Enantio- and diastereoselective [3+2] cycloadditions of azomethine ylides with Ag(I)-phosphinooxazoline catalysts

Article abstract of DOI:10.1055/s-2005-865313

Chiral Ag(I)-phosphinooxazoline (PHOX) complexes are efficient catalysts for [3+2] cycloadditions of azomethine ylides with α,β-unsaturated carboxylic esters. In intramolecular cycloadditions, virtually complete diastereocontrol and enantiomeric excesses of up to 99% have been observed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865313

PAPER
1431
Enantio- and Diastereoselective [3+2] Cycloadditions of Azomethine Ylides
with Ag(I)-Phosphinooxazoline Catalysts
Enantio- and
Diae
m
ive [3+2] Cycloadd
o
itions of
A
zomethi
S
ne
Y
lides tohler, Florentine Wahl, Andreas Pfaltz*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
E-mail: andreas.pfaltz@unibas.ch
Received 1 March 2005
Dedicated to Professor Bernd Giese on the occasion of his 65th birthday
tion of two geminal alkyl or aryl groups at C(5) of the ox-
Abstract: Chiral Ag(I)-phosphinooxazoline (PHOX) complexes
are efficient catalysts for [3+2] cycloadditions of azomethine ylides
with a,b-unsaturated carboxylic esters. In intramolecular cycloaddi-
tions, virtually complete diastereocontrol and enantiomeric excess-
es of up to 99% have been observed.
azoline ring also had a beneficial effect on the ee (entries
1–3 vs entries 5–11).8
CO2Me
N
CO2Me
Key words: asymmetric catalysis, Ag(I) complexes, [3+2] cyclo-
addition, azomethine ylides, phosphinooxazolines
1
2
[L*Ag(OAc)] (3 mol%),
toluene, 0 °C
Chiral pyrrolidine units are found in many natural prod-
ucts and pharmaceutically important compounds.1,2 [3+2]
Cycloadditions of azomethine ylides with olefins provide
a short, attractive route to such compounds with the poten-
tial to control the relative and absolute configuration by
means of a chiral catalyst.
MeO2C
MeO2C
CO2Me
CO2Me
N
N
H
H
Grigg and coworkers have pioneered the use of chiral
transition metal complexes to induce enantioselective cy-
cloadditions of this type.3 However, stoichiometric
amounts of metal complexes were employed in this work.
Recently, the first examples of catalytic enantioselective
cycloadditions of azomethine ylides were reported by the
groups of Zhang,4 Jørgenson,5 and Schreiber.6 Using
Ag(I) complexes with chiral diphosphines or QUINAP, or
Zn(II)-bisoxazoline complexes, good to excellent enan-
tio- and diastereoselectivities were achieved in intermo-
lecular cycloadditions with a,b-unsaturated carboxylic
esters as dipolarophiles.
3a
3b
Scheme 1 Asymmetric Ag(I)-catalyzed intermolecular [3+2] cy-
cloaddition
Table 1 PHOX-Ligands Used for the Screening Process
R2
R2
O
(R3)2P
N
R1
Here we report that Ag(I)-phosphinooxazoline (PHOX)
complexes7 are efficient catalysts for intramolecular
[3+2] cycloadditions of azomethine ylides, giving access
to tricyclic compounds with high levels of diastereo- and
enantiocontrol.
Ligand
R1
R2
R3
4
5
i-Pr
t-Bu
i-Pr
Ph
H
Ph
H
Ph
6
H
o-Tol
o-Tol
Ph
Initially, we screened various differently substituted
PHOX ligands (Figure 1) in the intermolecular Ag(I)-cat-
alyzed reaction of N-(2-naphthylidene)glycine methyl es-
ter (1) and methyl acrylate (2) (Scheme 1). After reaction
in toluene at 0 °C using 3 mol% of catalyst, prepared in
situ from standard PHOX ligands 4 or 5, the desired pyr-
rolidine 3 was obtained in high yield with high diastereo-
selectivity (Table 1, entries 1 and 2). However, the ee
values were low. Replacing the P-phenyl by P-ortho-tolyl
groups led to a moderate increase in ee (entry 3). Introduc-
7
H
8
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
n-Pr
Ph
Ph
Me
Ph
Cy
o-Tol
9
Ph
10
11
12
13
14
Cy
o-Tol
o-Tol
o-Tol
o-Tol
SYNTHESIS 2005, No. 9, pp 1431–1436
x
x
.
x
x
.2
0
0
5
Advanced online publication: 18.04.2005
DOI: 10.1055/s-2005-865313; Art ID: C01405SS
© Georg Thieme Verlag Stuttgart · New York

1432
R. Stohler et al.
PAPER
CHO
O
PHOX ligands 12 and 14 with P-ortho-tolyl and geminal
phenyl or ortho-tolyl groups in the oxazoline ring gave the
best results in this series (entries 9 and 11). The catalyst
derived from PHOX ligand 13 with geminal cyclohexyl
groups was found to be less reactive, as seen from the low
conversion (entry 10). Although the enantioselectivities in
this reaction were only moderate, very high enantiomeric
excesses could be obtained in analogous intramolecular
cycloadditions (Scheme 4).
CHO
OH
MeO2C
Br
K2CO3, DMF, r.t.
CO2Me
16
15
R2
H2N
R1
17 R1 = CO2Me, R2 = H
18 R1 = CO2t-Bu, R2 = H
19 R1 = CO2Me, R2 = Me
20 R1 = Py, R2 = H
R2
N
R1
Substrates 17–20 were prepared according to literature
procedures (Scheme 2).9,10 Surprisingly, when aldehyde
16 was reacted with glycine methyl ester and anhydrous
MgSO4 in CH2Cl2 at ambient temperature, substantial
amounts of a macrocyclic species 21 (>30% by 1H NMR)
were observed as a side product. The structure of this
macrocyclic compound, which resulted from dimerization
of imine 17 by a double intermolecular cycloaddition
(Scheme 3), was unambiguously determined by X-ray
analysis (Figure 1). Dimerization could be easily sup-
pressed by performing the reaction with glycine methyl
ester at 0 °C. In contrast to the glycine derivatives 17 and
18, imines 19 and 20 did not show any tendency to dimer-
ize at room temperature and, therefore, were synthesized
without cooling the reaction mixture.
MgSO4,
CH2Cl2
O
CO2Me
Scheme 2 Synthesis of substrates for the asymmetric Ag(I)-cata-
lyzed intramolecular [3+2] cycloaddition
O
O
O
O
NH
N
CO2Me
CO2Me
2
O
O
O
HN
O
O
O
O
17
21 (rac.)
When imine 17 was treated with Ag(I)-PHOX complexes
under the conditions used for the intermolecular cycload-
dition, the desired tricyclic product 22 was formed in good
Scheme 3 Dimerization of imine 17 to the macrocycle 21
Table 2 Asymmetric Ag(I)-Catalyzed Intermolecular [3+2] Cy-
cloaddition (Scheme 1)
Entrya
Ligand
T (h)
Yield (%)b 3a:3bc
ee (%)d
29
1
2
4
5
5
6
8
7
8
7
7
8
7
9
6
95
94
93
95
57
86
80
49
90
40
56
>40:1
>40:1
>40:1
>40:1
>24:1e
>40:1e
24:1e
24:1e
40:1e
9:1e
27
3
6
45
4
7
15
5
8
43
6
9
49
Figure 1 Crystal structure of 21
7
10
11
12
13
14
62
8
62
yield as a single diastereoisomer (Scheme 4).11 The enan-
tioselectivities induced by different ligands showed the
same trends as in the intermolecular cycloaddition. The
highest enantioselectivity was achieved with ligand 12
(Table 2). While the screening experiments were carried
out using 3 mol% of PHOX complex, the catalyst loading
could be reduced to 1 mol% without loss of enantioselec-
tivity or yield. The corresponding tert-butyl ester 18 gave
an even higher ee value of 99% (Table 3). Starting from
the alanine-derived substrate 19, four stereogenic centers
were formed with nearly perfect stereocontrol. Substrate
20, with a pyridine ring instead of an ester group, reacted
with lower enantioselectivity. The relative configuration
of products 22–25 was determined by 1H NMR spectros-
9
65
10
11
62
12:1e
67
a Reaction conditions: AgOAc (3 mol%), ligand (3.3 mol%), N-(2-
naphthylidene)glycine methyl ester (1 equiv), methyl acrylate (1.2
equiv), toluene, 0 °C.
b After column chromatography.
c Determined by 1H NMR.
d Determined by chiral HPLC. The absolute configuration was as-
signed on the basis of optical rotation in comparison to the value re-
ported for the analogous methyl-tert-butylester.6,
e In addition to 3a and 3b traces of the opposite regioisomer were
formed.
Synthesis 2005, No. 9, 1431–1436 © Thieme Stuttgart · New York

PAPER
Enantio- and Diastereoselective [3+2] Cycloadditions of Azomethine Ylides
1433
4-(2-Formylphenoxy)but-2-enoic Acid Methyl Ester (16)
copy (NOESY), but the absolute configuration has so far
not been assigned. In all cases the diastereoselectivity was
very high; no traces of other diastereoisomers could be de-
tected in the 1H and 13C NMR spectra.
Methyl 4-bromobut-2-enoate (1.64 mL, 12.4 mmol) was added to a
mixture of 2-hydroxybenzaldehyde (15; 1.10 mL, 11.5 mmol) and
K2CO3 (2.10 g, 15.0 mmol) in DMF (15 mL). The reaction was
monitored by TLC and worked up when all 2-hydroxybenzaldehyde
(15) was consumed (1 h). Toluene (25 mL) and H2O (25 mL) were
added and the aqueous layer was extracted with toluene (3 × 10
mL). The combined organic layers were washed with brine and
dried over MgSO4. After removal of the solvent the residue was pu-
rified by column chromatography (hexanes–EtOAc, 5:1) to give 16
(1.7 g, 66%) as a white solid; mp 62–64 °C; Rf 0.15 (hexanes–
EtOAc, 5:1).
O
5a
O
6
9
4
3a
[L*Ag(OAc)] (1–3 mol%)
toluene, 0 °C
H
9b
9a
CO2Me
3
HN1
R2 R1
H
2
N
CO2Me
R2
R1
(absolute configuration unknown)k
IR (KBr): 2953, 2871, 1641, 1719, 1685, 1662, 1597, 1485, 1442,
1396, 1307, 1242, 1193, 1169, 1079, 1019, 956, 846, 768, 662 cm–1.
1H NMR (400.1 MHz, CDCl3): d = 3.77 (s, 3 H, CH3), 4.84 (q, J =
2.0 Hz, 2 H, OCH2), 6.23 (dt, J = 15.9, 2.0 Hz, 1 H, CH2CH=CH),
6.94 (d, J = 8.3 Hz, 1 H, CH2CH=CH), 7.11 (m, 2 H, PhH), 7.55 (m,
1 H, PhH), 7.87 (dd, J = 7.6, 1.8 Hz, 1 H, PhH), 10.55 (s, 1 H, COH).
13C{1H} NMR (100.6 MHz, CDCl3): d = 52.2 (CH3), 67.2 (CH2),
112.9 (PhH), 121.8 (PhH), 122.4 (CH2CH=CH), 125.5 (PhC), 129.2
(PhH), 136.3 (PhH), 141.8 (CH2CH=CH), 160.5 (PhCO), 166.6
(CO), 189.6 (COH).
17 R1 = CO2Me, R2 = H
18 R1 = CO2t-Bu, R2 = H
19 R1 = CO2Me, R2 = Me
20 R1 = Py, R2 = H
22 R1 = CO2Me, R2 = H
23 R1 = CO2t-Bu, R2 = H
24 R1 = CO2Me, R2 = Me
25 R1 = Py, R2 = H
Scheme 4 Asymmetric Ag(I)-catalyzed intramolecular [3+2] cyclo-
addition
Table 3 Asymmetric Ag(I)-Catalyzed Intramolecular [3+2] Cyclo-
addition (Scheme 4)
Entrya
Substrate
Yield (%)b
ee (%)c
96
MS (FAB): m/z (%) = 221 (100) [M+ + H], 219 (14), 203 (10), 189
(15), 188 (14), 161 (48), 99 (54), 98 (22), 71 (16).
1
2
3
4
17
18
19
20
74
66
61
70
Anal. Calcd for C12H12O4 (220.07): C, 65.45; H, 5.49. Found: C,
65.37; H, 5.42.
99
96
Imine Synthesis; General Procedure
Et3N (250 mL, 1.8 mmol) and anhyd MgSO4 (770 mg, 6.4 mmol)
were added to a solution of the amine hydrochloride (1.6 mmol) in
CH2Cl2 (10 mL). After a stirring period of 1 h the aldehyde (1.5
mmol) was added (for the synthesis of imines 17 and 18 the reaction
mixture had to be cooled to 0 °C before the aldehyde was added).
The mixture was stirred for 24 h (in case of imines 17 and 18, 60 h
at 0 °C) before the MgSO4 was removed by filtration. The organic
layer was washed with H2O (3 × 5 mL), sat. NaHCO3 solution (3 ×
5 mL) and brine (5 mL) and dried over MgSO4. The solvent was re-
moved under reduced pressure and dried at 0.8 mbar/r.t. The result-
ing crude product, which contained 1–10 mol% of aldehyde 16 (1H
NMR), was isolated in quantitative yield and used without further
purification.
83
a Reaction conditions: AgOAc (3 mol%), ligand 12 (3.3 mol%), sub-
strate (1 equiv), toluene, 6 h, 0 °C.
b After column chromatography.
c Determined by chiral HPLC.
In summary, we have shown that chiral Ag(I)-PHOX
complexes are efficient enantioselective catalysts for in-
tramolecular cycloadditions of azomethine ylides. In
these reactions up to four stereogenic centers can be
formed with virtually perfect diastereoselectivity and
enantiomeric excesses of up to 99%.
[(Naphthalene-2-ylmethylene)amino]acetic Acid Methyl Ester
(1)
Slightly yellow solid; mp 88–90 °C; Rf 0.82 (hexanes–EtOAc, 1:1).
All reactions were performed in flame-dried glassware under Ar.
All commercial reagents were employed as supplied. Toluene was
dried over Na, distilled and degassed. CH2Cl2 was dried over CaH2
and distilled. Flash chromatography was performed on silica gel
(silica gel C-560 D, 0.040-0.063 mm, CU Chemie Uetikon AG).
TLC analyses were performed on Merck 60 F254 precoated silica gel
IR (KBr): 3056, 3002, 2952, 2878, 1721, 1642, 1424, 1267 cm–1.
1H NMR (400.1 MHz, CD2Cl2): d = 3.77 (s, 3 H, CH3), 4.45 (d, J =
1.3 Hz, 2 H, CH2), 7.52–7.58 (m, 2 H, Naph-H), 7.87–7.94 (m, 3 H,
Naph-H), 8.01 (dd, J = 8.6, 1.8 Hz, 1 H, Naph-H), 8.10 (s, 1 H,
Naph-H), 8.44 (s, 1 H, CH=N).
13C{1H} NMR (100.6 MHz, CD2Cl2): d = 52.5 (CH3), 62.4 (CH2),
124.1 (Naph-H), 127.1 (Naph-H), 128.0 (Naph-H), 128.4 (Naph-
H), 129.1 (Naph-H), 129.2 (Naph-H), 131.1 (Naph-H), 133.6
(Naph-C), 134.0 (Naph-C), 135.5 (Naph-C), 165.6 (CH=N), 171.1
(CO).
plates and visualized by quenching of UV (lmax = 254 nm, lmax
=
366 nm) or by staining with KMnO4. Racemic cycloaddition prod-
ucts were prepared with 3 mol% of AgOAc as catalyst and used as
reference compounds for ee determination. All NMR experiments
were performed on Bruker Avance 500 and 400 spectrometers op-
erating at 500.13 MHz and 400.13 MHz, respectively, for 1H NMR,
and at 125.8 MHz and 100.6 MHz, respectively, for 13C NMR (in-
ternal standard set to 5.32 ppm for CD2Cl2 and to 7.26 ppm for
CDCl3). The relative configuration of the pyrrolidine moieties was
determined by NOESY experiments. Optical rotations were mea-
sured on a Perkin Elmer 241 instrument. Melting points are uncor-
rected.
MS (FAB): m/z (%) = 228 (100), [M+ + H], 168 (20), 141 (16).
4-[2-(Methoxycarbonylmethyliminomethyl)phenoxy]but-2-
enoic Acid Methyl Ester (17)
Colorless oil; Rf 0.65 (hexanes–EtOAc, 1:1).
IR (NaCl): 3485, 3415, 3004, 2953, 2867, 1750, 1720, 1636, 1603,
1493, 1450, 1309, 1249, 1197, 1173, 1116, 1070, 1021, 754 cm–1.
Synthesis 2005, No. 9, 1431–1436 © Thieme Stuttgart · New York

1434
R. Stohler et al.
PAPER
1H NMR (400.1 MHz, CD2Cl2): d = 3.75 (s, 3 H, CH3), 3.76 (s, 3 H,
CH3), 4.42 (d, J = 1.2 Hz, 2 H, NCH2), 4.79 (dd, J = 4.3, 2.0 Hz, 2
H, OCH2), 6.19 (td, J = 15.7, 2.0 Hz, 1 H, CH2CH=CH), 6.92 (d,
J = 8.3 Hz, 1 H, PhH), 7.04 (t, J = 7.6 Hz, 1 H, PhH), 7.11 (td, J =
15.8, 4.3 Hz, 1 H, CH2CH=CH), 7.71–7.45 (m, 1 H, PhH), 8.00 (dd,
J = 7.8, 1.8 Hz, 1 H, PhH), 8.77 (s, 1 H, CH=N).
13C{1H} NMR (100.6 MHz, CD2Cl2): d = 52.1 (CH3), 52.4 (CH3),
62.8 (NCH2), 67.5 (OCH2), 112.8 (PhH), 122.0 (PhH), 122.3
(CH=CHCO2Me), 125.0 (PhC), 128.1 (PhH), 133.0 (PhH), 142.7
(CH=CHCO2Me), 158.0 (PhC), 161.0 (CH=N), 166.7 (CO), 171.2
(CO).
(td, J = 7.7, 1.8 Hz, 1 H, ArH), 8.03 (d, J = 4.6 Hz, 1 H, ArH), 8.55
(d, J = 4.6 Hz, 1 H, ArH), 8.93 (s, 1 H, CH=N).
13C{1H} NMR (100.6 MHz, CD2Cl2): d = 52.1 (CH3), 67.5 (CH2),
67.7 (CH2), 112.8 (ArH), 121.9 (ArH), 122.2 (CH2CH=CH), 122.4
(ArH), 122.7 (ArH), 125.5 (ArC), 128.0 (ArH), 132.5 (ArH), 136.9
(ArH), 142.8 (CH2CH=CH), 149.7 (ArH), 157.9 (ArC), 158.7
(CH=N), 160.2 (ArC), 166.7 (COOCH3).
MS (FAB): m/z (%) = 311 (100) [M+ + H], 93 (41), 92 (11).
Dimer (21)
Mp 321–323 °C; Rf 0.15 (hexanes–EtOAc, 5:1).
MS (FAB): m/z (%) = 292 (100) [M+ + H], 232 (17), 193 (13), 133
(16), 99 (17), 77 (14), 69 (11), 57 (20).
IR (KBr): 3324, 2952, 2883, 1735, 1604, 1499, 1456, 1436, 1380,
1285, 1246, 1170, 1124, 1066, 1015, 958, 912, 753, 678 cm–1.
1H NMR (500.1 MHz, CD2Cl2): d = 3.01 (m, 2 H, CH2CH), 3.83 (s,
6 H, OCH3), 3.91 (d, J = 7.3 Hz, 2 H, NHCHCO2Me), 4.12 (dd, J =
9.3, 3.5 Hz, 2 H, CH2), 4.47 (dd, J = 9.5, 1.0 Hz, 2 H, CH2), 5.06 (br
d, J = 6.4 Hz, 2 H, NHCHPh), 6.94 (dd, J = 8.2, 0.9 Hz, 2 H, PhH),
6.97 (td, J = 7.5, 0.8 Hz, 2 H, PhH), 7.18 (dd, J = 7.6, 1.4 Hz, 2 H,
PhH), 7.28 (ddd, J = 8.0, 7.4, 1.6 Hz, 2 H, PhH).
13C{1H} NMR (125.8 MHz, CD2Cl2): d = 48.1 (CH2CH), 51.7
(OCH3), 52.7 (OCH3), 52.8 (CHCO2Me), 61.3 (NHCHPh), 63.7
(NHCHCO2Me), 68.5 (CH2), 111.0 (PhH), 121.2 (PhH), 125.7
(PhH), 126.3 (PhC), 129.1 (PhH), 156.1 (PhO), 173.5 (CO), 174.3
(CO).
4-[2-(tert-Butoxycarbonylmethyliminomethyl)phenoxy]but-2-
enoic Acid Methyl Ester (18)
Colorless oil; Rf 0.41 (hexanes–EtOAc, 2:1).
IR (NaCl): 3415, 3050, 2978, 2865, 1726, 1641, 1600, 1485, 1448,
1372, 1284, 1245, 1158, 1020, 757 cm–1.
1H NMR (400.1 MHz, CD2Cl2): d = 1.48 [s, 9 H, C(CH3)3], 3.74 (s,
3 H, OCH3), 4.29 (s, 2 H, NCH2), 4.78 (dd, J = 4.0, 2.0 Hz, 2 H,
OCH2), 6.18 (td, J = 15.9, 2.0 Hz, 1 H, CH2CH=CH), 6.91 (d, J =
8.3 Hz, 1 H, PhH), 7.02 (t, J = 7.6 Hz, 1 H, PhH), 7.10 (td, J = 15.9,
4.0 Hz, 1 H, CH2CH=CH), 7.38–7.43 (m, 1 H, PhH), 7.99 (dd, J =
7.8, 1.5 Hz, 1 H, PhH), 8.72 (s, 1 H, CH=N).
13C{1H} NMR (100.6 MHz, CD2Cl2): d = 28.4 [C(CH3)3], 52.1
(OCH3), 63.6 (NCH2), 67.5 (OCH2), 81.5 [C(CH3)3], 112.8 (PhH),
121.9 (PhH), 122.3 (CH2CH=CH), 125.3 (PhC), 128.1 (PhH), 132.8
(PhH), 142.8 (CH2CH=CH), 158.0 (PhO), 160.7 (CH=N), 166.7
(CO), 170.0 (CO).
MS (FAB): m/z (%) = 583 (100) [M+ + H], 581 (10), 198 (12), 172
(12), 133 (10), 132 (14), 99 (18), 77 (12), 59 (15).
Anal. Calcd for C30H34N2O10 (582.22): C, 61.85; H, 5.88; N, 4.81.
Found: C, 61.60; H, 5.87; N, 4.81.
Crystal Structure Determination (Table 4)
MS (FAB): m/z (%) = 334 (85) [M+ + H], 278 (75), 232 (16), 218
(17), 180 (18), 133 (19), 99 (27), 77 (11), 57 (100).
Crystals suitable for single crystal X-ray structure determination
were obtained by dissolving compound 21 in CH2Cl2 and layering
the solution with hexane. Data collection was carried out on a Non-
ius Kappa CCD diffractometer using the Collect software suite. The
structure was solved by direct methods using the program SIR92.12
Anisotropic least squares refinement was carried out on all non-hy-
drogen atoms using the program CRYSTALS.13
(S)-4-[2-{(1-Methoxycarbonylethylimino)methyl}phenoxy]but-
2-enoic Acid Methyl Ester (19)
Colorless oil; Rf 0.65 (hexanes–EtOAc, 1:1).
IR (NaCl): 3415, 3050, 2978, 2865, 1726, 1641, 1600, 1485, 1448,
1372, 1284, 1245, 1158, 1020, 757 cm–1.
Table 4 Crystallographic Data of 21
1H NMR (400.1 MHz, CD2Cl2): d = 1.48 (d, J = 6.8 Hz, 3 H,
CHCH3), 3.72 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 4.17 (q, J = 6.8
Hz, 1 H, NCH), 4.78 (dd, J = 4.0, 2.0 Hz, 2 H, OCH2), 6.18 (td, J =
15.9, 2.0 Hz, 1 H, CH2CH=CH), 6.90 (d, J = 8.4 Hz, 1 H, PhH), 7.02
(t, J = 7.6 Hz, 1 H, PhH), 7.10 (td, J = 15.9, 4.0 Hz, 1 H,
CH2CH=CH), 7.38–7.43 (m, 1 H, PhH), 7.97 (dd, J = 7.8, 1.8 Hz, 1
H, PhH), 8.77 (s, 1 H, CH=N).
13C{1H} NMR (100.6 MHz, CD2Cl2): d = 19.9 (CHCH3), 52.1
(OCH3), 52.5 (OCH3), 67.5 (CHCH3), 68.8 (OCH2), 112.8 (PhH),
121.9 (PhH), 121.9 (CH2CH=CH), 125.2 (PhC), 128.2 (PhH), 132.9
(PhH), 142.8 (CH2CH=CH), 158.0 (PhO), 158.7 (CH=N), 166.7
(CO), 173.6 (CO).
Empirical formula
C30H34N2O10
582.61
Fw
Temperature
173
Wavelength
0.71073
Crystal system, space group
triclinic, P–1
9.8313(1)
11.3558(1)
13.4160(2)
94.4348(5)
108.2460(5)
97.9535(5)
1397.16(3)
2
a (Å)
b (Å)
MS (FAB): m/z (%) = 306 (100) [M+ + H], 246 (21), 207 (12), 148
(18), 132 (14), 99 (14), 77 (18).
c (Å)
a (°)
4-[2-{(Pyridin-2-ylmethylimino)methyl}phenoxy]but-2-enoic
Acid Methyl Ester (20)
Slightly yellow oil; Rf 0.72 (hexanes–EtOAc, 1:1).
b (°)
g (°)
IR (NaCl): 3388, 3008, 2949, 2893, 1722, 1636, 1599, 1487, 1435,
1375, 1307, 1246, 1173, 1113, 1045, 1020, 966, 838, 756 cm–1.
Volume
Z, calcd density
abs coeff (1/mm)
1H NMR (400.1 MHz, CD2Cl2): d = 3.74 (s, 3 H, CH3), 4.78 (s, 2 H,
NCH2), 4.93 (s, 2 H, OCH2), 6.20 (dt, J = 15.9, 2.0 Hz, 1 H,
CH2CH=CH), 6.92 (d, J = 8.3 Hz, 1 H, ArH), 7.03 (t, J = 7.5 Hz, 1
H, ArH), 7.11 (dt, J = 15.8, 4.1 Hz, 1 H, CH2CH=CH), 7.18 (dd,
J = 7.0, 5.2 Hz, 1 H, ArH), 7.40 (dd, J = 7.3, 1.8 Hz, 2 H, ArH), 7.68
0.105
Synthesis 2005, No. 9, 1431–1436 © Thieme Stuttgart · New York

PAPER
Enantio- and Diastereoselective [3+2] Cycloadditions of Azomethine Ylides
1435
1H NMR (500.1 MHz, CD2Cl2): d = 2.34 (qd, J = 11.5 Hz, J = 4.3
Hz, 1 H, H-3a), 2.55 (br s, 1 H, H-1), 3.08 (dd, J = 11.9, 10.0 Hz, 1
H, H-3), 3.67 [s, 3 H, C(3)CO2CH3], 3.69 [s, 3 H, C(2)CO2CH3],
3.77 (d, J = 11.2 Hz, 1 H, H-9b), 4.18 (dd, J = 11.5, 10.1 Hz, 1 H,
H-4), 4.38 (d, J = 10.1 Hz, 1 H, H-2), 4.57 (dd, J = 10.1, 4.3 Hz, 1
H, H-4), 6.81 (dd, J = 7.1, 1.0, 1.4 Hz, 1 H, H-6), 6.89 (td, J = 6.3,
1.1 Hz, 1 H, H-8), 7.13–7.17 (m, 1 H, H-7), 7.25 (dd, J = 4.7, 1.5
Hz, 1 H, 9).
13C{1H} NMR (125.8 MHz, CD2Cl2): d = 47.0 (C-3a), 50.3 (C-3),
52.7 [C(3)CO2CH3], 52.9 [C(2)CO2CH3], 60.6 (C-9b), 64.6 (C-2),
69.8 (C-4), 116.4 (C-6), 120.7 (C-8), 125.1 (C-9), 125.3 (C-9a),
129.1 (C-7), 153.7 (C-5a), 172.3 [C(3)CO], 172.3 [C(2)CO].
Table 4 Crystallographic Data of 21 (continued)
Empirical formula
F (000)
C30H34N2O10
616
Crystal size
0.16 × 0.20 × 0.21
q range of data collection (°)
Limiting indices (measured)
No. of reflections collected/unique
Completeness to q (%)
3.022 to 31.929
h
14, k 16, l 19
19142 / 9601
99.6
MS (FAB): m/z (%) = 292 (100) [M+ + H], 290 (28), 232 (32).
Anal. Calcd for C15H17NO5 (291.30): C, 61.85; H, 5.88; N, 4.81.
Found: C, 61.92; H, 5.83; N, 4.71.
No. of data/parameters
Goodness-of-fit on F
R1
2955 [I > 3s (I)], 227
1.0707
HPLC: Daicel Chiralcel OD-H (0.46 cm × 25 cm), n-heptane–i-
PrOH (90:10), 0.5 mL/min, 25 °C, tR = 35 min (major enantiomer),
48 min, l = 205, 277 nm.
0.0400
wR2
0.0479
(+)-1,2,3,3a,4,9b-Hexahydro-5-oxa-1-azacyclopenta[a]naph-
thalene-2,3-dicarboxylic Acid 2-tert-Butyl Ester 3-Methyl Ester
(23)
CCDC deposition number
264392
Yield: 305 mg (66%): white solid; mp 98–100 °C; [a]D20 +18.1 (c =
0.80, CHCl3; 99% ee); Rf 0.52 (hexanes–EtOAc, 4:1).
Asymmetric Ag(I)-Catalyzed [3+2] Cycloaddition; General
Procedure
A suspension of AgOAc (3 mol%) and the ligand (3.3 mol%) in tol-
uene was stirred for 10 h. The resulting solution was cooled to 0 °C
before the substrate(s) were added (concentration of the imine 0.05
M). After stirring for 5–9 h the solvent was removed under reduced
pressure and the residue was purified by column chromatography.
IR (KBr): 3378, 3259, 2970, 1735, 1648, 1577, 1486, 1451, 1382,
1314, 1288, 1212, 1172, 1095, 1059, 913, 842, 822, 763 cm–1.
1H NMR (500.1 MHz, CD2Cl2): d = 1.43 [s, 9 H, C(CH3)3], 2.33 (qd,
J = 11.6, 4.3 Hz, 1 H, H-3a), 2.49 (br s, 1 H, H-1), 3.02 (dd, J = 11.6,
10.4 Hz, 1 H, H-3), 3.70 (s, 3 H, OCH3), 3.71–3.75 (m, 1 H, H-9b),
4.15 (dd, J = 11.6, 10.4 Hz, 1 H, H-4), 4.24 (d, J = 9.1 Hz, 1 H, H-
2), 4.55 (dd, J = 10.1, 4.3 Hz, 1 H, H-4), 6.80 (d, J = 8.1 Hz, 1 H,
H-6), 6.88 (t, J = 7.6 Hz, 1 H, H-8), 7.15 (t, J = 7.6 Hz, 1 H, H-7),
7.26 (d, J = 7.3 Hz, 1 H, H-9).
13C{1H} NMR (125.8 MHz, CD2Cl2): d = 28.2 [C(CH3)3], 47.3 (C-
3a), 50.4 (C-3), 52.5 (OCH3), 60.4 (C-9b), 64.8 (C-2), 69.9 (C-4),
82.8 [C(CH3)3], 116.4 (C-6), 120.6 (C-8), 125.1 (C-9), 125.5 (C-
9a), 129.0 (C-7), 153.7 (C-5a), 170.8 [C(2)CO], 172.4 [C(3)CO].
(+)-5-Naphthalen-2-yl-pyrrolidine-2,4-dicarboxylic Acid Di-
methyl Ester (3a)
Colorless oil; [a]D +17.3 (c = 0.61, CHCl3; 62% ee); Rf 0.26
(Et2O–pentane, 3:1).
20
IR (KBr): 3446, 3053, 2995, 2951, 2886, 1736, 1600, 1508, 1438,
1374, 1207, 1169, 1126, 1036, 823, 750 cm–1.
1H NMR (400.1 MHz, CD2Cl2): d = 2.37–2.49 (m, 2 H, CH2), 2.85
(br s, 1 H, NH), 3.11 (s, 3 H, CH3), 3.39 (q, J = 7.5 Hz, 1 H,
CHCO2CH3), 3.81 (s, 3 H, CH3), 4.01 (t, J = 8.3 Hz, 1 H,
NHCHCO2CH3), 4.67 (d, J = 7.8 Hz, 1 H, NHCH), 7.41–7.50 (m, 3
H, Naph-H), 7.79–7.85 (m, 4 H, Naph-H).
MS (FAB): m/z (%) = 334 (60) [M+ + H], 278 (100), 232 (64), 172
(12), 131 (9), 57 (62), 41 (22).
Anal. Calcd for C18H23NO5 (333.38): C, 64.85; H, 6.95; N, 4.20.
Found: C, 64.86; H, 6.92; N, 4.22.
13C{1H} NMR (100.8 MHz, CD2Cl2): d = 33.8 (CH2), 50.1
(CHCO2CH3), 51.6 (CH3), 52.6 (CH3), 60.4 (NHCHCO2CH3), 66.3
(NHCH), 125.8 (Naph-H), 125.9 (Naph-H), 126.4 (Naph-H), 126.6
(Naph-H), 128.1 (Naph-H), 128.1 (Naph-H), 128.4 (Naph-H),
133.4 (Naph-C), 133.7 (Naph-C), 137.7 (Naph-C), 173.6
(CHCO2CH3), 174.3 (NHCHCO2CH3).
HPLC: Daicel Chiralcel AD-H (0.46 cm × 25 cm), n-heptane–i-
PrOH (90:10), 0.5 mL/min, 20 °C, tR = 33 min (major enantiomer),
52 min, l = 205, 276 nm.
(+)-2-Methyl-1,2,3,3a,4,9b-hexahydro-5-oxa-1-azacyclopen-
ta[a]naphthalene-2,3-dicarboxylic Acid Dimethyl Ester (24)
Yield: 280 mg (61%); white solid; mp 137–139 °C; [a]D20 +12.0
(c = 0.98, CHCl3; 96% ee); Rf 0.38 (hexanes–EtOAc, 5:1).
MS (FAB): m/z (%) = 314 (100) [M+ + H], 254 (19), 227 (16), 194
(15), 167 (13).
IR (KBr): 3445, 3326, 2986, 2889, 1727, 1608, 1576, 1488, 1439,
1375, 1326, 1212, 1170, 1097, 1037, 989, 916, 869, 831, 770 cm–1.
Anal. Calcd for C18H19NO4 (313.35): C, 68.99; H, 6.11; N, 4.47.
Found: C, 68.80; H, 6.10; N, 4.47.
1H NMR (500.1 MHz, CD2Cl2): d = 1.66 [s, 3 H, C(2)CH3], 2.48
(dq, J = 11.6, 4.3 Hz, 1 H, H-3a), 2.65 (d, J = 12.1 Hz, 1 H, H-3),
2.77 (s, 1 H, H-1), 3.65 [s, 3 H, C(2)CO2CH3], 3.67 [s, 3 H,
C(3)CO2CH3], 3.90 (d, J = 11.1 Hz, 1 H, H-9b), 4.14 (dd, J = 11.4,
10.1 Hz, 1 H, H-4), 4.55 (dd, J = 10.1, 4.3 Hz, 1 H, H-4), 6.80 (d,
J = 8.1 Hz, 1 H, H-6), 6.87 (t, J = 6.8 Hz, 1 H, H-8), 7.12–7.20 (m,
2 H, H-7, H-9).
13C{1H} NMR (125.8 MHz, CD2Cl2): d = 27.4 [C(2)CH3], 47.0 (C-
3a), 52.6 [C(3)CO2CH3], 53.1 [C(2)CO2CH3], 58.5 (C-3), 58.9 (C-
9b), 69.9 (C-4), 70.6 (C-2), 116.4 (C-6), 120.6 (C-8), 125.1 (C-9),
HPLC: Daicel Chiralcel AD-H (0.46 cm × 25 cm), n-heptane–i-
PrOH (80:20), 0.5 mL/min, 25 °C, tR = 41 min, 72 min (major enan-
tiomer), l = 225, 275 nm.
(+)-1,2,3,3a,4,9b-Hexahydro-5-oxa-1-azacyclopenta[a]naph-
thalene-2,3-dicarboxylic Acid Dimethyl Ester (22)
Yield: 390 mg (74%); white solid; mp 132–134 °C; [a]D20 +19.5
(c = 0.93, CHCl3; 96% ee); Rf 0.29 (hexanes–EtOAc, 1:1).
IR (KBr): 3301, 2988, 2946, 1732, 1622, 1599, 1512, 1471, 1433,
1386, 1370, 1270, 1226, 1208, 1171, 1132, 1109, 1038, 1024, 973,
902, 880, 828, 785, 754, 645, 517, 443 cm–1.
Synthesis 2005, No. 9, 1431–1436 © Thieme Stuttgart · New York

1436
R. Stohler et al.
PAPER
125.6 (C-9a), 128.9 (C-7), 153.8 (C-5a), 172.1 [C(3)CO], 174.3
[C(2)CO].
MS (FAB): m/z (%) = 306 (100) [M+ + H], 246 (62), 214 (6), 186
References
(1) Maclean, D.; Schullek, J. R.; Murphy, M. M.; Ni, Z.-J.;
Gordon, E. M.; Gallop, M. A. Proc. Natl. Acad. Sci. U.S.A.
1997, 94, 2805.
(8), 173 (6), 131 (8), 102 (27), 42 (7).
(2) (a) Gong, Y.-D.; Kim, S.-K.; Yoo, S.-E.; Kurth, M. J. Bull.
Chem. Soc. Jpn. 2002, 75, 2477. (b) Snider, B. B.; Ahn, Y.;
Foxman, B. M. Tetrahedron Lett. 1999, 40, 3339.
(c) Mallassene, R.; Sanchez-Bajo, L.; Toupet, L.; Hurvois,
J.-P.; Moinet, C. Synlett 2002, 1500. (d) Ho, T. C. T.; Jones,
K. Tetrahedron 1997, 53, 8287. (e) Lovely, C. J.; Mahmud,
H.; Dias, H. V. R. Tetrahedron 2001, 57, 4095. (f) Fejes, I.;
Nyenges, M.; Töke, L. Tetrahedron Lett. 2000, 41, 7951.
(g) Gu, Y. G.; Zhang, X.; Clark, R. F.; Djuric, S.; Ma, Z.
Tetrahedron Lett. 2004, 45, 3051. (h) Nakagawa, M.; Lai,
Z.; Torisawa, Y.; Hino, T. Heterocycles 1990, 31, 999.
(3) (a) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5817.
(b) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2457.
(4) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc.
2002, 124, 13400.
Anal. Calcd for C16H19NO5 (305.33): C, 62.94; H, 6.27; N, 4.59.
Found: C, 63.05; H, 6.21; N, 4.64.
HPLC: Daicel Chiralcel OD-H (0.46 cm × 25 cm), n-heptane–i-
PrOH (90:10), 0.5 mL/min, 25 °C, tR = 27 min (major enantiomer),
58 min, l = 205, 275 nm.
(–)-2-Pyridin-2-yl-1,2,3,3a,4,9b-hexahydro-5-oxa-1-azacyclo-
penta[a]naphthalene-3-carboxylic Acid Methyl Ester (25)
Yield: 350 mg (70%); white solid; mp 92–94 °C; [a]D20 –30.1 (c =
0.56, CHCl3; 83% ee); Rf 0.10 (hexanes–EtOAc, 1:1).
IR (KBr): 3433, 2947, 2925, 2868, 2400, 1723, 1594, 1571, 1484,
1455, 1426, 1374, 1314, 1254, 1201, 1171, 1135, 1082, 1032, 982,
931, 881, 812, 750, 677, 632 cm–1.
1H NMR (500.1 MHz, CD2Cl2): d = 2.60 (dqd, J = 4.4, 11.7, 0.3 Hz,
1 H, H-3a), 3.17 (dd, J = 10.2, 11.8, 1 H, H-3), 3.21 [s, 3 H,
C(3)CO2CH3], 3.90 (dt, J = 11.2, 1.1 Hz, 1 H, H-9b), 4.17 (dd, J =
11.7, 9.9 Hz, 1 H, H-4), 4.54 (dd, J = 9.9, 4.3 Hz, 1 H, H-4), 4.99
(d, J = 10.1 Hz, 1 H, H-2), 6.83 (dd, J = 8.2, 1.1 Hz, 1 H, H-6), 6.90
(td, J = 7.4, 1.2 Hz, 1 H, H-8), 7.16 (dddd, J = 8.3, 7.5, 1.8, 0.8 Hz,
1 H, H-7), 7.17 [ddd, J = 7.5, 4.8, 1.2 Hz, 1 H, Py(5)], 7.32 (dddd,
J = 7.5, 1.7, 1.2, 0.5 Hz, 1 H, H-9), 7.33 [dt, J = 7.8, 1.1 Hz, 1 H,
Py(3)], 7.65 [td, J = 7.6, 1.8 Hz, 1 H, Py(4)], 8.46 [ddd, J = 4.8 Hz,
JH,H = 1.7 Hz, J = 1.0 Hz, 1 H, Py(6)] (NH not visible).
13C{1H} NMR (125.8 MHz, CD2Cl2): d = 45.3 (C-3a), 51.5
[C(3)CO2CH3], 52.5 (C-3), 60.3 (C-9b), 66.8 (C-2), 70.1 (C-4),
116.2 (C-6), 120.3 (C-8), 123.0 [Py(5)], 123.8 [Py(3)], 125.1 (C-
9),126.0 (C-9a), 128.7 (C-7), 136.5 [Py(4)], 149.2 [Py(6)], 153.8
(C-5a), 159.0 [Py(2)], 171.6 [C(3)CO].
(5) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgenson, K.
A. Angew. Chem. Int. Ed. 2002, 41, 4236.
(6) Chen, C.; Li, S.; Schreiber, S. L. J. Am. Chem. Soc. 2003,
125, 10174.
(7) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
(8) For bisoxazoline ligands with two geminal substituents at
C(5) see: (a) Denmark, S. E.; Stavenger, R. A.; Faucher,
A.-M.; Edwards, J. P. J. Org. Chem. 1997, 62, 3375.
(b) Gupta, A. D.; Bhuniya, D.; Singh, V. K. Tetrahedron
1994, 50, 13725. (c) Alexander, K.; Cook, S.; Gibson, C. L.
Tetrahedron Lett. 2000, 41, 7135. (d) Andrus, M. B.;
Argade, A. B.; Chen, X.; Pamment, M. G. Tetrahedron Lett.
1995, 36, 2945.
(9) Ciganek, E. Synthesis 1995, 1311.
(10) Ayerbe, M.; Arrieta, A.; Cossío, F. P. J. Org. Chem. 1998,
MS (FAB): m/z (%) = 311 (100) [M+ + H], 310 (22), 309 (25), 290
(28), 232 (32), 131 (13), 108 (36), 107 (42), 89 (11), 78 (11), 77
(19), 73 (12), 57 (12), 55 (12), 51 (13), 43 (14), 41 (14), 39 (15).
63, 1795.
(11) For analogons of non-enantioselective reactions, see:
(a) Grigg, R.; Duffy, L. M.; Dorrity, M. J.; Malone, J. F.;
Rajviroongit, S.; Thornton-Pett, M. Tetrahedron 1990, 46,
2213. (b) Adill, H.; Grigg, R.; Sridhanan, V.;
Anal. Calcd for C18H18N2O3 (310.35): C, 69.66; H, 5.85; N, 9.03.
Found: C, 69.68; H, 5.91; N, 8.97.
Surendrakumar, S. Tetrahedron 1988, 44, 4953. (c) Tsuge,
O.; Ueno, K.; Oe, K. Chem. Lett. 1981, 135. (d) Grigg, R.;
Donegan, G.; Gunaratne, H. Q. N.; Kennedy, D. A.; Malone,
J. F.; Sridhanan, V.; Thianpatanagul, S. Tetrahedron 1989,
45, 1723.
HPLC: Daicel Chiralcel AD-H (0.46 cm × 25 cm), n-heptane–i-
PrOH (90:10), 0.5 mL/min, 25 °C, tR = 49 min, 99 min (major enan-
tiomer), l = 205, 263 nm.
(12) Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi,
A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Cryst.
1994, 27, 435.
(13) Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge, P.
W.; Cooper, R. I. CRYSTALS, Issue 11; Chemical
Crystallography Laboratory: Oxford, 2001.
Acknowledgment
We thank Markus Neuburger and Eva Neumann for the X-ray ana-
lysis and Klaus Kulicke for the support in evaluating the NMR spec-
tra. Financial support by the Swiss National Science Foundation is
gratefully acknowledged.
Synthesis 2005, No. 9, 1431–1436 © Thieme Stuttgart · New York