Synthesis of spirolactones by 1,3-dipolar cycloadditions to methyl (S)-3-[(E)-cyanomethylidene]-2-oxotetrahydrofuran-5-carboxylate

Article abstract of DOI:10.1002/jhet.5570390227

Treatment of methyl (S)-5-[(E)-(dimethylamino)methylidene]-2-oxotetrahydrofuran-5-carboxylate (2) with potassium cyanide in acetic acid gave (S)-5-[(E)-cyanomethylidene]-2-oxotetrahydrofuran-5-carboxylate (3), which was used as chiral dipolarophile in 1,3-dipolar cycloadditions. Reactions of 3 with diazomethane (4) and nitrile oxides 5a-c afforded spirolactones 6-8 in 24-34% diastereomeric excess, while with diazomethane (4) in the presence of triethylamine, methyl 3-cyanomethyl-2-methoxyfuran-5carboxylate (12) was obtained.

Full text of DOI:10.1002/jhet.5570390227

Mar-Apr 2002
Synthesis of Spirolactones by 1,3-Dipolar Cycloadditions to Methyl
411
(S)-3-[(E)-Cyanomethylidene]-2-oxotetrahydrofuran-5-carboxylate
ˇ
Samo Pirc, Simon Recˇnik, Marko Skof, Jurij Svete,* Ljubo Golicˇ, Anton Meden,
and Branko Stanovnik*
Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Asˇkercˇeva 5, 1000 Ljubljana, Slovenia
Received November 27, 2001
Dedicated to Professor Emeritus Miha Tisˇler on the occasion of his 75th birthday
Treatment of methyl (S)-5-[(E)-(dimethylamino)methylidene]-2-oxotetrahydrofuran-5-carboxylate (2)
with potassium cyanide in acetic acid gave (S)-5-[(E)-cyanomethylidene]-2-oxotetrahydrofuran-5-car-
boxylate (3), which was used as chiral dipolarophile in 1,3-dipolar cycloadditions. Reactions of 3 with
diazomethane (4) and nitrile oxides 5a–c afforded spirolactones 6–8 in 24–34% diastereomeric excess,
while with diazomethane (4) in the presence of triethylamine, methyl 3-cyanomethyl-2-methoxyfuran-5-
carboxylate (12) was obtained.
J. Heterocyclic Chem., 39, 411 (2002).
tetrahydrofuran-2-one-5-carboxylic acid (1) [11], which is
also available in one step from L-glutamic acid [12].
Enaminone 2 was then treated with potassium cyanide in
acetic acid at room temperature to give methyl (S)-5-[(E)-
cyanomethylidene]-2-oxotetrahydrofuran-5-carboxylate (3)
in 73% yield. The (E)-configuration of the exocyclic double
bond in compounds 2 and 3 was determined by nmr (HMBC
γ-Lactones are an important class of heterocyclic com-
pounds, not only due to their synthetic utility but also
because the γ-lactone structural motif is widely repre-
sented among numerous natural products and biologically
active compounds [1]. Examples of spiro γ-lactones, iso-
lated from natural sources, are bakkenolides [2,3], salvi-
languidulines [4], syringolides [5], secosyrins [6], and
hyperolactones [7] (Figure 1).
technique) on the basis of long-range heteronuclear cou-
3
pling constants, J
. The magnitude of coupling con-
C–H
3
stants, J
= 4.8 and 4.5 Hz, indicates the cis-orientation
C–H
between H–3' and C–2 (carbon atom of the ring carbonyl
group) and is in agreement with the magnitudes reported in
the literature. Generally, the magnitude of coupling constant
3
J
for nuclei with cis-configuration around the C=C
C–H
double bond is smaller (2–6 Hz) than that for trans-oriented
nuclei (8–12 Hz) [10,13–15] (Scheme 1).
Compound 3, when treated with diazomethane (4) and
nitrile oxides 5a–c as 1,3-dipoles, gave the corresponding
spiro compounds 6–9 as cycloadducts. Thus, treatment
with diazomethane (4) furnished optically active methyl
Figure 1. Some naturally occurring spiro γ-lactones.
In the course of our studies towards the synthesis of hete-
rocyclic systems, 3-(dimethylamino)- and 3-cyano-
propenoates have been employed as easily available and ver-
satile reagents. Their chiral analogs, derived from L-pyro-
glutamic acid and 2-oxotetrahydrofuran-5-carboxylic acid,
have been used as reagents for the preparation of optically
active 3-heteroarylalanine- and 3-(heteroaryl)lactic acid
derivatives and heterocyclic systems with an α-amino- or α-
hydroxy acid structural element [8,9]. In this connection, we
have recently reported the preparation of methyl (S)-1-ben-
zoyl-3-[(E)-cyanomethylidene]-2-oxopyrrolidinone-5-car-
boxylate and its transformation into cyclic β-heteroarylala-
nine- and α-heteroarylglycine analogs by 1,3-dipolar
cycloaddition reactions [10]. In continuation of our work in
this field, we now report the preparation and cycloaddition
reactions of (S)-5-[(E)-cyanomethylidene]-2-oxotetrahydro-
furan-5-carboxylate (3).
Scheme 1
The starting compound, methyl (S)-3-[(E)-(dimethyl-
amino)methylidene]-2-oxotetrahydrofuran-5-carboxylate
t
Reagents and conditions: i) CH N (4), Et O, 0 °C; ii) Bu OCH(NMe ) ,
2
2
2
2 2
2) was prepared in 2 steps from commercially available (S)-
(
toluene, 100 °C; iii) KCN, AcOH, 20 °C.

ˇ
412
S. Pirc, S. Recˇnik, M.Skof, J. Svete, L. Golicˇ, A. Meden, and B. Stanovnik
Vol. 39
(4S,5S,8S)-4-cyano-6-oxo-7-oxa-1,2-diaza[4.4]non-1-ene-
8-carboxylate (6) and its (4R,5R,8S)-isomer (7) in a ratio
of 62:38, respectively. Upon chromatographic separation,
isomerically and analytically pure compounds 6 and 7
were obtained. On the other hand, reactions of 3 with
nitrile oxides 5a–c in chloroform under reflux afforded
racemic methyl rel-(4R,5S,8S)-3-aryl-4-cyano-6-oxo-1,7-
dioxa-2-aza[4.4]non-2-ene-8-carboxylates 8a–c and their
rel-(4S,5R,8S)-isomers 9a–c in a ratio of 2:1, respectively.
In this case, only the major isomers 8a–c were obtained in
isomerically and analytically pure form (Scheme 2).
In all cases, the cycloadditions proceeded regiospecifi-
cally and in agreement with regiochemistry of analogous
cycloadditions [10,16–20]. Poor stereoselectivity of
cycloadditions (24–34% diastereomeric excess) was some-
how expected and was most probably due to a large dis-
tance between the stereodirecting center at 5-position and
the exocyclic C=C double bond. Similar stereoselectivity
has been observed previously by analogous cycloadditions
in 2-pyrrolidinone series. To our surprise, racemization
took place upon treatment of 3 with nitrile oxides 5a–c
under essentially neutral conditions. At this moment, we
do not have a firm explanation for racemization, especially
since cycloaddition of 2,4,6-trimethoxybenzonitrile oxide
(5b) to closely related methyl (S)-1-benzoyl-3-[(E)-
cyanomethylidene]pyrrolidin-2-one-5-carboxylate
afforded optically active spiro pyrrolidinone [10] (Scheme
2). However, formation of racemic spiro compounds 8, 9
might be explained by initial racemization of the dipo-
larophile 3 via tautomeric equilibrium between its iso-
meric forms 10 and 11 (Scheme 3).
Scheme 2
Scheme 3
1
2
Compounds
R
R
6 : 7 or 8 : 9 D.e. [%] Yield [%]
6 or 8
7
6/7
62 : 38
66 : 34
67 : 33
67 : 33
24
32
34
34
43 24
5a, 8a/9a
5b, 8b/9b
5c, 8c/9c
Me
MeO
Cl
Me
MeO
H
27
25
48
Reagents and conditions: i) CH N (4), Et O, CH Cl , Et N, 20 °C.
2
2
2
2
2
3
Reagents and conditions: i) CH N (4), Et O, CH Cl , –10°C, then chro-
2
2
2
2
2
matographic separation; ii) benzonitrile oxide (5a–c), CHCl , reflux, then
chromatographic separation.
Structures of novel compounds 6–8, 12 were determined
3
1
13
by spectroscopic methods (ir, H- and C nmr) and by
analyses for C, H, and N. The structures of cycloadducts 6,
7, 8a,c were also determined by X-ray diffraction which
also offered an additional proof for the configuration of the
exocyclic C=C bond in the dipolarophile 3 (Figures 2–5).
Cycloadditions of diazomethane (4) and nitrile oxides
5a–c to methyl (S)-3-[(E)-cyanomethylidene]-2-oxotetra-
hydrofuran-5-carboxylate (3) showed that spiro γ-lactones,
such as 7-oxa-1,2-diazaspiro[4.4]non-1-ene- (6, 7) and
1,7-dioxa-2-azaspiro[4.4]non-2-ene derivatives (8a–c),
can be prepared regioselectively in one step from easily
available dipolarophile 3. Due to generally poor diastere-
oselectivity and racemization, which took place upon
cycloadditions of nitrile oxides 5 to the dipolarophile 3,
further studies in this field will be focused towards stereo-
chemical and separation issues.
S)-1-
Since closely related cycloadditions to methyl (
benzoyl-3-[(E)-cyanomethylidene]-2-oxopyrrolidin-5-car-
boxylate, carried out in the presence of a base, gave fused
pyrrolidinones instead of spiro compounds [10], we also
performed the above mentioned cycloadditions in the pres-
ence of triethylamine. Unfortunately, analogous cycloaddi-
tions of 3 to nitrile oxides 5a–c furnished only unseparable
tarry mixtures of products. However, treatment of 3 with
diazomethane (4) in the presence of triethylamine gave
methyl 3-cyanomethyl-2-methoxyfuran-5-carboxylate
(12). Formation of 12 might be explained by a base-cat-
alyzed isomerization into intermediate 10 followed by
aromatization into 2-hydroxyfuran derivative 11, which is
then methylated with diazomethane (4) (Scheme 3).

Mar-Apr 2002
Synthesis of Spirolactones by 1,3-Dipolar Cycloadditions
413
Figure 2. Ortep view of compound 6 at the 50% probability level. H atoms
are drawn as circles of arbitrary radii.
Figure 5. Ortep view of compound 8c at the 50% probability level. H
atoms are drawn as circles of arbitrary radii.
0.035 mm (Merck); column dimensions (dry filled): 15 x 460
mm; backpressure: 10–15 bar; detection: UV 254 nm; sample
amount: 100–150 mg of isomeric mixture per each run. Tlc: alu
foils coated with silica gel 60 F 254, 0.2mm (Merck). Mp: Kofler
micro hot stage. Optical rotations: Perkin-Elmer 241 MC
1
13
polarimeter. H nmr (300 MHz), C nmr (75.5 MHz), and 2D
HMBC spectra: Bruker Avance DPX 300 spectrometer with deu-
teriochloroform and dimethyl sulfoxide–d as solvents and
6
tetramethylsilane as internal standard. Ir: Perkin-Elmer Spectrum
BX FTIR spectrometer (KBr). Ms: Autospeck Q (VG-
Analytical) spectrometer. Elemental analyses for C, H, and N:
Perkin-Elmer CHN Analyser 2400.
Figure 3. Ortep view of compound 7 at the 50% probability level. H
atoms are drawn as circles of arbitrary radii.
Diastereomeric excess of major isomers 6, 8a–c were deter-
mined by taking H nmr spectra of crude isomeric mixtures.
1
The following compounds were prepared according to the pro-
cedures described in the literature: methyl (S)-3-[(E)-(dimethy-
lamino)methylidene]-2-oxotetrahydrofuran-5-carboxylate (2)
[11], diazomethane (4) [22], and benzonitrile oxides (5a–c) [23].
Methyl (S)-3-[(E)-Cyanomethylidene)]-2-oxotetrahydrofuran-5-
carboxylate (3).
Potassium cyanide (0.254 g, 3.9 mmoles) was dissolved in a
solution of 2 (0.597 g, 3 mmoles) in acetic acid (100%, 20 ml) and
the solution was left at room temperature for 4 days. The reaction
mixture was evaporated in vacuo to 1/4 of the initial volume (~5
ml), water (50 ml) was added, and the product was extracted with
diethyl ether (4 x 50 ml). Organic phases were combined, dried
over anhydrous sodium sulfate, filtered, and the filtrate was evapo-
rated in vacuo. The residue was purified by column chromatogra-
phy (ethyl acetate). Fractions containing the product were com-
bined and evaporated in vacuo to give 3 which was used for further
transformations without purification. Yield: 0.396 g (73%), color-
Figure 4. Ortep view of compound 8a at the 50% probability level. H
atoms are drawn as circles of arbitrary radii.
21
–1
less oil. [α]
= +89.7° (c = 1.04, dichloromethane). Ir (cm ):
D
1
2230 (C≡N), 1760 (C=O). H nmr (deuteriochloroform): δ 3.32
(1H, ddd, J = 3.0, 4.1, 19.6 Hz, 4–Ha); 3.51 (1H, ddd, J = 3.4, 9.0,
19.6 Hz, 4–Hb); 3.86 (3H, s, OMe); 5.11 (1H, dd, J = 4.1, 9.0 Hz,
EXPERIMENTAL
13
5–H); 6.40 (1H, dd, J = 3.0, 3.4 Hz, 3'–H). C nmr (deuteriochlo-
All starting materials were commercially available (in most
cases from Fluka AG) and purified following the standard tech-
niques. Column chromatography: silica gel, silica gel 60,
0.04–0.06 mm (Fluka). Medium pressure liquid chromatography:
Büchi isocratic system with detection [21], silica gel 60, 0.015−
roform): δ 31.9, 53.7, 73.5, 105.9, 115.0, 145.6, 166.5, 169.2.
Anal. Calcd. for C H NO (181.15): C, 53.04; H, 3.89; N,
8
7
4
7.73. Found: C, 52.71; H, 3.96; N, 7.45. Hrms Calcd. for
C H NO : 181.037508. Found: 181.038100.
8
7
4

ˇ
414
S. Pirc, S. Recˇnik, M.Skof, J. Svete, L. Golicˇ, A. Meden, and B. Stanovnik
Vol. 39
Table 1
Crystal Data, Data Collection, and Refinement Data for Compounds 6, 7, 8a, and 8c
6
7
8a
8c
Crystal data
Chemical formula
C H N O
9 9 3 4
C H N O
9 9 3 4
C
H
N O
C
H Cl N O
18 18 2 5
15 10 2 2 5
M
223.188
223.188
342.351
Monoclinic
P2 /c
16.462(3)
10.251(1)
10.681(2)
101.89(1)
1763.8(5)
4
369.16
Monoclinic
P2 /c
15.057(3)
10.125(8)
10.665(2)
102.04(1)
1590(1)
4
r
Cell seting
Space group
a (Å)
Monoclinic
Orthorhombic
P2 /n
P2 2 2
1
1 1 1
1
1
9.3493(9)
11.410(1)
10.397(1)
112.836(7)
1022.2(2)
4
5.4504(3)
10.2657(5)
17.325(1)
/
b (Å)
c (Å)
b (°)
V (Å )
3
969.36(9)
4
1.529
Z
–3
D (Mg m
Radiation type
)
1.450
Mo Ka
1.289
Mo Ka
1.542
Mo Ka
x
Mo Ka
No. of reflect. for cell parameters
θ range (°)
75
6723 [a]
1.02–26.02 [a]
0.1230
100
9.13–17.71
0.0952
75
8.36–17.34
0.1166
10.13–14.47
0.4368
–1
m (mm
)
Temperature (K)
Crystal form, color
Crystal size (mm)
Data collection
293(1)
Block, colorless
0.64x0.57x0.53
293(1)
Plate, colorless
0.20x0.10x0.05
293(1)
Plate, colorless
1.29x0.80x0.10
293(1)
Plate, colorless
1.07x0.65x0.25
Diffractometer
Nonius CAD-4
w - 2q
none
9920
2459
1960
I > 2.5s(I)
0.0110
Nonius Kappa CCD
Nonius CAD-4
w - 2q
none
17042
4235
2690
I > 2.5s(I)
0.0437
Nonius CAD-4
w - 2q
none
15442
3830
2780
I > 2.5s(I)
0.0148
Profile data scans
Absorption corr.
Measured reflect.
Independent refl.
Observed refl.
φ and ω
none
6723
1130
967
2
2
Criterion for obs. reflections
F > 1.5s(F )
0.061
R
int
q
(°)
27.95
26.02
27.93
27.97
max
Range of h, k, l
–12 →h→ 12
–15 →k→ 15
–13 →l→ 13
333
–6 →h→ 6
–12 →h→ 12
–21 →h→ 21
/ [b]
–21 →h→ 21
–13 →k→ 13
–14 →l→ 14
333
–19 →h→ 19
–13 →k→ 13
–14 →l→ 14
333
3 Standard refl. frequency (min)
Intens. decay (%)
1.03
/ [b]
1.77
4.86
Refinement
Refinement on
F
F
F
F
R
wR
S
0.040
0.045
1.001
1960
0.043
0.048
1.085
967
0.058
0.068
1.001
2690
0.046
0.057
0.972
2780
No. of refl. used in refinement
No. of parameters
Weighting scheme
(∆/σ)
(∆/σ)
172
181
280
247
empirical
0.0549
0.00203
0.343
–0.308
Regina [26]
0.0114
0.00094
0.210
–0.210
empirical
0.1349
0.0042
0.468
–0.431
empirical
0.00079
0.000042
0.659
–0.480
max
aver
–3
∆ρ
∆ρ
(e Å )
max
–3
(e Å
)
min
[a] The unit cell was determined during the image integration procedure; [b] These values are not applicable for the CCD diffractometer.
Preparation of Methyl (4S,5S,8S)-4-Cyano-6-oxo-7-oxa-1,2-
diazaspiro-[4.4]non-1-ene-8-carboxylate (6) and Its (4R,5R,8S)-
Isomer (7).
pressure liquid chromatography (ethyl acetate/petroleum ether,
1:2, R of 6 = 8 min, R of 7 = 9.5 min). Fractions containing sin-
gle isomers 6 and 7 were evaporated in vacuo to give isomeri-
cally and analitycally pure compounds 6 and 7.
t
t
A cold solution (0–5°) of diazomethane (4) in diethyl ether
(~0.4 M, 12 ml, ~5 mmoles) was added to a solution of 3 (0.181g,
1 mmol) in dichloromethane (5 ml) at –10° and the solution was
left at –10° for 12 h. Volatile components were left to evaporate
in a ventilated hood and the residue was purified by column chro-
matography (ethyl acetate). Fractions containing the products
were combined and volatile components were evaporated in
vacuo to give a mixture 6 and 7 which were separated by medium
The following compounds were prepared in this manner:
Methyl (4S,5S,8S)-4-Cyano-6-oxo-7-oxa-1,2-diazaspiro[4.4]-
non-1-ene-8-carboxylate (6).
This compound was prepared from 3 and diazomethane (4)
followed by chromatographic purification and separation. Yield:
0.096 g (43%), mp 115–116° (from ethyl acetate/petroleum ether,
21
1:2), colorless crystals. [α]
= +325° (c = 0.52, dichloro-
D

Mar-Apr 2002
Synthesis of Spirolactones by 1,3-Dipolar Cycloadditions
415
–1
1
Methyl (4R,5S,8S)-4-Cyano-6-oxo-3-(2,4,6-trimethoxyphenyl)-
1,7-dioxa-2-azaspiro[4.4]non-2-ene-8-carboxylate (8b).
methane). Ir (cm ): 2255 (C≡N), 1785, 1755 (C=O). H nmr
(deuteriochloroform): δ 2.90 (1H, dd, J = 6.4, 14.3 Hz, 9–Ha);
3.34 (1H, dd, J = 7.9, 14.3 Hz, 9–Hb); 3.50 (1H, dd, J = 4.5, 9.0
Hz, 4–H); 3.91 (3H, s, OMe); 5.07 (1H, dd, J = 9.0, 18.1 Hz,
3–Ha); 5.22 (1H, dd, J = 4.5, 18.1 Hz, 3–Hb); 5.46 (1H, dd, J =
This compound was prepared from 3 and 2,4,6-trimethoxyben-
zonitrile oxide (5b), medium pressure liquid chromatography
(ethyl acetate/petroleum ether, 1:2, R of 8b = 18.5 min, R of 9b
t
t
13
6.4, 7.9 Hz, 8–H). C nmr (deuteriochloroform): δ 29.5, 34.6,
53.8, 74.9, 82.9, 96.5, 116.8, 169.1, 170.0.
Anal. Calcd. for C H N O (223.19): C, 48.43; H, 4.06; N,
18.83. Found: C, 48.51; H, 4.01; N, 18.63.
= 22 min). Yield: 0.097 g (25%), mp 204–207° (from chloro-
–1
form/n-hexane), colorless crystals. Ir (cm ): 2255 (C≡N), 1798,
1
9
9 3 4
1757 (C=O). H nmr (deuteriochloroform): δ 2.79 (1H, dd, J =
7.2, 14.7 Hz, 9–Ha); 3.08 (1H, dd, J = 7.2, 14.3 Hz, 9–Hb); 3.86
and 3.87 (12H, 2s, 3:1, 4OMe); 5.16 (1H, deg dd, J = 7.2 Hz,
Methyl (4R,5R,8S)-4-Cyano-6-oxo-7-oxa-1,2-diazaspiro[4.4]-
non-1-ene-8-carboxylate (7).
13
8–H); 5.34 (1H, s, 4–H); 6.18 (2H, s, C H ). C nmr (dimethyl
6
2
sulfoxide–d ): δ 34.7, 47.9, 53.6, 56.5, 57.1, 74.4, 86.2, 92.3,
6
This compound was prepared from 3 and diazomethane (4)
followed by chromatographic purification and separation. Yield:
0.054 g (24%), mp 120–125° (from ethyl acetate/petroleum ether,
96.2, 114.8, 148.3, 160.7, 164.4, 169.4, 171.7.
Anal. Calcd. for C H N O (390.34): C, 55.39; H, 4.65; N,
18 18
2 8
7.18. Found: C, 55.47; H, 4.56; N, 6.85.
21
1:2), colorless crystals. [α]
= –116° (c = 0.3, dichloro-
1
D
Minor (4S,5R,8S)-Isomer (9b). H nmr (deuteriochloroform):
–1
1
methane). Ir (cm ): 2254 (C≡N), 1795, 1744 (C=O). H nmr
(deuteriochloroform): δ 3.08 (1H, dd, J = 3.0, 14.3 Hz, 9–Ha);
3.18 (1H, dd, J = 9.0, 14.3 Hz, 9–Hb); 3.45 (1H, dd, J = 6.8, 7.9
δ 2.96 (1H, dd, J = 3.4, 14.7 Hz, 9–Ha); 3.05 (1H, dd, J = 8.7,
14.7 Hz, 9–Hb); 3.86 and 3.89 (12H, 2s, 3:1, 4OMe); 5.12 (1H,
dd, J = 3.4, 8.7 Hz, 8–H); 5.37 (1H, s, 4–H); 6.18 (2H, s, C H ).
6
2
Hz, 4–H); 3.91 (3H, s, OMe); 5.08–5.15 (2H, m, 3–CH ); 5.31
(1H, dd, J = 3.0, 9.0 Hz, 8–H). C nmr (deuteriochloroform): δ
29.0, 34.4, 53.8, 74.9, 82.6, 96.0, 116.5, 169.0, 170.3.
2
13
Methyl (4R,5S,8S)-4-Cyano-3-(2,6-dichlorophenyl)-6-oxo-1,7-
dioxa-2-azaspiro[4.4]non-2-ene-8-carboxylate (8c).
Anal. Calcd. for C H N O (223.19): C, 48.43; H, 4.06; N,
18.83. Found: C, 48.56; H, 4.01; N, 18.53.
9
9 3 4
This compound was prepared from 3 and 2,6-dichlorobenzoni-
trile oxide (5c), medium pressure liquid chromatography (ethyl
acetate/petroleum ether, 1:3, R of 8c = 8 min, R of 9c = 11 min).
t
t
General Procedure for the Preparation of Methyl (4R,5S,8S)-3-
Aryl-4-cyano-6-oxo-1,7-dioxa-2-azaspiro[4.4]non-2-ene-8-car-
boxylates (8a–c).
Yield: 0.178 g (48%), mp 169–173° (from chloroform/n-hexane),
–1
1
colorless crystals. Ir (cm ): 2252 (C≡N), 1797, 1742 (C=O). H
nmr (deuteriochloroform): δ 2.93 (1H, dd, J = 6.0, 14.7 Hz, 9–Ha);
3.17 (1H, dd, J = 7.5, 14.7 Hz, 9–Hb); 3.89 (3H, s, OMe); 5.20
A mixture of 3 (0.181 g, 1 mmol), nitrile oxide 5a–c (1 mmol),
and chloroform (10 ml) was refluxed for 2 h. Volatile compo-
nents were evaporated in vacuo and the residue was purified by
column chromatography (ethyl acetate/petroleum ether, 1:2).
Fractions containing the product were combined and volatile
components were evaporated in vacuo to give a mixture of iso-
mers 8 and 9 which was purified by medium pressure liquid chro-
matography. Fractions containing the major (4R,5S,8S)-isomer 8
were evaporated in vacuo to give isomerically and analytically
pure compound 8 [24].
(1H, dd, J = 6.0, 7.5 Hz, 8–H); 5.24 (1H, s, 4–H); 7.35–7.50 (3H,
13
m, C H ). C nmr (deuteriochloroform): δ 36.4, 47.3, 53.9, 73.8,
6
3
87.0, 111.8, 124.5, 129.0, 133.3, 136.3, 148.7, 168.9, 170.2.
Anal. Calcd. for C H Cl N O (369.16): C, 48.80; H, 2.73;
15 10
2 2 5
N, 7.59. Found: C, 48.68; H, 2.56; N, 7.37.
1
Minor (4S,5R,8S)-Isomer (9c). H nmr (deuteriochloroform): δ
3.07 (1H, dd, J = 3.0, 14.7 Hz, 9–Ha); 3.16 (1H, dd, J = 8.7, 14.7
Hz, 9–Hb); 3.92 (3H, s, OMe); 5.19 (1H, dd, J = 3.0, 8.7 Hz,
8–H); 5.29 (1H, s, 4–H); 7.40–7.50 (3H, m, C H ).
6
3
The following compounds were prepared in this manner:
Methyl 3-Cyanomethyl-2-methoxyfuran-5-carboxylate (12).
Methyl (4R,5S,8S)-4-Cyano-6-oxo-3-(2,4,6-trimethylphenyl)-
1,7-dioxa-2-azaspiro[4.4]non-2-ene-8-carboxylate (8a).
Triethylamine (0.1 ml, 0.7 mmol) and a solution of dia-
zomethane (4) in diethyl ether (~0.5 M, 10 ml, ~5 mmoles) were
added to a solution of 3 (0.091 g, 0.5 mmol) in dichloromethane
(10 ml) and the solution was left at room temperature for 20 h.
Volatile components were left to evaporate in a ventilated hood
and the residue was purified by column chromatography (diethyl
ether). Fractions containing the product were combined, evapo-
rated in vacuo, and the solid residue was crystallized from
dichloromethane/diethyl ether to give 12. Yield: 0.054 g (55%),
mp 51–54° (from dichloromethane/diethyl ether), colorless crys-
This compound was prepared from 3 and 2,4,6-trimethylben-
zonitrile oxide (5a), medium pressure liquid chromatography
(ethyl acetate/petroleum ether, 1:2, R of 8a = 5 min, R of 9a =
t
t
7 min). Yield: 0.094 g (27%), mp 150–152° (from chloro-
–1
form/n-hexane), colorless crystals. Ir (cm ): 2248 (C≡N),
1
1796, 1743 (C=O). H nmr (deuteriochloroform): δ 2.32 and
2.34 (9H, 2s, 1:2, 3Me–C H ); 2.92 (1H, dd, J = 6.0, 14.7 Hz,
6
2
9–Ha); 3.16 (1H, dd, J = 7.5, 14.7 Hz, 9–Hb); 3.88 (3H, s,
OMe); 4.85 (1H, s, 4–H); 5.18 (1H, dd, J = 6.0, 7.5 Hz, 8–H);
–1
1
tals. Ir (cm ): 2240 (C≡N), 1710, 1630 (C=O). H nmr (deuterio-
13
6.96 (2H, s, C H ). C nmr (dimethyl sulfoxide–d ): δ 20.1,
6
2
6
chloroform): δ 3.40 (2H, s, CH ); 3.85 and 4.10 (6H, 2s, 1:1,
2
21.6, 34.3, 48.2, 53.6, 74.7, 87.3, 114.3, 122.7, 129.5, 138.3,
140.9, 153.2, 169.2, 171.8.
2OMe); 7.15 (1H, s, 4–H).
Anal. Calcd. for C H NO (195.17): C, 55.39; H, 4.65; N,
9
9
4
Anal. Calcd. for C H N O (342.35): C, 63.15; H, 5.30; N,
18 18
2
5
7.18. Found: C, 55.14; H, 4.54; N, 7.01.
8.18. Found: C, 63.16; H, 5.22; N, 7.89.
X-Ray Crystallographic Study.
1
Minor (4S,5R,8S)-Isomer (9a). H nmr (deuteriochloroform):
δ 2.32 and 2.33 (9H, 2s, 1:2, 3Me–C H ); 3.07 (1H, dd, J = 3.0,
14.7 Hz, 9–Ha); 3.14 (1H, dd, J = 8.3, 14.7 Hz, 9–Hb); 3.92 (3H,
s, OMe); 4.91 (1H, s, 4–H); 5.17 (1H, dd, J = 3.0, 8.3 Hz, 8–H);
Structures of compounds 6, 7, 8a, and 8c were solved by direct
methods using the SIR92 [25] program. In the structures 6, 8a, and
8c, all hydrogen atoms were located by difference Fourier synthesis
and included in refinement with positional parameters and fixed
6
2
6.96 (2H, s, C H ).
6
2

ˇ
416
S. Pirc, S. Recˇnik, M.Skof, J. Svete, L. Golicˇ, A. Meden, and B. Stanovnik
Vol. 39
Clardy, J. Org. Chem., 58, 2940 (1993).
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1118 (1995).
[7] Y. Aramaki, K. Chiba and M. Tada, Phytochemistry, 38, 1419
(1995).
individual isotropic displacement parameters of the bonded atoms.
In the structure of 7 the hydrogen atoms were refined with
restrained bonds and angles. All four structures were refined by a
full-matrix least-squares procedure on F with anisotropic displace-
ment parameters of all non-hydrogen atoms. Empirical weighting
schemes were applied for the following three structures: compound
[8] B. Stanovnik and J. Svete, Synlett, 1077 (2000).
[9] B. Stanovnik and J. Svete, Targets in Heterocyclic Systems, 4,
6: w = w *w , w (F <2.1) = (F /2.1), w (F >8.9) = (8.9/F ), w
f
s
f
o
o
f
o
o
f
105 (2000).
3
(2.1<F <8.9)=1.0, w (sinθ/λ<0.53) = ((sinθ/λ)/0.53) ,
o
s
ˇ
[10] M.Skof, J. Svete, B. Stanovnik, L. Golicˇ, S. Golicˇ Grdadolnik
4
w (sinθ/λ>0.70) = (0.7.0/(sinθ/λ)) , w (0.53<sinθ/λ<0.70) = 1.0,
s
s
and L. Selicˇ, Helv. Chim. Acta, 81, 2332 (1998).
2.0
compound 8a: w = w *w , w (F <3.8) = (F /3.8) , w (F >7.5) =
f
s
f
o
o
f
o
ˇ
[11] M. Skof, J. Svete, M. Kmeticˇ, S. Golicˇ Grdadolnik and B.
1.5
(7.5/F ) , w (3.8<F <7.5)=1.0, w (sinθ/λ<0.52) =
o
f
o
s
Stanovnik, Eur. J. Org. Chem., 1581 (1999).
[12] O. H. Gringore and F. P. Rouessac, Org. Synth., Coll. Vol. 7,
99 (1990).
[13] S. Golicˇ Grdadolnik and B. Stanovnik, Magn. Reson. Chem.
35, 482 (1997).
[14] T. Ando, N. Koseki, R. E. Toia and J. E. Casido, Magn. Reson.
Chem. 31, 90 (1993).
[15a] R. Jaksˇe, S. Recˇnik, J. Svete, A. Golobicˇ, L. Golicˇ and B.
Stanovnik, Tetrahedron, 57, 8395 (2001); [b] J. Basˇ, S. Recˇnik, J. Svete,
S. Golicˇ Grdadolnik and B. Stanovnik, ARKIVOC, 2, 1189 (2001); [c] D.
Bevk, M. Kmeticˇ, S. Recˇnik, J. Svete, L. Golicˇ, A. Golobicˇ and B.
Stanovnik, Chemistry of Heterocyclic Compounds, 1651 (2001); and ref-
erences cited therein.
[16] J.-P. Bouillon, Z. Janousek, H. G. Viehe, B. Tinant and J.-P.
Declercq, J. Chem. Soc. Perkin Trans. 1, 1853 (1996).
[17] P. Micuch, L. Fisˇera, V. Ondrus and P. Ertl, Molecules, 2, 57
(1997).
2
4
((sinθ/λ)/0.52) , w (sinθ/λ>0.54)
=
(0.54/(sinθ/λ)) ,
w (0.52<sinθ/λ<0.54) = 1.0, compound 8c: w = w *w , w
f
s
s
f
s
(F <3.6) = (F /3.5), w (F >7.9) = (7.9/F ), w (3.6<F <7.9)=1.0,
o
o
f
o
o
f
o
2
w (sinθ/λ<0.41) = ((sinθ/λ)/0.41) , w (sinθ/λ>0.70) =
(0.70/(sinθ/λ)) , w (0.41<sinθ/λ<0.70) = 1.0, and Regina [26]
s
s
4
s
weighting scheme was used for the structure of 7 (Table 1). The
Xtal3.4 [27] system of crystallographic programs was used for the
reduction of data, structure refinement and interpretation. ORTEPII
[28] was used to produce molecular graphics. Crystallographic data
(excluding structure factors) for the structures reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 171724 - 171727.
Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: (internat.)
+44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
[18] L. Fisˇera, L. Jarosˇková, I. Matejková and H. Heimgartner,
Heterocycles, 40, 271 (1995).
Acknowledgements.
The financial support from the Ministry of Science and
Technology, Slovenia, is gratefully acknowledged. The authors
are grateful to the Alexander von Humboldt Foundation,
Germany, for the donation of the Büchi MPLC chromatograph.
One crystallographic dataset was collected on the Kappa CCD
Nonius diffractometer in the Laboratory of Inorganic Chemistry,
Faculty of Chemistry and Chemical Technology, University of
Ljubljana, Slovenia. We acknowledge with thanks the financial
contribution of the Ministry of Science and Technology, Republic
of Slovenia, through grant Packet X-2000 and PS-511-102,
which thus made the purchase of the apparatus possible.
[19] L. Fisˇera, L. Jarosˇková, A. Lévai, E. Jedlovská, G. Tóth and
M. Poláková, Heterocycles, 45, 1651 (1997).
[20] U. Grosˇelj, A. Drobnicˇ, S. Recˇnik, J. Svete, A. Golobicˇ, N.
Lah, I. Leban, A. Meden, B. Stanovnik and S. Golicˇ Grdadolnik, Helv.
Chim. Acta, 84, 3403 (2001).
[21] Donation of Alexander von Humboldt Foundation, Germany.
[22] Th. J. de Boer and H. J. Backer, Org. Synth., Coll. Vol. 4, 250
(1963).
[23] C. Grundmann and J. M. Dean, J. Org. Chem., 30, 2809
(1965).
[24] Evaporation of fractions containing the minor (4S,5R,8S)-iso-
mers (9a–c) afforded isomerically enriched compounds 9a–c (37–54%
diastereomeric excess) which were contaminated with starting compound
3 and nitrile oxides 5a–c. So far, we were unable to obtain minor isomers
9a–c in isomerically and analytically pure form upon further purification
by medium pressure liquid chromatography and/or crystallization.
[25] A. Altomare, M. C. Burla, M. Camalli, G. Dascarano, C.
Giacovazzo, A. Guagliardi and G. Polidori, J. Appl. Cryst., 27, 435
(1994).
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