47.3, 74.6, 126.8, 127.5, 128.0, 129.4,
136.0, 137.6, 173.0. Anal. calcd for C20H27ClO2: C,
71.73; H, 8.13. Found: C, 71.77; H, 8.07%.
4.5.9. t-Butoxy-cyclopropanecarboxylic acid d-men-
thylester ester 24-cis. 81% ee determined by GLC (Chi-
raldex B-DA (30 M×0.25 mm): column temperature
170°C, injector and detector temperature 200°C, detec-
tion FID, tR=26.4 (cis, minor), 28.3 (cis, major) min.
[h]D=+87.0 (c 1.00, CH2Cl2, 24.5°C). White solid
(mp=65.0–66.0°C). IR (neat): 2956, 2930, 2865, 1725,
1454, 1390, 1264, 1232, 1191, 1158, 1106, 981, 945, 826,
760 cm−1. 1H NMR (CDCl3, 300 MHz): l 0.74 (d,
J=6.9, 3H), 0.78–1.11 (m, 10H), 1.23 (s, 3H), 1.30–1.53
(m, 3H), 1.59–1.70 (m, 3H), 1.92–2.10 (m, 2H), 3.54
(ddd, J=6.9, 6.9, 4.9, 1H), 4.69 (ddd, J=10.8, 10.8,
4.4, 1H). 13C NMR (CDCl3, 75 MHz): l 12.7, 16.2,
21.0, 21.6, 22.1, 23.3, 25.8, 27.9, 31.5, 34.4, 41.2, 47.1,
52.9, 74.3, 75.2, 170.2.
4.5.6. 2-Butoxy-cyclopropanecarboxylic acid d-men-
thylester ester(trans) 22. 95% ee determined by GLC
(GL Sciences TC-WAX (30 M×0.25 mm): column tem-
perature 145°C, injector and detector temperature
175°C, detection FID, tR=44.7 (trans, major), 46.4
(trans, minor), 65.8 (cis), 67.9 (cis) min. [h]D=+85.3 (c
1.00, CH2Cl2, 21.3°C). Colorless oil. IR (neat): 2952,
2870, 1721, 1451, 1379, 1323, 1258, 1220, 1171, 1100,
1
1035, 947, 870 cm−1. H NMR (CDCl3, 300 MHz): l

S. Iwasa et al. / Tetrahedron: Asymmetry 14 (2003) 855–865
865
4.5.10. Intramolecular cyclopropanation of trans-cin-
namyl diazoester7b (Table 3, entry 6). To a solution of
Ru(pybox-he)(ethylene) complex (7.8 mg, 5 mol%) in
toluene (1.0 mL)/H2O (1.0 mL) was added dropwise to
a solution of trans-cinnamyl daizoacetate (60.7 mg, 0.3
mmol) in toluene (1.5 mL) at 40°C for 6 h under an
argon atmosphere. After addition of diazoacetate, the
stirring was continued for another 1 h. The reaction
mixture was concentrated and the residue was purified
by flash column chromatography on silica gel (EtOAc/
hexane=5:1) to give bicyclo[3.1.0]hexane 27 (26.1 mg)
in 70% yield as white solid. 52% ee determined by GLC
(SPERCO b-DEX-225, 30 m×0.25 mm): column tem-
perature 170°C, injector and detector temperature
200°C, detection FID, tR=67.5 (cis, minor), 69.9 (cis,
major) min.
Wiley-VCH: Weinheim, 1998; (c) Sinou, D. Transition
Metals for Organic Synthesis, Beller, M.; Bolm, C., Eds.;
Wiley-VCH: Weinheim, 1998; Vol. 2, p. 398; (d) Lind-
stro¨m, U. M. Chem. Rev. 2002, 102, 2751. Papers for
examples: (e) Yonehara, K.; Hashizume, T.; Mori, K.;
Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 5593; (f)
Holz, J.; Heller, D.; Stu¨rmer, R.; Bo¨rner, A. Tetrahedron
Lett. 1999, 40, 7059; (g) Kobayashi, S.; Nagayama, S.;
Busujima, T. Tetrahedron 1999, 55, 8739; (h) Xie, W.;
Fang, J.; Li, J.; Wang, P. G. Tetrahedron 1999, 55, 12929;
(i) Che, C.-M.; Huangand, J.-S. Coord. Chem. 2002, 231,
151 and references cited therein.
5. Iwasa, S.; Nakamura, H.; Nishiyama, H. Heterocycles
2000, 52, 939.
6. Related researches: review for chemistry of oxazoline
ligands: (a) Ghosh, K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1; (b) Fache, F.; Schulz,
E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000,
100, 2159; (c) Du, Da-M.; Wang, Z.-Y.; Xu, D.-C.; Hua,
W.-T. Synthesis 2002, 16, 2347.
Acknowledgements
7. (a) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.;
Itoh, K. J. Am. Chem. Soc. 1994, 116, 2223; (b)
Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.;
Park, S.-B.; Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68, 1247;
(c) Nishiyama, H.; Soeda, N.; Naito, T.; Motoyama, Y.
Tetrahedron: Asymmetry 1998, 9, 2865; (d) Davies, H. M.
L.; Bruzinski, P.; Hutcheson, D. K.; Kong, N.; Fall, M.
J. J. Am. Chem. Soc. 1996, 118, 6897.
8. Wynne, D. C. M.; Olmstead, M.; Jessop, P. G. J. Am.
Chem. Soc. 2000, 122, 7638 and references for solvent
effect in catalytic cyclopropanation cited therein.
9. Fritchi, H.; Leutenegger, U.; Pfaltz, A. Helv. Chim. Acta
1988, 71, 1553.
We thank Ministry of Education, Culture, Sports, Sci-
ence and Technology for partial financial support.
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