Synthesis of trisubstituted 4-oxepanones by the Lewis acid-promoted three-component ring-expansion reaction of cyclopropapyranones, silyl enolates and glyoxylates

Article abstract of DOI:10.3987/COM-01-9192

In the presence of SnCl₄, cyclopropapyranones easily reacted with silyl enolates and ethyl glyoxylate to give the trisubstituted 4-oxepanones in good yields.

Full text of DOI:10.3987/COM-01-9192

HETEROCYCLES, Vol. 55, No. 5, 2001, pp. 855 – 859, Received, 1st March, 2001
SYNTHESIS OF TRISUBSTITUTED 4-OXEPANONES BY THE LEWIS
ACID-PROMOTED
THREE-COMPONENT
RING-EXPANSION
REACTION OF CYCLOPROPAPYRANONES, SILYL ENOLATES AND
GLYOXYLATES
Yoshiaki Sugita,* Chikasa Kimura, and Ichiro Yokoe
Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama 350-0295,
Japan
Abstract – In the presence of SnCl4, cyclopropapyranones easily reacted with
silyl enolates and ethyl glyoxylate to give the trisubstituted 4-oxepanones in
good yields.
The seven-membered oxacycles are an important class of oxygenated heterocyclic compounds that have
attracted the attention of organic chemists and biochemists due to their biological activities and
occurrence in natural products.1 Various methods for the construction of the seven-membered oxacycles
have been reported.2
We recently reported the synthesis of 2,7-disubstituted 4-oxepanones by the Lewis acid-promoted ring-
opening addition reactions of cyclopropapyranones (1) with silyl enolates as nucleophiles (eq. 1, Scheme
1).3 From these reactions, the trans-isomers were mainly obtained.
We expected that the treatment of a cyclopropapyranone derivative with a Lewis acid readily generates a
cyclic 1,3-zwitterion,4 which can react with both silyl enolates and appropriate electrophiles to produce
the trisubstituted 4-oxepanones (eq. 2). A cyclopropane with donor and acceptor substituents at the vicinal
position on the cyclopropane ring is an equivalent of a ring-opened 1,3-zwitterion. Therefore,
cyclopropapyranone (1) is recognized as a good reactant for electrophiles and nucleophiles.5 We now
report the synthesis of trisubstituted 4-oxepanones by the Lewis acid-promoted three-component ring-
expansion reaction of cyclopropapyranones as the synthetic equivalents of cyclic 1,3-zwitterions.
Nu
Nu
O
+
-
O
R
R
O
O
R
R
Nucleophile
quench
Lewis acid
eq. 1)
eq. 2)
-
O
O
O
O
1
Nu
O
R
Electrophile
E
Scheme 1
O
In our previous study, we have found that when the ring-opening addition reaction of the
cyclopropapyranone (1a) with ketene silyl acetal (2a) was carried out, the use of SnCl4 (0.3 eq.) as a
Lewis acid gave the best result and the corresponding oxepanone (5a) was obtained in 71% yield with

moderate trans-selectivity.3 The reaction of 1a, 2a with ethyl glyoxylate (3a)6 was chosen as the model,
and several reaction conditions were examined. Cyclopropapyranone (1a) and ketene silyl acetal (2a) in
CH2Cl2 were reacted with SnCl4 (0.3 eq.) at –78 °C for 10 min, and the resulting mixture was treated with
ethyl glyoxylate (3a) to give the desired oxepanone (4) in 22% yield. However, the adduct (5a) was
mainly obtained because the aldol type reaction as the second step did not completely occur using a
catalytic amount of SnCl4 (Table 1, Entry 1). In contrast, it was found that the use of a stoichiometric
amount of SnCl4 for the addition of 3a resulted in an improvement of the chemical yield of the desired
oxepanone from 22% to 48% (Entry 2). We also found that the addition of powdered molecular sieves
4A7 (MA 4A) to the reaction mixture was effective for obtaining the desired product in good yield (77%
yield) although the role of MS 4A is not clear (Entry 3).8 In this reaction, the order of the addition of the
reagents dramatically influenced the yield. Namely, the addition of 2a to the reaction mixture of 1a and
3a led to the formation of a complex mixture not containing the desired product.
OSiMe3
OMe
O
3a
O
O
O
O
2a
CO2Me
CO2Et
CO2Me
Ph
H
CO2Et
Ph
Ph
CO2Me
Ph
+
SnCl4 (0.3 eq.)
CH2Cl2, -78 °C
SnCl4 (eq.)
O
O
O
OSiMe3
OH
4
5a
1a
Table 1. Three-component reaction of 1a, 2a and ethyl glyoxylate (3a)
Entry
SnCl4 (eq.)
Yield 4/%
Yield 5a/%
MS 4A
-
-
53
21
1
2
0
22
48
1.0
+
0
3
1.0
77
The obtained product (4) could be converted into four stereoisomeric oxepanones (6) by the mesylation of
the hydroxy group of 4 followed by an elimination reaction (Scheme 2). The ratio of the stereoisomers
(TE : CE : TZ : CZ) was determined as 71:19:8:2 by 1H-NMR, and the stereochemical assignment of the
isomers was established by the analysis of their NOE experiments (Figure 1). It was noted that in the 1H-
NMR spectrum the olefinic proton signal of the Z-isomers (TZ- and CZ-6) appeared at high field
compared with that of the E-isomers (TE- and CE-6).
H
H
H
MsCl
Et3N, CH2Cl2
H
H
H
O
Ph
O
O
Ph
Ph
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
+
then DBU
85%
H
O
O
O
OH
CE-6
TE-6
4
(cis-E)
(trans-E)
H
H
H
H
Ph
O
Ph
O
CO2Me
CO2Me
+
+
O
O
CO2Et
CO2Et
CZ-6
TZ-6
(cis-Z)
(trans-Z)
Scheme 2

6.3%
10.8%
H
H
H
Ph O
H
H
H
H
CO2M e
Ph O
H
Ph
Ph
CO2 Me
H
O
H
O
O
H
H
O
O
CO2Me
CO2Me
12.9%
O
H
H
H
H
H
H
H
15.8%
10.3%
H
20.8%
H
H
H
H
H
H
EtO2 C
EtO2C
18.8%
8.3%
H
11.9%
H
CO2Et
CO2Et
6.49 ppm
6.58 ppm
5.86 ppm
TZ-6
TE-6
CE-6
5.83 ppm
CZ-6
Figure 1
Several examples of the three-component ring-expansion reaction of 1a were examined and these results
are summarized in Table 2 (Entries 1-4). For the reaction of 1a, 2a, and methyl glyoxylate (3b),6 a similar
tendency was observed (Entry 2). As the nucleophiles, silyl enol ethers (2b, 2c) also reacted with 1a
under similar conditions to give the corresponding oxepanones (8,9 9), even though a slight decrease in
yield was observed compared to that of the reactions of the ketene silyl acetal (2a) (Entries 3, 4).
Nucleophile
SnCl4 (0.3 eq.)
MsCl
Et3N, CH2Cl2
Nu
CO2R2
Nu
R1
R1
O
O
R1
O
MS 4A, CH2Cl2, -78 °C
CO2R2
OH
then
then DBU
SnCl4 (1.0 eq.)
O
O
O
O
3a: R=Et
1
CO2R2 3b: R=Me
6-12
H
Table 2. Three-component reaction of cyclopropapyranones (1), silyl enolates (2) and glyoxylates (3)
a
b
Entry Cyclopropane Nucleophile Glyoxylate
Product
Yield /% (TE : CE : TZ : CZ)
Ph
O
O
OSiMe3
OMe
Ph
Ph
Ph
CO2Me
1
2
3
4
5
6
7
2a
2a
2b
2c
2a
2a
2a
3a
3b
3a
3a
3a
3b
3b
6
66 (71 : 19 : 8 : 2)
CO2Et
O
O
1a
O
OSiMe3
OMe
CO2Me
CO2Me
1a
7
57 (73 : 17 : 5 : 5)
48 (78 : 13 : 8 : 1)
O
O
OSiMe3
Ph
COPh
CO2Et
1a
8
O
COtBu
CO2Et
O
OSiMe3
tBu
Ph
c
1a
9
26 (81 : 10 : 8 : 1)
O
BnO
BnO
O
O
OSiMe3
OMe
CO2Me
CO2Et
10
11
12
57 (81 : 12 : 5 : 2)
58 (80 : 10 : 9 : 1)
O
O
1b
BnO
BnO
O
OSiMe3
OMe
CO2Me
CO2Me
1b
O
BnO
H
H
O
O
O
OSiMe3
OMe
CO2Me
CO2Me
d
66 (80 : 15 : 5 : - )
O
1c
a
b
c
Total yield from 1. The ratio of the srereoisomers was determined by 500 MHz 1H-NMR. Disubstituted
d
4-oxepanone (5) was also obtained in 45%. Not detected.

In order to extend the scope and synthetic utility of this methodology, the reactions of other
cyclopropapyranones under similar conditions were examined. The reactions of 1b,3 2a, and alkyl
glyoxylates (3a, 3b) gave the corresponding oxepanones (10,9 11) in good yields (Entries 5, 6). Under
similar conditions, the chiral cyclopropapyranone (1c)3 also reacted with 2a and 3b to give the
corresponding chiral oxepanone (12) in 66% yield with moderate stereoselectivity (Entry 7). In all the
reactions, the trans-E-isomer was mainly obtained.
In summary, we have demonstrated that the SnCl4-promoted three-component ring-expansion reaction of
cyclopropapyranones, silyl enolates, and glyoxylates smoothly proceeded to afford the corresponding
trisubstituted 4-oxepanones in good yields with moderate stereoselectivity. Further applications of this
reaction are now under investigation in our laboratory.
A typical experimental procedure is described for the reaction of cyclopropane (1a), ketene silyl acetal
(2a), and ethyl glyoxylate (3a): To a mixture of 1a (75 mg, 0.4 mmol), 2a (104 mg, 0.6 mmol), and
molecular sieves 4A (150 mg) in CH2Cl2 (3 mL) was added SnCl4 (1.0 M sol. in CH2Cl2, 0.12 mL, 0.12
mmol) at –78 ˚C under an argon atmosphere. After the mixture was stirred for 10 min, 3a (82 mg, 0.8
mmol) and SnCl4 (1.0 M sol. in CH2Cl2, 0.4 mL, 0.4 mmol) were successively added. After being stirred
for 1 h at the same temperature, the reaction was quenched with saturated aqueous NaHCO3. The mixture
was filtered through a celite pad, and the filtrate was concentrated. The residue was dissolved in THF-1N
HCl (2:1, 4 mL) and stirred for 10 min at 0 ˚C. The mixture was then extracted with ether. After the
combined organic layers were dried and concentrated, the residue was chromatographed on silica gel to
produce 4 (121 mg, 77%). To a solution of 4 (117 mg, 0.3 mmol), Et3N (121 mg, 1.2 mmol), and DMAP
(4 mg, 0.03 mmol) in CH2Cl2 (4 mL) was added MsCl (69 mg, 0.6 mmol) in CH2Cl2 (0.5 mL) at 0 ˚C.
After being stirred for 1 h at rt, DBU (91 mg, 0.6 mmol) was added to the mixture and refluxed for 2 h.
After an extractive work up and purification by silica gel column chromatography, the corresponding
oxepanone (6) was obtained in 85% yield (95 mg).
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9. The stereochemical assignment of the compounds (TE-8, CE-8, and TZ-10) was also mainly
established by analysis of their NOE experiments (see figure below).
11.6%
7.3%
H
Ph
H
H
OBn
H
O
H
O
H
Ph
COPh
O
H
H
O
O
H
CO2Me
14.9%
COPh
O
H
H
H
H
11.8%
17.9%
H
H
H
H
H
H
EtO2C
H
18.0%
H
CO2Et
CO2Et
6.64 ppm
6.59ppm
TZ-10
TE-8
CE-8
5.70 ppm