New bis(oxazoline) ligands with secondary binding sites for the asymmetric cyclopropanation of furans

Article abstract of DOI:10.1016/S0957-4166(03)00094-6

The diastereo- and enantioselective cyclopropanation of furans was achieved in up to 91% ee using a new set of chiral bis(oxazoline) ligands that are able to use secondary binding sites to enhance selectivity. In contrast, with substrates such as styrene

Full text of DOI:10.1016/S0957-4166(03)00094-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 765–771
New bis(oxazoline) ligands with secondary binding sites for the
asymmetric cyclopropanation of furans
Marina Schinnerl, Claudius Bo¨hm, Michael Seitz and Oliver Reiser*
Institut fu¨r Organische Chemie der Universita¨t, Universita¨tsstr. 31, 93053 Regensburg, Germany
Received 6 December 2002; accepted 14 January 2003
Abstract—The diastereo- and enantioselective cyclopropanation of furans was achieved in up to 91% ee using a new set of chiral
bis(oxazoline) ligands that are able to use secondary binding sites to enhance selectivity. In contrast, with substrates such as
styrene and N-Boc-pyrrole, with which no secondary interactions with the ligands can occur, only moderate selectivities (<50%
ee) were achieved. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2.1. Preparation of the ligands
The concept of C2-symmetry has proved to be invalu-
able for asymmetric catalysis.1 Among the vast number
of ligands known, the most successful ones such as the
binaphthyls2 or the bisoxazolines3 contain a C2-symme-
try axis, and only a few notable exceptions such as
phosphinooxazolines4 or ferrocenyl ligands5 are equally
effective chiral inductors.
In order to test this concept in the cyclopropanation of
alkenes, we synthesized the bisoxazoline 1a according
In a C2-symmetrical chiral catalyst two diagonally
opposite quadrants are sterically blocked, which allows
the unambiguous side approach of a trans-alkene in
copper-catalyzed, asymmetric carbene and nitrene
transfer reactions following the model proposed by
Pfaltz (Fig. 1a)6 for semicorrin ligands and the experi-
mental data available.7 In contrast, the approach of a
cis-alkene is ambiguous if R and R1 are similar in their
steric volume, which should result in a less effective
differentiation of the enantiotopic faces of the double
bond (Fig. 1b),7b being reflected in only limited success
in the asymmetric cyclopropanation of such substrates
to date.8 However, if the sterically blocking substituent
in the ligand could form an attractive interaction to one
of the substituents of the cis-alkene, its selective recog-
nition might become possible (Fig. 1c). The concept of
molecules being able to interact with substrates by
means of secondary interactions is long known from
enzymes, but has only recently led to the successful
development of unnatural ligands for asymmetric
catalysis.9
Figure 1. Model for cyclopropanation of alkenes with cop-
* Corresponding author.
per(I) bis(oxazoline) complexes.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00094-6

766
M. Schinnerl et al. / Tetrahedron: Asymmetry 14 (2003) 765–771
to literature precedent.10,11 It was felt that 1a would be
a suitable starting ligand as it would allow further
attachment of side chains with the possibility of exert-
ing a secondary interaction with a substrate. Indeed, 1a
was readily acylated with carboxylic acids by the
method of Steglich,12 giving rise to 1b and the protected
a-amino acid containing ligands 2 (Scheme 1).
tion of styrene (Table 1). Not too surprisingly, only
moderate enantioselectivities were observed (<50% ee)
since the substituents blocking substrate approach are
not particularly sterically demanding13 (ligands 1a and
1b). Moreover, the side groups of ligands 2 are quite
flexible, such that they can interfere with the approach
of the substrate in the void quadrants, as evidenced by
the decrease in selectivity switching from 1 to 2.
2.3. Asymmetric cyclopropanation of 2,3-dihydrofuran
We next investigated the asymmetric cyclopropanation
of 2,3-dihydrofuran (Table 2), which should also be a
poor substrate on the basis of the steric arguments put
forward above, but offers the possibility of hydrogen
bonding with the ligand through the oxygen of the
furan ring.
Nevertheless, the obtained diastereo- and enantioselec-
tivities were disappointingly low as well (<40% ee in all
cases), however, molecular modeling studies confirmed
that the furan oxygen cannot interact with the ligand
side chains for steric reasons. Moreover, it is important
to note that with all of the substrates described, the
selectivities changed little in reactions with the different
ligands 1 and 2.
2.4. Asymmetric cyclopropanation of furans
Furan itself gave very poor results for the cyclopropa-
nation with diazoacetates in the presence of ligands 1
and 2. Only moderate enantioselectivities (<50% ee)
and especially very low yields (<20%) did not encourage
us to investigate this substrate in more detail. However,
the situation changed dramatically when methyl furan-
carboxylates 5 were subjected to cyclopropanation with
our ligands (Table 3).14,15
Scheme 1.
2.2. Asymmetric cyclopropanation of styrene
To benchmark our new set of ligands, we first tested
some of them in the copper(I)-catalyzed cyclopropana-
In all cases, cyclopropanation took place at the lesser
substituted (presumably more electron-rich) double
Table 1. Cyclopropanation of styrene 3 with methyl diazoacetatea
Entry
Ligand
Yieldc (%)
trans:cisd
transe % ee
cise % ee
1
2
3
1a
1b
2b
60
61
67
60:40
61:39
58:42
42
46
21
49
58
35
a All reactions were carried out under nitrogen.
b Cu(I)-ligand (1 mol%), N2CHCO2Me, CH2Cl2, rt, 12 h.
c Isolated yields.
d Determined by 1H NMR.
e Determined by GC analysis using Chrompack CP-Chirasil DEX CB column.

M. Schinnerl et al. / Tetrahedron: Asymmetry 14 (2003) 765–771
Table 2. Cyclopropanation of 2,3-dihydrofuran 4 with methyl diazoacetatea
767
Entry
Ligand
Yieldc (%)
exo:endod
exoe % ee
endoe % ee
1
2
3
4
1a
1b
2a
2b
63
41
43
66
82:18
84:16
83:17
80:20
15
18
25
25
12
25
36
37
a All reactions were carried out under nitrogen.
b Cu(I)-ligand (1 mol%), N2CHCO2Me, CH2Cl2, rt, 12 h.
c Isolated yields.
d Determined by 1H NMR.
e Determined by GC analysis using Macherey Nagel Lipodex E column.
Table 3. Cyclopropanation of methyl furan-2-carboxylate 5
bond, yielding the exo-adduct 6 exclusively. Using the
ligand 1a, 6a-Me was already obtained with respectable
69% ee (Table 2, entry 1). Taking into account the
relatively small steric requirements of the CH2OH-
groups, as suggested in the experiments using 3 and 4 as
substrates, the hydroxy groups might act as hydrogen
donors, interacting with the carbomethoxy group in 5a
as a hydrogen acceptor. This could constrain 5a, conse-
quently limiting its degrees of freedom to approach the
metal center of the catalyst (Fig. 2).
with ethyl and methyl diazoacetatea
In accordance with this model, the enantioselectivity for
6a-Me dropped significantly to 45% ee (Table 3, entry
2) if the ligand 1b was used in which the possibility for
hydrogen donation was removed. Moreover, using lig-
ands 2 the enantioselectivity was further increased.
With these ligands, hydrogen donation could be possi-
ble through the amino groups in the amino acid side
chain. Accordingly, the selectivities were highest with
the ligands containing the strongest hydrogen donors.
Thus, switching from 2b (R1=tert-butoxycarbonyl) via
2c (R1=acetyl) to 2d (R1=tosyl) the enantioselectivity
for 6a increased from 77–83% ee to 88–91% ee (Table 3,
entries 4–8). Switching from 6a to 6b (entries 9 and 10),
in which the ester group is moved out by one carbon,
the selectivity dramatically decreases again, which is
consistent with the proposal that secondary interactions
from the ligand are less efficient in these cases.
Entry
Substrate
R
Ligand
Yieldc (%)
6d % ee
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
Me 1a
Me 1b
Me 2a
Me 2b
Me 2d
Et
Et
Et
Et
Et
45
46
41
43
39
42
33
36
31
19
69
45
62
77
88
83
85
91e
68
40
2b
2c
2d
2b
2d
10
a All reactions were carried out under nitrogen.
b Cu(I)-ligand (2 mol%), N2CHCO2R, CH2Cl2, rt, 12 h.
c Isolated yields.
d Determined by HPLC using Daicel Chiralcel OD-H column.
e 99% ee after recrystallization from pentane.
2.5. Asymmetric cyclopropanation of N-Boc-pyrrole
When N-Boc-pyrrole 7 was used as a substrate the
enantioselectivities obtained were again low in all cases
(Table 4), which further supports our reasoning that
secondary interactions might play a decisive role in
governing the selectivity of the cyclopropanation of 5.
With 7, hydrogen bonding might be possible through
the carbonyl oxygen of the N-Boc group. However, the
steric bulk of this group impedes such an interaction
with the ligand. Consequently, the selectivities were
poor and the product ee did not exceed 50%. Most
Figure 2.

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M. Schinnerl et al. / Tetrahedron: Asymmetry 14 (2003) 765–771
Table 4. Cyclopropanation of N-Boc-pyrrole 7 with
4. Experimental
4.1. General remarks
methyl diazoacetatea
Reactions with moisture-sensitive chemicals were per-
formed under nitrogen in a flame-dried reaction flask.
Solvents were dried by standard methods.
Chromatography was completed using Macherey-Nagel
silica gel (0.03–0.06 mm). Enantiomeric excesses were
determined by analytical HPLC using a ‘Chiracel OD-
H’ column (50×4.6 mm, 10 mm, flow: 1 ml/min, 20°C)
and a UV detector at 254 nm. TLC analysis was
completed using commercially pre-coated aluminium
sheets 60 F 254 (Merck). Melting points (uncorrected)
were obtained using a Bu¨chi SMP 20 machine. IR
spectra were obtained using Mattson Genesis series
Perkin Elmer 298 FT-IR and Bruker IFS 66 machines,
Entry
Ligand
Yieldc (%)
8d % ee
1
2
3
4
5
1a
1b
2a
2b
2c
52
50
57
48
46
46
22
28
34
27
a All reactions were carried out under nitrogen.
1
w values are reported in units of cm−1. H NMR and
b Cu(I)-ligand (1.5 mol%), N2CHCO2Me, CH2Cl2, rt, 12 h.
c Isolated yields.
13C NMR spectra were recorded using Bruker ARX
400, Avance 300 and AC 250 F machines with l values
reported in ppm and J values reported in Hz. Multiplic-
ities were determined by DEPT (distortionless enhance-
ment by polarization transfer) measurements. MS were
recorded on Finnigan MAT 95 and Varian MAT 311A
machines. Elemental analyses were completed using a
Heraeus CHN-Rapid machine. XRD analyses were
obtained with a Stoe Imaging Plate System, Siemens
Stoe AED2. Optical rotation values were obtained
using a Perkin–Elmer polarimeter PE 241.
d Determined by HPLC using Daicel Chiralcel OD-H column.
importantly, 7 is cyclopropanated predominantly with
opposite diastereofacial selectivity to 5,16 indicating that
the approach of 7 is indeed controlled by steric hin-
drance with the N-Boc group (cf. Fig. 1b; 7: R1=N-
Boc; R=CH; 5: R1=O; R=CH). Unfortunately,
methyl pyrrole-2-carboxylates, being analogous to the
furan 6a, failed to undergo cyclopropanation with our
ligands, preventing further comparison between furans
and pyrroles in this transformation.
4.2. Ligand synthesis
4.2.1. 2,2-Bis[(4S,5S)-4-hydroxymethyl-5-phenyl-1,3-oxa-
zolin-2-yl]propane, 1a. ZnCl2 (79.9 mg, 0.59 mmol, 6
mol%) was melted at 0.1 Torr and subsequently
allowed to cool to rt under a nitrogen atmosphere.
(1S,2S)-(+)-2-amino-1-phenylpropane-1,3-diol (4.93 g,
29.5 mmol) and 2,2-dimethyl-malononitrile (0.92 g, 9.77
mmol) in chlorobenzene (30 ml) were added and the
mixture was heated under reflux for 24 h. After cooling
to room temperature the mixture was filtered and con-
centrated. The residue was dissolved in CH2Cl2 (30 ml)
and extracted with water (3×20 ml), and the combined
aqueous phases were extracted once with CH2Cl2 (30
ml). The combined organic layers were dried (Na2SO4)
and concentrated, the residue was purified by silica
chromatography (EtOAc/MeOH 10:1). The product
obtained this way was further purified by refluxing in
diethyl ether to yield 1.97 g (51%) 1a as colorless
crystals. Rf=0.34 (EtOAc/MeOH 10:1). Mp=157–
158°C; [h]2D0 −86.0 (c 1.00, CH2Cl2); IR (KBr): w=3329,
3004, 3000, 2946, 2923, 2868, 1651, 1497, 1459, 1389,
1273, 1239, 1151, 1117, 1091, 974, 952, 935, 894, 763,
3. Conclusion
In conclusion, the new ligands 2 effect the enantioselec-
tive cyclopropanation of 5a, in which hydrogen bond-
ing as a secondary interaction from the ligands to the
substrate appears to control the selectivity, as was
suggested by control experiments with ligands 1 and
substrates 3, 4, 5b and 7.
Furthermore, the cyclopropanation of 5a seems to be
useful for the stereoselective synthesis of g-butyrolac-
tones 10, which have been used as precursors for para-
conic acids (Scheme 2). Cyclopropane 6a-Et can be
obtained in enantiopure form by a single recrystalliza-
tion from pentane. Ozonolysis of 6 leads to the trisub-
stituted aldehyde 9 which upon addition of nucleophiles
and base triggered saponification of the oxalic ester
followed by a retroaldol-lactonization cascade, gives
rise to trans-disubstituted g-butyrolactones 10 in good
yields.16a,17
1
699 cm−1; H NMR (250 MHz, CDCl3, D2O-exchange):
l=1.69 (s, 6H, CH3), 3.64 (dd, J=11.9, 3.0 Hz, 2H,
CH2OH), 3.96 (dd, J=11.9, 2.6 Hz, 2H, CH2OH), 4.11
(ddd, J=6.2, 3.0, 2.6 Hz, 2H, H-4), 5.54 (d, J=6.2 Hz,
2H, H-5), 7.25–7.41 (m, 10H, Ph-H); 13C NMR (62
MHz, CDCl3): l=23.86 (+, CH3), 39.74 (Cquat
,
C(CH3)2), 63.99 (−, CH2OH), 75.87 (+, CHPh), 83.39
(+, CHCH2OH), 125.57 (+, Ph-C), 128.38 (+, Ph-C),
128.85 (+, Ph-C), 140.51 (Cquat, Ph-C), 171.12 (Cquat,
Scheme 2.

M. Schinnerl et al. / Tetrahedron: Asymmetry 14 (2003) 765–771
769
C-2); MS (EI): m/z (%)=394 (2) [M+], 364 (42) [M+−
CH2OH], 219 (100), 91 (11). C23H26N2O4 (394.47):
calcd: C, 70.03; H, 6.64; N, 7.10; found: C, 69.7; H,
6.57; N, 6.95%.
5.33 (m, 4H, H-5, NH), 7.29–7.34 (m, 20H, Ph-H); 13C
NMR (62 MHz, CDCl3): l=17.57 (+, CH(CH3)2),
18.96 (+, CH(CH3)2), 24.61 (+, C(CH3)2), 31.29 (+,
CH(CH3)2), 39.22 (Cquat, C(CH3)2), 59.20 (+, CHN-
HCbz), 65.91 (−, CH2OCO, CH2Ph), 67.07 (−,
CH2OCO, CH2Ph), 73.05 (+, CHPh), 84.02 (+,
CHCH2O), 125.86 (+, Ph-C), 127.53 (+, Ph-C), 128.10
(+, Ph-C), 128.17 (+, Ph-C), 128.53 (+, Ph-C), 128.86
(+, Ph-C), 136.33 (Cquat, Ph-C), 139.96 (Cquat, Ph-C),
156.18 (Cquat, CO2CH2Ph), 170.15 (Cquat, C-2), 171.82
(Cquat, COCHNHZ); MS (FAB) (NBA/CH2Cl2): m/z
(%)=1722.8 (100) [2MH+], 861.6 (100) [MH+].
C49H56N4O10 (861.00): calcd: C, 68.36; H, 6.56; N,
6.51; found: C, 68.11; H, 6.72; N, 7.45%.
4.2.2. General procedure for the coupling of carboxylic
acids with 1a (GP1). To the carboxylic acid (2.1
equiv.) in CH2Cl2 was added with stirring 4-dimethyl-
aminopyridine (DMAP, 2.8 equiv.) and the bis(oxazo-
line) 1a (1.0 equiv.). N,N%-Dicyclohexylcarbodiimide
(DCC, 2.3 equiv.) was added during 5 min at 0°C,
followed by stirring for 15–20 h at rt. After filtration,
the solution was concentrated, and the residue was
purified on silica.
4.2.5. (2S)-tert-Butoxycarbonylamino-propionic acid 2-
{1-[(4S)-((2S)-tert-butoxycarbonylaminopropionyloxy-
methyl)-(5S)-phenyl-4,5-dihydro-oxazol-2-yl]-1-methyl-
ethyl}-(5S)-phenyl-4,5-dihydro-oxazol-(4S)-ylmethyl
ester, 2b. Bis(oxazoline) 1a (497 mg, 1.26 mmol, 1.0
equiv.), N-Boc-alanine (501 mg, 2.65 mmol, 2.1
equiv.), DMAP (431 mg, 3.53 mmol, 2.8 equiv.) and
DCC (598 mg, 2.90 mmol, 2.3 equiv.) in CH2Cl2 (20
ml) were reacted according to GP1. Purification on
silica (CH2Cl2/EtOH 40:1) yielded 895 mg (96%) 2b as
a colorless foam: mp: 63–65°C; Rf=0.31 (CH2Cl2/
EtOH 20:1). [h]2D0 −48.8 (c 1.0 in CH2Cl2). IR (KBr):
w=3377, 2981, 2937, 1747, 1712, 1657, 1520, 1456,
1390, 1367, 1252, 1165, 1120, 1068, 700 cm−1. 1H
NMR (400 MHz, CDCl3): l=1.28 (d, J=7.2 Hz, 6H,
CH3-CH-NHBoc), 1.44 (s, 18H, Boc-CH3), 1.68 (s,
6H, CH3), 4.25–4.44 (m, 8H), 5.05–5.07 (m, 2H, NH),
5.29–5.31 (m, 2H, 5,5%-H), 7.27–7.30 (m, 10H, Ph-H);
13C NMR (101 MHz, CDCl3): l=18.51 (+, CH3-CH-
NHBoc), 24.55 (+, CH3), 28.27 (+, C(CH3)3), 39.13
(Cquat), 49.14 (+, CH3-CH-NHBoc), 65.71 (−, CH2),
73.44 (+, C-5(5%)), 79.85 (Cquat, C(CH3)3), 83.80 (+,
C-4(4%)), 125.83, 128.52 and 128.82 (+, Ph-C), 139.89
4.2.3. Acetic acid 2-[1-((4S)-acetoxymethyl-(5S)-phenyl-
4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-(5S)-phenyl-4,5-
dihydro-oxazol-(4S)-ylmethyl ester, 1b. Bis(oxazoline)
1a (100 mg, 0.25 mmol, 1.0 equiv.), acetic acid (33 mg,
0.53 mmol, 2.1 equiv.), DMAP (87 mg, 0.71 mmol, 2.8
equiv.) and DCC (119 mg, 0.58 mmol, 2.3 equiv.) in
CH2Cl2 (10 ml) were reacted according to GP1. Purifi-
cation by chromatography on silica (CH2Cl2/EtOH
40:1) yielded 1b as a colorless oil (118 mg, 98%):
Rf=0.52 (CH2Cl2/EtOH 20:1); [h]2D0 −22.1 (c 1.0,
CH2Cl2); IR (Neat): w=3033, 2985, 2940, 1744, 1658,
1456, 1384, 1237, 1149, 1124, 1041, 977, 960, 760, 700
cm−1; 1H NMR (250 MHz, CDCl3): l=1.69 (s, 6H,
CH3), 2.03 (s, 6H, COCH3), 4.21–4.35 (m, 6H, 4(4%)-H
and CH2), 5.26 (d, J=6.2 Hz, 2H, 5(5%)-H), 7.23–7.33
(m, 10H, Ph-H); 13C NMR (62 MHz, CDCl3): l=
20.65 (+, CH3CO), 24.71 (+, CH3), 39.19 (Cquat
,
C(CH3)2), 65.45 (−, CH2), 73.62 (+, C-5(5%)), 84.27 (+,
C-4(4%)), 125.77, 128.42 and 128.78 (+, Ph-C), 140.11
(Cquat, Ph-C), 170.10 (Cquat, C-2(2%)), 170.65 (Cquat
,
COCH3); MS (EI): m/z (%)=478.4 (80, M+), 418.3
(62, M+−CH3COOH), 405.4 (64, M+−CH3COOH-
CH2), 261.2 (59), 186.1 (23), 158.0 (22), 155.0 (20),
133.9 (40), 90.9 (26), 69.0 (28), 43.1 (100). C27H30N2O6
(478.55): calcd: C, 67.77; H, 6.32; N, 5.85; found: C,
67.98; H, 6.32; N, 5.83%.
(Cquat, Ph-C), 155.02 (Cquat, OCON), 170.13 (Cquat
,
C-2(2%)), 173.13 (Cquat
, CO2); MS (FAB) (NBA/
CH2Cl2): m/z (%)=737.6 (100, MH+), 215.3 (12).
C39H52N4O10 (736.86): calcd: C, 63.57; H, 7.11; N,
7.60; found: C, 63.43; H, 7.22; N, 7.85%.
4.2.4.
(2S)-Benzyloxycarbonylamino-3-methyl-butyric
acid 2-{1-[(4S)-((2S)-benzyloxycarbonyl-amino-3-methyl-
butyryloxymethyl)-(5S)-phenyl-4,5-dihydro-oxazol-2-yl]-
1-methyl-ethyl}-(5S)-phenyl-4,5-dihydro-oxazol-(4S)-yl-
methyl ester, 2a. Bis(oxazoline) 1a (500 mg, 1.27
mmol, 1.0 equiv.), N-Cbz-L-valin (668 mg, 2.66 mmol,
2.1 equiv.), DMAP (433 mg, 3.55 mmol, 2.8 equiv.)
and DCC (601 mg, 2.91 mmol, 2.3 equiv.) in CH2Cl2
(10 ml) were reacted according to GP1. Purification on
silica (CH2Cl2/EtOH 40:1) yielded 940 mg (86%) 2a as
a colorless foam: Rf=0.29 (CH2Cl2/EtOH 30:1); mp=
56–57°C; [h]2D0 −36.5 (c 1.31, CH2Cl2); IR (KBr): w=
3300, 3095, 2936, 2851, 1740, 1690, 1645, 1465, 1320,
4.2.6. (2S)-Acetylamino-propionic acid 2-{1-[(4S)-((2S)-
acetylamino-propionyloxymethyl)-(5S)-phenyl-4,5-dihy-
dro-oxazol-2-yl]-1-methyl-ethyl}-(5S)-phenyl-4,5-dihydro-
oxazol-(4S)-yl-methyl ester, 2c. 1a (250 mg, 0.63
mmol, 1 equiv.), N-Ac-alanine (169 mg, 1.29 mmol,
2.0 equiv.), DMAP (198 mg, 1.62 mmol, 2.6 equiv.)
and DCC (305 mg, 1.48 mmol, 2.3 equiv.) in CH2Cl2
(15 ml) were reacted according to GP1. Purification on
silica (CH2Cl2/EtOH 30:1) yielded 307 mg (78%) 2c as
a colorless foam: Rf=0.32 (CH2Cl2/MeOH 30:1).
Mp=58–60°C; [h]2D0 −32.6 (c 1.07, CH2Cl2); IR (KBr):
w=3299, 2977, 2927, 1747, 1710, 1649, 1533, 1444,
1153, 1120, 970, 752, 700 cm−1; H NMR (250 MHz,
1366, 1255, 1145, 1078, 700, 689 cm−1; H NMR (250
1
1
CDCl3): l=0.81 (d, J=6.8 Hz, 6H, CH(CH3)2), 0.90
(d, J=6.8 Hz, 6H, CH(CH3)2), 1.66 (s, 6H, C(CH3)2),
2.03–2.21 (m, 2H, CH(CH3)2), 4.25–4.41 (m, 8H, H-4,
CH2OCO, CHNHCbz), 5.10 (s, 4H, CH2Ph), 5.27–
MHz, CDCl3): l=1.34 (d, J=7.2 Hz, 6H,
CH3CHNHAc), 1.68 (s, 6H, CH3), 1.97 (s, 6H,
CH3CO), 4.25–4.43 (m, 6H), 4.55–4.64 (m, 2H), 5.23–
5.32 (m, 2H, H-5), 6.26–6.29 (m, 2H, NH), 7.24–7.38

770
M. Schinnerl et al. / Tetrahedron: Asymmetry 14 (2003) 765–771
(m, 10H, Ph-H); 13C NMR (63 MHz, CDCl3): l=18.37
(+, CH3CHNHAc), 23.00 (+, C(CH3)2), 24.67 (+,
ee, rt 16.7 min (1R,5R,6R)-isomer, 19.7 min
(1S,5S,6S)-isomer. Rf (hexanes/EE 5:1)=0.14. Recrys-
tallization at −30°C from pentane yielded colorless
crystals (99% ee): mp 42°C; [h]2D0 −272 (c 1.0, CH2Cl2);
1H NMR (250 MHz, CDCl3): l=1.16 (dd, J=2.7, 1.1
Hz, 1H, 6–H), 1.23 (t, J=7.1 Hz, 3H, CH3), 2.87 (ddd,
J=5.3, 2.9, 2.7 Hz, 1H, 5-H), 3.78 (s, 3H, OCH3), 4.12
(q, J=7.1 Hz, 2H, CH2), 4.97 (dd, J=5.3, 1.1 Hz, 1H,
1-H), 6.39 (d, J=2.9 Hz, 1H, 4-H); 13C NMR (62.9
MHz, CDCl3): d=14.2 (+, CH3), 21.5 (+, C-6), 31.9 (+,
C-5), 52.1 (+, OCH3), 61.0 (−, CH2), 67.5 (+, C-1),
116.0 (+, C-4), 149.3 (Cquat, C-3), 159.5 (Cquat, CO),
171.7 (Cquat, CO); IR (KBr): w˜=3118, 2956, 1720, 1617,
1428, 1380, 1297, 1166, 1124, 1041, 954, 831, 725 cm−1;
MS (70 eV, EI): m/z (%)=212.1 [M+] (9.8), 153.0
[M+−CO2Me] (11.5), 139.0 [M+−CO2Et] (100), 124.9
(24.4), 98.9 (28.6), 96.9 (31.7), 78.9 (11.3), 59.0 (13.5),
52.1 (11.5). C10H12O5 (212.2): calcd: C, 56.60; H, 5.70;
found: C, 56.51; H, 5.73%.
CH3CO), 39.23 (Cquat
,
C(CH3)2), 48.04 (+,
CH3CHNHAc), 65.77 (−, CH2), 73.47 (+, CHPh),
83.75 (+, CHCH2O), 125.84 (+, Ph-C), 128.64 (+, Ph-
C), 128.93 (+, Ph-C), 139.91 (Cquat, Ph-C), 170.21
(Cquat, C-2), 172.85 (Cquat, COCH3, CO2), 172.98 (Cquat
,
COCH3, CO2); MS (FAB) (NBA/CH2Cl2): m/z (%)=
621.4 (100) [MH+], 508.4 (38). C33H40N4O8 (620.70):
calcd: C, 63.86; H, 6.50; N, 9.03; found: C, 64.05; H,
6.71; N, 8.76%.
4.2.7. (2S)-Tosylamino-propionic acid 2-{1-[(4S)-((2S)-
tosylaminopropionyloxymethyl)-(5S)-phenyl-4,5-dihydro-
oxazol-2-yl]-1-methyl-ethyl}-(5S)-phenyl-4,5-dihydro-
oxazol-(4S)-ylmethyl ester, 2d. Bis(oxazoline) 1a (487
mg, 1.24 mmol, 1.0 equiv.), N-tosylalanine (634 mg,
2.61 mmol, 2.1 equiv.), DMAP (424 mg, 3.47 mmol, 2.8
equiv.) and DCC (588 mg, 2.85 mmol, 2.3 equiv.) in
CH2Cl2 (20 ml) were reacted according to GP1. Purifi-
cation on silica (CH2Cl2/EtOH 40:1) yielded 860 mg
(82%) 2b as a colorless foam: mp: 69–70°C; Rf=0.26
(CH2Cl2/EtOH 40:1). [h]2D0 −31.6 (c 1.0, CH2Cl2); IR
(KBr): w=3280, 3064, 2987, 2939, 1747, 1655, 1456,
4.3.3.
(1S,5R,6S)-2-Oxa-bicyclo[3.1.0]hex-3-ene-4,6-
dicarboxylic acid 6-ethyl ester-3-methyl ester (6b-Et).
According to GP2 (9 mmol 5b, 3 mmol ethyl diazoac-
etate) with ligand 2b (2 mol%), 210 mg (31%) were
obtained as a yellow oil. HPLC analysis (Chiracel
OD-H, hexane/ethanol 99.7:0.3, 1.0 ml/min): 68% ee, rt
18.45 min (1R,5S,6R), 24.50 min (1S,5R,6S). [h]2D0 −272
1
1336, 1165, 1146, 1093, 976, 700, 663 cm−1; H NMR
(250 MHz, CDCl3): l=1.30 (d, J=7.2 Hz, 6H, CH3-
CH-NHTs), 1.69 (s, 6H, CH3), 2.33 (s, 6H, Ts-CH3),
3.96–4.26 (m, 8H, 4(4%)-H, CH2 and CH3-CH-NHTs),
5.08 (d, J=6.5 Hz, 2H, NH), 5.64 (d, J=8.9 Hz, 2H,
5(5%)-H), 7.15–7.34 (m, 16H, Ph-H), 7.68–7.75 (m, 4H,
Ph-H); 13C NMR (63 MHz, CDCl3): l=19.62 (+, CH3-
CH-NHTs), 21.42 (+, Ts-CH3), 24.73 (+, CH3), 39.23
(Cquat), 51.63 (+, CH3-CH-NHTs), 65.83 (−, CH2),
73.44 (+, C-5(5%)), 83.62 (+, C-4(4%)), 125.62, 127.23,
128.68, 128.97 and 129.66 (+, Ph-C and Ts-C), 137.16
(Cquat, Ts-C), 139.88 (Cquat, Ph-C), 143.57 (Cquat, Ts-C),
170.26 (Cquat, C-2(2%)), 171.96 (Cquat, CO); MS (FAB)
(NBA/ CH2Cl2): m/z (%)=1690.7 (100, 2MH+), 845.5
(100, MH+). C43H48N4O10S2 (845.01): calcd: C, 61.12;
H, 5.73; N, 6.63; found: C, 60.98; H, 5.90; N, 6.62%.
1
(c 1.0, CH2Cl2); H NMR (250 MHz, CDCl3): l=1.14
(ddd, J=2.9, 1.0, 0.5 Hz, 1H, 6-H), 1.27 (t, J=7.1 Hz,
3H, CH3), 3.10 (ddd, J=5.7, 2.9, 0.5 Hz, 1H, 5-H), 3.77
(s, 3H, CH3), 4.15 (q, J=7.1 Hz, 2H, CH2), 5.02 (ddd,
J=5.7, 1.0, 0.9 Hz, 1H, 1-H), 7.21 (ddd, J=0.9, 0.6, 0.5
Hz, 1H, 3-H); 13C NMR (62.9 MHz, CDCl3): l=14.2
(+, CH3), 21.7 (+, C-5), 29.5 (+, C-6), 51.4 (+, CH3),
61.0 (−, CH2), 68.9 (+, C-1), 156.3 (+, C-3), 164.0 (Cquat
,
CO), 171.4 (Cquat, CO); IR (neat): w˜=3109, 2986, 2957,
1730, 1604, 1031; MS (EI, 70 eV): m/z (%)=212.2 (12)
[M+], 184.1 (11), 139.1 (100), 127.1 (16), 126.1 (11),
111.1 (129), 108.1 (18), 107.1 (24), 99.1 (61), 95.1 (13),
83.1 (11), 79.1 (15), 58.1 (16), 43.1 (64), 29.1 (36).
C10H12O5 (212.2): calcd: C, 56.60; H, 5.70; found: C,
56.64; H, 5.58%.
4.3. Asymmetric cyclopropanation
4.3.1. General procedure for the cyclopropanation of
alkenes (GP2). A mixture of the ligand 1 or 2 (0.032
mmol) and Cu(OTf)2 (0.024 mmol) in 2 ml of CH2Cl2
was stirred for about 30 min at room temperature
before one drop of phenylhydrazine (:15 ml) and the
alkene (7 mmol) was added. The light brown mixture
was stirred for about 5 min. A solution of alkyl dia-
zoacetate (1.5 mmol) in 10 ml of CH2Cl2 was added
dropwise at room temperature during 12 h. The reac-
tion mixture was filtered through a short pad of basic
alumina and the solvent was evaporated in vacuo. The
residue was purified on silica to provide the product.
4.3.4. 2-Azabicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid
2-tert-butyl ester 6-methyl ester, 8. Using GP2 (7 mmol
7, 2.4 mmol methyl diazoacetate) with ligand 1a (1.5
mol%), 298 mg (52%) were obtained as a yellow oil.
HPLC analysis (Chiracel OD, hexane/ethanol 99:1, 1.0
ml/min): 46% ee, rt 1.1 min (1R,5R,6R)-isomer, 1.8 min
1
(1S,5S,6S)-isomer. H NMR (250 MHz, CDCl3, signal
doubling because of rotamers) l 0.92 (br s, 1H), 1.46 (s,
9H), 2.77 (br s, 1H), 3.62 and 3.65 (s, 3H), 4.26–4.40
(m, 1H), 5.28–5.36 (m, 1H), 6.40–6.55 (br s, 1H); 13C
NMR (62.9 MHz, CDCl3, signal doubling because of
rotamers) l 22.62 and 22.76, 28.11, 30.91 and 32.16,
44.06 and 44.19, 51.72, 81.61, 109.78, 129.55 and
129.74, 150.84 and 151.14, 173.23 and 173.50; MS
(DCI(NH3)) 257 (100) [M++NH3+H]; C12H17NO4
(239.3): calcd: C, 60.24; H, 7.16; found: C, 60.46; H,
7.17%.
4.3.2. (1S,5S,6S)-(−)-2-Oxa-bicyclo[3.1.0]hex-3-ene-3,6-
dicarboxylic acid 6-ethyl ester 3-methyl ester 6a-Et.
Using GP2, 115 mg (36%) of 6a-Et were obtained from
5a with ligand 2d as a colorless oil. HPLC analysis
(Chiracel OD-H, hexane/ethanol 99:1, 1.0 ml/min): 91%

M. Schinnerl et al. / Tetrahedron: Asymmetry 14 (2003) 765–771
771
Acknowledgements
is an inferior catalyst for the transformation. However, in
our hands it works equally well compared to Cd(OAc)2.
Aggarwal, V. K.; Bell, L.; Coogan, M. P.; Jubault, P. J.
Chem. Soc., Perkin Trans. 1 1998, 2037–2042.
Financial Support of the Deutsche Forschungsgemein-
schaft (SPPP1118, Re 948/5-1) and the Fonds der
Chemischen Industrie as well as generous gifts of chem-
icals by Degussa AG are gratefully acknowledged.
12. Neises, B.; Steglich, W. Angew. Chem. 1978, 90, 556–557.
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butyl instead of CH2OH, H instead of phenyl) as the
blocking substituent) is used: Evans, D. A.; Woerpel, K.
A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc.
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