Stereocontrolled Synthesis of trans/ cis-2,3-Disubstituted Cyclopropane-1,1-diesters and Applications in the Syntheses of Furanolignans

Article abstract of DOI:10.1021/acs.joc.8b01798

A new Michael addition/intramolecular alkylation sequence of (Z)-3-(2-bromo-3-arylacryloyl)oxazolidin-2-ones and malonates was developed. By a simple switch of the reaction conditions including the base promoter, solvent, and reaction temperature, both of the cis- and trans-isomers of a series of oxazolidinone-containing 2,3-disubstituted cyclopropane-1,1-diesters could be obtained in good-to-excellent yields and with an excellent diastereoselectivity. The utility of the cyclopropane products was demonstrated in the diastereoselective syntheses of (±)-urinaligran and a stereoisomer of (±)-virgatusin involving the AlCl₃-promoted [3+2] annulation with veraldehyde or piperonal as the key step.

Full text of DOI:10.1021/acs.joc.8b01798

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Article
Stereocontrolled Synthesis of trans/cis-2,3-Disubstituted Cyclopropane
1,1-Diesters and Applications in the Syntheses of Furanolignans
Yue Shen, Jun Chai, Gaosheng Yang, Wenlong Chen, and Zhuo Chai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01798 • Publication Date (Web): 17 Sep 2018
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Stereocontrolled Synthesis of trans/cisꢀ2,3ꢀDisubstituted Cycloproꢀ
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pane 1,1ꢀDiesters and Applications in the Syntheses of Furanolignans
Yue Shen,†,‡ Jun Chai,† Gaosheng Yang,*,† Wenlong Chen† and Zhuo Chai†
†Key Laboratory of Functionalized Molecular Solids, Ministry of Education, Anhui Key Laboratory of MoleculeꢀBased Maꢀ
terials (State Key Laboratory Cultivation Base), College of Chemistry and Materials Science, Anhui Normal University,
Wuhu, Anhui 241000, China
‡Traditional Chinese Medicine College, Bozhou University, Bozhou, Anhui 236800, China
Supporting Information Placeholder
TOC:
ABSTRACT: A new Michael addition/intramolecular alkylation sequence of (Z)ꢀ3ꢀ(2ꢀbromoꢀ3ꢀarylacryloyl)oxazolidinꢀ2ꢀones and
malonates was developed. By a simple switch of the reaction conditions including the base promoter, solvent and reaction temperaꢀ
ture, both the cis and trans isomers of a series of oxazolidinoneꢀcontaining 2,3ꢀdisubstituted cyclopropaneꢀ1,1ꢀdiesters could be
obtained in goodꢀtoꢀexcellent yields and with excellent diastereoselectivity. The utility of the cyclopropane products was demonꢀ
strated in the diastereoselective syntheses of (±)ꢀurinaligran and a stereoisomer of (±)ꢀvirgatusin involving the AlCl3ꢀpromoted [3 +
2] annulation with veraldehyde or piperonal as the key step.
INTRODUCTION
phorous and arsonium as Michael donor.5 The latter system
usually involves the addition of 2ꢀhalomalonates to α,βꢀ
unsaturated aldehydes/ketone or nitroolefins.6 However, all of
theses systems are restricted to the syntheses of transꢀ2,3ꢀ
disubstituted cyclopropane 1,1ꢀdiesters, and the development
of methods enabling diastereoselective syntheses of cisꢀ2,3ꢀ
disubstituted cyclopropane 1,1ꢀdiesters remains a significant
challenge.7 Moreover, our previous studies have shown that
the cisꢀisomers tend to bear better reactivity in relevant Lewis
acidꢀmediated ringꢀopening reactions of such cyclopropanes to
give products with complementary stereochemistries.3b, 4
The chemistry of donor–acceptor (D–A) cyclopropanes has
been a flourishing field to spawn many efficient methods for
the construction of diverse useful molecular skeletons.1 In this
realm, the cyclopropane 1,1ꢀdiesters, especially 2ꢀ
monosubstitutedꢀ1,1ꢀdiester cyclopropanes,2 have been the
mostly studied type of D–A cyclopropanes. On the other hand,
the synthesis and application of densely substituted D–A cyꢀ
clopropanes have recently attracted considerable attentions
leading to not only expanded product scope with rich structurꢀ
al diversity and complexity but also the discovery of some
interesting novel reactivity, as examplified by recent intensive
studies on 2,3ꢀdisubstituted cyclopropane 1,1ꢀdiesters.3,4
Our group have developed a cascade Michael addiꢀ
tion/intramolecular alkylation reaction of αꢀbromochalcones
and diethyl malonate, which provided the first access to the
thermodynamically less favored cisꢀisomers of diethyl 2ꢀaroylꢀ
3ꢀphenylꢀcyclopropaneꢀ1,1ꢀdiesters (Scheme 1).8 However,
such a system suffers from not only the poor diastereoselectivꢀ
ity and moderate yield but also a rather limited convertibility
of the 2ꢀaroyl group to other useful structures. Given this, we
presumed that a judicious choice of reaction conditions (kinetꢀ
ic vs thermodynamic) may enable better stereocontrol over the
cis/trans ratio; and replacing the aroyl group with a synthetiꢀ
cally versatile oxazolidineꢀ2ꢀone group would enhance the
The development of efficient synthetic methods for D–A
cyclopropanes has been undoubtedly of fundamental imꢀ
portance for this chemistry. In this regard, the Michael initiatꢀ
ed ring closure (MIRC) strategy is a particularly useful apꢀ
proach to 2,3ꢀdisubstituted cyclopropane 1,1ꢀdiesters. In genꢀ
eral, methods following such a strategy could be classified into
two kinds by the standard that either the Michael acceptor or
the Michael donor contains the 1,1ꢀdiester moiety. The former
system typically utilizes βꢀsubstituted methylidenemalonates
as Michael acceptor and various ylides including sulfur, phosꢀ
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potential of utility of the resultant D–A cyclopropanes. Herein,
we report the details of this study.
3
DMAP
DMSO
25
25
24
24
4
0
4
pyridine DMSO
0
4
5
6
82c (<1:19)
94 (3.5:1)
79c (19:1)
92c (>19:1)
91c (19:1)
85c,d (>19:1)
87c,e (19:1)
89 (6:1)
Scheme 1. Syntheses of 2,3ꢀDisubstitutedꢀ1,1ꢀDiester Cyꢀ
clopropanes via MIRC
5
DBU
DMSO
DMSO
DMF
25
6
K2CO3
K2CO3
15
4
7
–20
–20
–35
–20
–20
–20
–20
–20
–20
44
24
48
48
48
40
40
40
40
7
8
9
8
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 toluene
Cs2CO3 THF
Cs2CO3 CH2Cl2
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10
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93 (2.8:1)
91 (2.2:1)
96 (4.3:1)
Cs2CO3
–
RESULTS AND DISCUSSION
b
aReaction scale: 0.3 mmol. Isolated yield of the mixture of the
1
Our study began with the screen of reaction conditions for the
two cis/trans isomers. The ratio of cis:trans is determined by H
NMR analysis of the crude reaction mixture. cIsolated yield of the
model
reaction
between
(Z)ꢀ3ꢀ(2ꢀbromoꢀ3ꢀ
d
e
phenylacryloyl)oxazolidinꢀ2ꢀone 1a and diethyl malonate 2a
(Table 1). First, several organic and inorganic bases were testꢀ
ed in the reaction (entries 1–5). In the presence of K2CO3, the
desired cyclopropane products were obtained in excellent
combined yield but with a poor diastereoselectivity (entry 1).
While Et3N, DMAP and pyridine were found to be ineffective
promoters for this reaction, the more basic DBU could effect
the reaction to provide the almost diasteremerically pure transꢀ
3aa in a high yield within 4.0 h (entries 2–5). Then we turned
our attention to further improve the yield and selectivity for
the synthesis of the thermodynamically less stable cisꢀ3aa.
Not unexpectedly, the diastereoselectivity favorable for the
formation of cisꢀ3aa could be improved significantly by perꢀ
forming the reaction at a lower temperature (entry 6). Using
DMF as solvent enables further lowering the reaction temperaꢀ
ture to –20 oC and an excellent diastereoseletivity (19:1) could
be achieved (entry 7). The use of a stronger base (Cs2CO3) not
only greatly enhanced the reaction efficiency but also led to a
slightly better diastereoselectivity (entry 8). Further lowering
the reaction temperature, reducing the amount of either 2a or
the base, and the use of other solvents such as toluene, THF
and CH2Cl2 or performing the reaction in a solventꢀfree fashꢀ
ion all led to inferior results (entries 9–15). Notably, the oxaꢀ
zolidineꢀ2ꢀone group in 1 is crucial for the excellent diastereꢀ
oselectivity favoring the cis cyclopropane product (see
Scheme S1 in the Supporting Information for a direct comparꢀ
ison with αꢀbromo chalcone), while we are unable to provide a
rationale for this effect at present.
pure major isomer product. 2.0 equiv of 2a was used. 1.0 equiv
of Cs2CO3 was used.
Table 2. Preparation of transꢀ3a
entry 1 (Ar)
t (h)
transꢀ3
2
(yield %)b
1
3aa (82)
3ab (82)
3ba (81)
3ca (81)
3da (80)
3ea (78)
3fa (81)
3ga (81)
3ha (73)
3ia (80)
3ja (79)
3ka (78)
2a
2b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
1a (Ph)
4
5
5
5
5
4
5
5
4
5
5
5
2
1a (Ph)
3
1b (4ꢀFC6H4)
4
1c (4ꢀClC6H4)
5
1d (3ꢀClC6H4)
6
1e (4ꢀBrC6H4)
7
1f (4ꢀMeC6H4)
8
1g (4ꢀMeOC6H4)
1h (3ꢀMeOC6H4)
1i (3,4ꢀ(MeO)2C6H3)
1j (3,4,5ꢀ(MeO)3C6H2)
1k (3,4ꢀ(OCH2O)2C6H3)
9
10
11
12
aReaction scale: 0.5 mmol. bIsolated yield of the pure product.
Table 1. Screen of Reaction Conditionsa
With the optimum reaction conditions in hand (Table 1, enꢀ
try 5), we then probed the substrate scope with regard to the
synthesis of transꢀ3aa (Table 2). Diethyl or dimethyl malonate
are almost equally effective in the reaction (entries 1 and 2). A
series of 1 bearing different substitutents on the benzene ring
of the Ar group were examined in the reaction, and generally
good yields of the corresponding products were obtained. Neiꢀ
ther the electronic nature nor the positions of the substituents
on the benzene ring showed consistent trend of influence on
the reaction (entries 3–12). Notably, substrates 1i–1k bearing
multiple electronꢀdonating groups are also wellꢀtolerated in
this reaction. Also of note is that in all of the cases examined,
entry
base
solvent
T
t (h)
yield
(oC)
(cis:trans)b
1
2
K2CO3
Et3N
DMSO
DMSO
25
25
4
95% (1.7:1)
0
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the trans cyclopropane products were isolated in almost diaꢀ
stereomerically pure form.
ospecific [3 + 2] annulation of a chiral transꢀ2,3ꢀdisubsitutedꢀ
1,1ꢀdiester cyclopropane with piperonal as lynchpin reaction
in a fiveꢀstep synthesis of (+)ꢀvirgatusin.3a Having established
an efficient diastereoselective way to the oxazolidinoneꢀ
containing D–A cyclopropanes cisꢀ3, we then became interestꢀ
ed in exploring their reactivity for the construction of such
densely substituted 2,5ꢀdiaryltetrahydrofuran structures. First,
we screened the conditions for the [3 + 2] annulation between
the cyclopropane cisꢀ3kb and veratral (Table 4, entries 1–10).
Under the promotion of 1.0 equiv of AlCl3 in CH2Cl2, the deꢀ
sired product 4a could be obtained in excellent yields as a
single diastereomer in the presence of 10.0 equiv of the aldeꢀ
hyde (entry 2). In general, the reactivity of this oxalidinoneꢀ
containing cisꢀ2,3ꢀdisubstituted cyclopropane in such a reacꢀ
tion seems to be inferior to its counterparts containing an aroyl
group used in our previous studies, in which typically only 0.5
equiv. of AlCl3 and 5.0 equiv of the aldehyde were required to
give excellent yields.4 Varying the reaction solvent failed to
improve the result. Notably, the use of a catalytic amount of
Lewis acids including Sc(OTf)3 and Al(OTf)3 led to no reacꢀ
tion. Piperonal was more reactive under the optimum reactions
to deliver the desired product 4b in 92% yield as a single diaꢀ
stereomer within 2 hours (entry 11).
4
5
6
7
8
9
Subsequently, the reaction scope with regard to the forꢀ
mation of cisꢀ3aa was investigated (Table 3). Under the optiꢀ
mized reaction conditions (Table 1, entry 8), the correspondꢀ
ing cyclopropane products were generally obtained in excelꢀ
lent yields and with excellent diastereoselectivity. Similar to
the formation of corresponding trans cyclopropanes, no obviꢀ
ous substituent effect related to the electronic nature and/or
positions of the substituents on the benzene ring of the Ar
group was observed, except that the presence of an electronꢀ
donating group at the para position seemed to be favorable in
terms of diastereoselectivity (entries 3–8). Substrates 1i–1k
bearing multiple electrondonating groups also participated
well in the reaction to provide the corresponding cis cycloproꢀ
panes in excellent yields and diastereoselectivity (entries 10–
13). The reaction efficiency was also inert to a change in the
ester group (R) of the malonates 2 from an ethyl to a methyl
group (entries 2 and 13). The relative configuration of the
product cisꢀ3ha was confirmed by Xꢀray crystallographic
analysis (see Figure S1 in the Supporting Information).9 Unꢀ
fortunately, our attempts to realize enantioselective syntheses
of cisꢀ3 by introducing chiral oxazolidinone (Evans auxiliaries)
into 1 led to a diasetereomeric mixture of very poor dr value
(around 1:1, see Scheme S2 in the Supporting Information).
10
11
12
13
14
15
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Table 4. Screen of Reaction Conditions for the [3 + 2] Anꢀ
nulation of cisꢀ3kb With Veratral/Piperonala
Table 3. Preparation of cisꢀ3a
entry 1 (Ar)
drb
cisꢀ3
entry Lewis
(equiv)
acid solvent
t (h) 4a/4b
(yield %)b
2
(yield %)c
1
4a (91)
4a (91)
4a (80)
4a (71)
4a (89)
4a (87)
4a (91)
4a (0)
AlCl3 (1.5)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (0.5)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CCl4
2
1
>19:1
>19:1
15.7:1
15.7:1
19:1
2a
2b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
1a (Ph)
3aa (92)
3ab (93)
3ba (87)
3ca (88)
3da (90)
3ea (96)
3fa (91)
3ga (91)
3ha (87)
3ia (93)
3ja (90)
3ka (90)
3kb (90)
2
4
2
1a (Ph)
3
24
80
9
3
1b (4ꢀFC6H4)
4
4
1c (4ꢀClC6H4)
5
5
1d (3ꢀClC6H4)
6
24
4.5
48
48
48
2
6
15.7:1
19:1
1e (4ꢀBrC6H4)
7
DCE
7
1f (4ꢀMeC6H4)
8
toluene
8
>19:1
15.7:1
>19:1
19:1
1g (4ꢀMeOC6H4)
1h (3ꢀMeOC6H4)
1i (3,4ꢀ(MeO)2C6H3)
1j (3,4,5ꢀ(MeO)3C6H2)
1k (3,4ꢀ(OCH2O)2C6H3)
9
4a (0)
Sc(OTf)3 (0.1)
Al(OTf)3 (0.1)
AlCl3 (1.0)
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11
4a (0)
10
11
12
13
4b (92)
19:1
aReaction scale: 0.5 mmol. bIsolated yield of the pure product.
1k (3,4ꢀ(OCH2O)2C6H3)
19:1
Subsequently, we embarked on the elaboration of the prodꢀ
ucts 4 to (±)ꢀurinaligran and a stereoisomer of (±)ꢀvirgatusin
(Scheme 2). Reduction of 4 with LiBH4 was followed by sponꢀ
taneous intramolecular lactonization to provide 5 in good
yields. Subjecting 5 to the conditions of the Krapcho decarꢀ
boxylation reaction led to the selective loss of the sterically
less encumbered lactone carbonyl to give 6, which were reꢀ
duced to the diols 7 in high yields. Methylation of 7 with NaH
and CH3I furnished 8a, a stereoisomer of (±)ꢀvirgatusin, and
(±)ꢀurinaligran 8b in excellent yields, respectively.
aReaction scale: 0.5 mmol. Determined by H NMR analysis of
b
1
the crude reaction mixture. cIsolated yield of the pure product.
(–)ꢀVirgatusin and (+)ꢀurinaligran belong to a large family
of furanolignans bearing interesting biological and pharmaceuꢀ
tical activities such as antioxidant, antimicrobial, antiꢀ
inflammatory and anticancer activities,10 and considerable
attention has been paid to their syntheses.3a,11 In particular,
Johnson and coꢀworkers have succeeded in utilizing the stereꢀ
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Scheme 2. Syntheses of (±)ꢀUrinaligran and a Stereoisomer
of (±)ꢀVirgatusin
to cisꢀ2,3ꢀdisubstituted cyclopropaneꢀ1,1ꢀdiesters in high
yields and excellent stereoselectivity. The reactivity of the cis
D–A cyclopropane products in Lewis acidꢀpromoted [3 + 2]
annulation with aryl aldehydes was probed, which led to conꢀ
cise diastereoselective syntheses of two furanolignan comꢀ
pounds.
O
O
O
O
O
N
O
CO2Me
NaCl (8.0 eq)
DMSO / H2O
CO2Me
CO2Me
LiBH4 (1.0 eq)
THF, rt, 8 h
reflux, 24 h
O
O
OR
O
OR
8
9
O
O
EXPERIMENTAL SECTION
OR
OR
5a: R = Me (71%)
5b: R = -CH2- (71%)
4a: R = Me
4b: R = -CH2-
General Information. All reactions were carried out with
flameꢀdried Schlenkꢀtype glassware using a Schlenk line. All
the 3ꢀcinnamoyloxazolidinꢀ2ꢀones 12a–k used were syntheꢀ
sized following a literature procedure method as described in
the Supporting Information (SI). All the other reagents were
purchased from commercial suppliers and purified by standard
techniques. Flash column chromatography was performed
using silica gel (200–400 mesh). For thinꢀlayer chromatogꢀ
raphy (TLC), silica gel plates (HSGF 254) were used and
CO2Me
HO
10
11
12
13
14
15
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HO
OH
(1) NaH (10.0 eq)
THF, rt, 0.5 h
(2) CH3I (10.0 eq)
OR
THF, rt, 1 h
LiAlH4 (4.0 eq)
THF, rt
O
O
O
O
OR
O
O
OR
OR
7a: R = Me (91%)
6a: R = Me (69%)
6b: R = -CH2- (68%)
7b: R = -CH2- (92%)
MeO
OMe
MeO
OMe
O
O
O
O
O
OMe
O
O
O
8a (92%)
8b (93%)
OMe
1
a stereoisomer of ( )-virgatusin
(
)-urinaligran
compounds were visualized by irradiation with UV light. H
NMR (500/300 MHz) and 13C NMR (125/75 MHz) spectra
were recorded in CDCl3. All chemical shifts (δ) are given in
ppm relative to TMS (δ = 0 ppm) as internal standard. Data are
reported as follows: chemical shift, multiplicity, coupling conꢀ
stants and integration. Melting points were uncorrected. IR
spectra were reported in frequency of absorption (cmꢀ1). High
resolution mass spectral (HRMS) data were obtained with an
ionization mode of APCI or ESI and a TOF analyzer.
Very recently, we have observed that γꢀbutyrolactone fused
cyclopropanes could be more reactive than their parent 2,3ꢀ
disubstituted cyclopropanes in Lewis acidꢀmediated annulaꢀ
tion with carbonyls and heterocumulenes.12 For example, the
cyclopropane 9, which could be prepared via a cascade proꢀ
cess involving organocatalytic Michael additionꢀinitiated cyꢀ
clopropanation/reduction/lactonization
between
cinnaꢀ
monaldehyde and 2ꢀbromomalonate, is highly efficient in the
[3 + 2] annulation with benzaldehyde to provide the densely
substituted γꢀbutyrolactone fused tetrahydrofuran 10 in excelꢀ
lent yield and diastereoselectivity (Scheme 3). Given this, we
then reasoned that the use of corresponding γꢀbutyrolactone
fused cyclopropanes, which could be readily available from
the product cisꢀ3, might lead to an alternative efficient catalytꢀ
ic way to the useful γꢀbutyrolactone fused tetrahydrofuran
products such as 5a and 5b. Using the simple cisꢀ3ab as an
example, we first realized the transformation of cisꢀ3ab to 11
with a moderate yield via reduction with LiBH4. Surprisingly,
as compared to the cyclopropane 9, the cyclopropane 11
demonstrated much poorer reactivity in the annulation with
benzaldehyde under similar reaction conditions: the desired
product 5c was only obtained in 21% yield even after a proꢀ
longed reaction time at a higher reaction temperature while
most starting materials remained intact.
General Procedure for the Syntheses of (Z)ꢀ3ꢀ(2ꢀBromoꢀ
3ꢀarylacryloyl)oxazolidinꢀ2ꢀone (1). A suspension of 3ꢀ
cinnamoyloxazolidinꢀ2ꢀones 12a–k (10 mmol) in CCl4 (20 mL)
was stirred until a homogeneous solution was formed. Broꢀ
mine (11 mmol, 1.758 g) was added dropwise to the above
solution at 0 ºC (at –30 ºC for 12j) and the resulting mixture
was slowly warmed up to room temperature and stirred for 2 h.
The solution was then cooled down to 0 ºC, filtered and
washed with iceꢀcold CCl4 (3 × 20 mL). The crude dibromide
thus obtained was used in the next reaction without further
purification. To a solution of the dibromide in toluene (40 mL)
was added DBU (12 mmol) at room temperature. The reaction
mixture was stirred at rt until full conversion of the dibromide
was achieved (monitored by TLC). Upon completion, the reacꢀ
tion mixture was diluted with 20 mL of H2O and extracted
with ethyl acetate (3 × 50 mL). The combined organic layers
were washed with water (2 × 50 mL), dried with anhydrous
sodium sulfate, and concentrated under reduced pressure to
yield a crude product. The crude product was purified by colꢀ
umn chromatography to provide the desired products 1a–k.
Scheme 3. Conversion of cisꢀ3ab to γꢀButyrolactone Fused
Cyclopropane 11 and Reactivity Comparison
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀphenylacryloyl)oxazolidinꢀ2ꢀone
(1a).
Purified by column chromatography (petroleum ether/ethyl
acetate = 15/1) to afford a white solid in 53% yield (1.6 g, 5.3
mmol). Mp: 173–174 ºC. 1H NMR (CDCl3, 500 MHz): δ
7.80–7.72 (m, 2H), 7.46–7.36 (m, 4H), 4.51 (t, J = 7.8 Hz, 2H),
4.12 (t, J = 7.8 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ 165.8,
152.0, 136.7, 133.6, 129.8, 128.4, 111.9, 62.4, 43.4. HRMS
(APCIꢀTOF, m/z) calcd for C12H11BrNO3 [M + H]+: 295.9917,
found: 295.9914.
CONCLUSION
In summary, we have developed a MIRC strategyꢀbased
method that enables access to both the cis and trans isomers of
oxazolidinoneꢀcontaining 2,3ꢀdisubstituted cyclopropaneꢀ1,1ꢀ
diesters in a controllable and highly diastereoselective way.
This work represents the first example enabling direct access
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀ(4ꢀfluorophenyl)acryloyl)oxazolidinꢀ2ꢀ
one (1b). Purified by column chromatography (petroleum
ether/ethyl acetate = 12/1) to afford a white solid in 39% yield
1
(1.2 g, 3.9 mmol). Mp: 154–155 ºC. H NMR (CDCl3, 500
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MHz): δ 7.82–7.73 (m, 2H), 7.35 (s, 1H), 7.16–7.06 (m, 2H),
ether/dichloromethane = 15/1) to afford a white solid in 53%
yield (1.7 g, 5.3 mmol). Mp: 134–135 ºC. H NMR (CDCl3,
4.51 (t, J = 7.9 Hz, 2H), 4.12 (t, J = 7.9 Hz, 2H). 13C NMR
(CDCl3, 125 MHz): δ 165.6, 163.3 (d, 1JC–F = 251.2 Hz), 152.1,
1
500 MHz): δ 7.41–7.27 (m, 4H), 6.99–6.90 (m, 1H), 4.55–4.46
(m, 2H), 4.16–4.08 (m, 2H), 3.83 (s, 3H). 13C NMR (CDCl3,
125 MHz): δ 165.7, 159.4, 152.1, 136.6, 134.7, 129.4, 122.5,
115.9, 114.5, 112.0, 62.4, 55.4, 43.3. HRMS (APCIꢀTOF, m/z)
calcd for C13H13BrNO4 [M + H]+: 326.0022, found: 326.0016.
2
135.6, 131.8, 129.7, 115.6 (d, JC–F = 21.8 Hz), 111.7, 62.4,
43.3. 19F NMR (CDCl3, 470 MHz): δ 140.7. HRMS (APCIꢀ
TOF, m/z) calcd for C12H10BrFNO3 [M + H]+: 313.9823, found:
313.9821.
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀ(4ꢀchlorophenyl)acryloyl)oxazolidinꢀ2ꢀ
one (1c). Purified by column chromatography (petroleum
ether/dichloromethane = 12/1) to afford a white solid in 52%
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀ(3,4ꢀ
9
dimethoxyphenyl)acryloyl)oxazolidinꢀ2ꢀone (1i). Purified by
column chromatography (petroleum ether/dichloromethane =
10/1) to afford a white solid in 51% yield (1.8 g, 5.1 mmol).
Mp: 127–128 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.53 (s, 1H),
7.39 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H),
4.50 (t, J = 7.8 Hz, 2H), 4.11 (t, J = 7.8 Hz, 2H), 3.92 (s, 6H).
13C NMR (CDCl3, 125 MHz): δ 166.0, 152.2, 150.7, 148.6,
137.4, 126.2, 124.6, 112.4, 110.8, 109.5, 62.4, 56.0, 43.6.
HRMS (APCIꢀTOF, m/z) calcd for C14H15BrNO5 [M + H]+:
356.0128, found: 356.0129.
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18
19
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26
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29
30
31
32
33
34
35
36
37
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yield (1.7 g, 5.2 mmol). Mp: 125–126 ºC. H NMR (CDCl3,
500 MHz): δ 7.70 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H),
7.32 (s, 1H), 4.56–4.47 (m, 2H), 4.16–4.08 (m, 2H). 13C NMR
(CDCl3, 125 MHz): δ 165.5, 152.0, 135.7, 135.3, 131.0, 128.7,
112.6, 62.5, 43.3. HRMS (APCIꢀTOF, m/z) calcd for
C12H10BrClNO3 [M + H]+: 329.9527, found: 329.9525.
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀ(3ꢀchlorophenyl)acryloyl)oxazolidinꢀ2ꢀ
one (1d). Purified by column chromatography (petroleum
ether/dichloromethane = 12/1) to afford a white solid in 53%
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀ(3,4,5ꢀ
1
yield (1.8 g, 5.3 mmol). Mp: 124–125 ºC. H NMR (CDCl3,
trimethoxyphenyl)acryloyl)oxazolidinꢀ2ꢀone (1j). Purified by
column chromatography (petroleum ether/dichloromethane =
8/1) to afford a white solid in 50% yield (1.9 g, 5.0 mmol). Mp:
123–124 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.17 (s, 1H), 6.48
(s, 2H), 4.44–4.31 (m, 2H), 4.06–3.95 (m, 2H), 3.84 (s, 3H),
3.81 (s, 6H). 13C NMR (CDCl3, 125 MHz): δ 165.8, 153.0,
152.2, 139.6, 137.0, 128.7, 110.9, 107.4, 62.4, 61.0, 56.2, 43.5.
HRMS (APCIꢀTOF, m/z) calcd for C15H17BrNO6 [M + H]+:
386.0234, found: 386.0236.
500 MHz): δ 7.75 (s, 1H), 7.63–7.57 (m, 1H), 7.40–7.32 (m,
2H), 7.29 (s, 1H), 4.52 (t, J = 7.9 Hz, 2H), 4.12 (t, J = 7.9 Hz,
2H). 13C NMR (CDCl3, 125 MHz): δ 165.4, 152.0, 135.3,
134.8, 134.4, 129.70, 129.66, 129.4, 127.8, 113.4, 62.5, 43.2.
HRMS (APCIꢀTOF, m/z) calcd for C12H10BrClNO3 [M + H]+:
329.9527, found: 329.9524.
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀ(4ꢀbromophenyl)acryloyl)oxazolidinꢀ2ꢀ
one (1e). Purified by column chromatography (petroleum
ether/dichloromethane = 10/1) to afford a white solid in 51%
(Z)ꢀ3ꢀ(3ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ2ꢀ
1
yield (1.9 g, 5.1 mmol). Mp: 141–142 ºC. H NMR (CDCl3,
bromoacryloyl)oxazolidinꢀ2ꢀone (1k). Purified by column
chromatography (petroleum ether/dichloromethane = 10/1) to
afford a white solid in 52% yield (1.8 g, 5.2 mmol). Mp: 139–
500 MHz): δ 7.62 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H),
7.30 (s, 1H), 4.51 (t, J = 7.9 Hz, 2H), 4.11 (t, J = 7.9 Hz, 2H).
13C NMR (CDCl3, 125 MHz): δ 165.5, 152.0, 135.3, 132.5,
131.7, 131.1, 124.0, 112.7, 62.4, 43.3. HRMS (APCIꢀTOF,
m/z) calcd for C12H10Br2NO3 [M + H]+: 373.9022, found:
373.9019.
1
140 ºC. H NMR (CDCl3, 500 MHz): δ 7.51 (d, J = 1.4 Hz,
1H), 7.33 (s, 1H), 7.20 (dd, J = 8.1, 1.2 Hz, 1H), 6.84 (d, J =
8.1 Hz, 1H), 6.02 (s, 2H), 4.49 (t, J = 7.8 Hz, 2H), 4.10 (t, J =
7.8 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ 166.0, 152.1,
149.1, 147.7, 137.0, 127.5, 126.0, 109.8, 109.2, 108.4, 101.6,
62.4, 43.5. HRMS (APCIꢀTOF, m/z) calcd for C13H11BrNO5
[M + H]+: 339.9815, found: 339.9813.
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀ(pꢀtolyl)acryloyl)oxazolidinꢀ2ꢀone (1f).
Purified
by
column
chromatography
(petroleum
ether/dichloromethane = 15/1) to afford a white solid in 50%
1
yield (1.6 g, 5.0 mmol). Mp: 110–111 ºC. H NMR (CDCl3,
General Procedure for the Syntheses of Diethyl transꢀ2ꢀ
(2ꢀoxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀarylcyclopropaneꢀ1,1ꢀ
dicarboxylate (transꢀ3). A solution of (Z)ꢀ3ꢀ(2ꢀbromoꢀ3ꢀ
arylacryloyl)oxazolidinꢀ2ꢀones 1a−k (0.5 mmol), malonate
2a−b (1.5 mmol) and DBU (0.75 mmol) in DMSO (5 mL) was
stirred at 25 ºC until the reaction was finished (monitored by
TLC). Upon completion, the reaction mixture was diluted with
5 mL of H2O and extracted with dichloromethane (3 × 10 mL).
The combined organic layers were washed twice with water,
dried with anhydrous sodium sulfate, filtered, and concentratꢀ
ed under reduced pressure to yield a crude product, which was
500 MHz): δ 7.69 (d, J = 7.9 Hz, 2H), 7.38 (s, 1H), 7.22 (d, J
= 7.9 Hz, 2H), 4.49 (t, J = 7.8 Hz, 2H), 4.11 (t, J = 7.8 Hz, 2H),
2.37 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 165.9, 152.1,
140.2, 137.1, 130.7, 129.9, 129.2, 110.8, 62.4, 43.4, 21.5.
HRMS (APCIꢀTOF, m/z) calcd for C13H13BrNO3 [M + H]+:
310.0073, found: 310.0075.
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀ(4ꢀmethoxyphenyl)acryloyl)oxazolidinꢀ2ꢀ
one (1g). Purified by column chromatography (petroleum
ether/dichloromethane = 12/1) to afford a white solid in 50%
1
yield (1.6 g, 5.0 mmol). Mp: 134–135 ºC. H NMR (CDCl3,
1
analyzed by H NMR to determine the diastereoselectivity
500 MHz): δ 7.80 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 6.93 (d, J
= 8.0 Hz, 2H), 4.49 (t, J = 8.0 Hz, 2H), 4.10 (t, J = 8.0 Hz, 2H),
3.84 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 166.1, 161.0,
152.2, 137.3, 131.9, 126.0, 113.9, 109.4, 62.4, 55.4, 43.6.
HRMS (APCIꢀTOF, m/z) calcd for C13H13BrNO4 [M + H]+:
326.0022, found: 326.0023.
(cis:trans). The crude product was purified by column chroꢀ
matography to provide the transꢀ3.
Diethyl
transꢀ2ꢀ(2ꢀoxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀ
phenylcyclopro paneꢀ1,1ꢀdicarboxylate (transꢀ3aa). Purified
by column chromatography (petroleum ether/ethyl acetate =
10/1) to afford a colorless oil in 82% yield (154 mg). 1H NMR
(500 MHz, CDCl3): δ 7.37 (d, J = 7.2 Hz, 2H), 7.32–7.20 (m,
(Z)ꢀ3ꢀ(2ꢀBromoꢀ3ꢀ(3ꢀmethoxyphenyl)acryloyl)oxazolidinꢀ2ꢀ
one (1h). Purified by column chromatography (petroleum
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3H), 4.70 (d, J = 7.5 Hz, 1H), 4.51–4.42 (m, 2H), 4.35–4.25
(m, 2H), 4.10–4.02 (m, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.69 (d,
J = 7.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.1 Hz,
3H). 13C NMR (125 MHz, CDCl3): δ 168.6, 166.3, 165.2,
153.5, 133.0, 128.9, 128.3, 127.7, 62.2, 62.0, 61.8, 45.4, 42.9,
37.2, 30.4, 14.1, 13.7. HRMS (ESIꢀTOF, m/z) calcd for
C19H22NO7 [M + H]+: 376.1391, found: 376.1392
fied by column chromatography (petroleum ether/ethyl acetate
= 9/1) to afford a colorless oil in 78% yield (177 mg). H
1
NMR (500 MHz, CDCl3): δ 7.42 (d, J = 8.4 Hz, 2H), 7.31–
7.22 (m, 2H), 4.64 (d, J = 7.5 Hz, 1H), 4.47 (t, J = 8.0 Hz, 2H),
4.35–4.25 (m, 2H), 4.10–4.02 (m, 2H), 4.00–3.91 (m, 2H),
3.61 (d, J = 7.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.97 (t, J =
7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.2, 166.1,
165.0, 153.5, 132.1, 131.4, 130.7, 121.8, 62.3, 62.13, 62.06,
45.2, 42.9, 36.4, 30.5, 14.1, 13.8. HRMS (ESIꢀTOF, m/z) calcd
for C19H21BrNO7 [M + H]+: 454.0496, found: 454.0498.
Dimethyl
transꢀ2ꢀ(2ꢀoxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀ
9
phenylcyclopro paneꢀ1,1ꢀdicarboxylate (transꢀ3ab). Purified
by column chromatography (petroleum ether/ethyl acetate =
11/1) to afford a colorless oil in 82% yield (142 mg). 1H NMR
(500 MHz, CDCl3): δ 7.37 (d, J = 7.4 Hz, 2H), 7.33–7.22 (m,
3H), 4.71 (d, J = 7.5 Hz, 1H), 4.47 (t, J = 8.0 Hz, 2H), 4.06 (t,
J = 8.0 Hz, 2H), 3.84 (s, 3H), 3.70 (d, J = 7.5 Hz, 1H), 3.45 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 168.6, 166.9, 165.6,
153.5, 132.8, 128.8, 128.4, 127.8, 62.2, 53.2, 52.8, 45.2, 42.9,
37.5, 30.5. HRMS (ESIꢀTOF, m/z) calcd for C17H18NO7 [M +
H]+: 348.1078, found: 348.1077.
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13
14
15
16
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18
19
20
21
22
23
24
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26
27
28
29
30
31
32
33
34
35
36
37
38
39
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Diethyl
transꢀ2ꢀ(2ꢀoxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀ(pꢀ
tolyl)cyclopro paneꢀ1,1ꢀdicarboxylate (transꢀ3fa). Purified by
column chromatography (petroleum ether/ethyl acetate = 11/1)
1
to afford a colorless oil in 81% yield (158 mg). H NMR (300
MHz, CDCl3): δ 7.30–7.22 (m, 2H), 7.09 (d, J = 7.8 Hz, 2H),
4.66 (d, J = 7.5 Hz, 1H), 4.52–4.41 (m, 2H), 4.34–4.24 (m,
2H), 4.10–4.02 (m, 2H), 3.99–3.88 (m, 2H), 3.65 (d, J = 7.5
Hz, 1H), 2.30 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 168.6, 166.4, 165.2,
153.5, 137.3, 129.8, 128.9, 128.7, 62.2, 62.0, 61.8, 45.4, 42.8,
37.0, 30.4, 21.1, 14.0, 13.7. HRMS (ESIꢀTOF, m/z) calcd for
C20H24NO7 [M + H]+: 390.1547, found: 390.1548.
Diethyl
transꢀ2ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (transꢀ3ba). Puriꢀ
fied by column chromatography (petroleum ether/ethyl acetate
= 10/1) to afford a white solid in 81% yield (159 mg). Mp:
1
122–123 ºC. H NMR (500 MHz, CDCl3): δ 7.41–7.33 (m,
Diethyl transꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (transꢀ3ga). Puriꢀ
fied by column chromatography (petroleum ether/ethyl acetate
2H), 7.03–6.95 (m, 2H), 4.65 (d, J = 7.5 Hz, 1H), 4.51–4.44
(m, 2H), 4.34–4.24 (m, 2H), 4.10–4.03 (m, 2H), 3.99–3.90 (m,
2H), 3.64 (d, J = 7.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.95 (t,
J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.3, 166.2,
1
= 9/1) to afford a colorless oil in 81% yield (164 mg). H
NMR (500 MHz, CDCl3): δ 7.28 (d, J = 8.6 Hz, 2H), 6.81 (d, J
= 8.6 Hz, 2H), 4.63 (d, J = 7.4 Hz, 1H), 4.45 (t, J = 8.0 Hz,
2H), 4.33–4.21 (m, 2H), 4.08–3.99 (m, 2H), 3.98–3.88 (m,
2H), 3.76 (s, 3H), 3.61 (d, J = 7.4 Hz, 1H), 1.30 (t, J = 7.1 Hz,
3H), 0.95 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ
168.6, 166.4, 165.2, 159.0, 153.5, 130.0, 124.8, 113.6, 62.2,
61.9, 61.8, 55.2, 45.4, 42.8, 36.7, 30.5, 14.0, 13.8. HRMS
(ESIꢀTOF, m/z) calcd for C20H24NO8 [M + H]+: 406.1496,
found: 406.1497.
1
165.1, 162.3 (d, JC–F = 246.3 Hz), 153.6, 130.6, 128.8, 115.2
2
(d, JC–F = 21.7 Hz), 62.2, 62.1, 62.0, 45.3, 42.9, 36.4, 30.6,
14.1, 13.8. 19F NMR (470 MHz, CDCl3): δ –115.0. HRMS
(ESIꢀTOF, m/z) calcd for C19H21FNO7 [M + H]+: 394.1297,
found: 394.1300.
Diethyl
transꢀ2ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (transꢀ3ca). Puriꢀ
fied by column chromatography (petroleum ether/ethyl acetate
1
= 10/1) to afford a colorless oil in 81% yield (166 mg). H
Diethyl transꢀ2ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (transꢀ3ha). Puriꢀ
fied by column chromatography (petroleum ether/ethyl acetate
NMR (300 MHz, CDCl3): δ 7.37–7.22 (m, 4H), 4.64 (d, J =
7.5 Hz, 1H), 4.52–4.42 (m, 2H), 4.36–4.22 (m, 2H), 4.11–4.01
(m, 2H), 4.01–3.90 (m, 2H), 3.63 (d, J = 7.5 Hz, 1H), 1.31 (t, J
= 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 168.2, 166.1, 165.0, 153.5, 133.6, 131.5, 130.3,
128.4, 62.2, 62.1, 62.0, 45.2, 42.8, 36.4, 30.5, 14.0, 13.8.
HRMS (ESIꢀTOF, m/z) calcd for C19H21ClNO7 [M + H]+:
410.1001, found : 410.1005.
1
= 9/1) to afford a colorless oil in 73% yield (148 mg). H
NMR (500 MHz, CDCl3): δ 7.19 (t, J = 7.8 Hz, 1H), 7.01–6.92
(m, 2H), 6.83–6.76 (m, 1H), 4.67 (d, J = 7.5 Hz, 1H), 4.50–
4.43 (m, 2H), 4.34–4.25 (m, 2H), 4.10–4.01 (m, 2H), 3.99–
3.90 (m, 2H), 3.79 (s, 3H), 3.67 (d, J = 7.5 Hz, 1H), 1.31 (t, J
= 7.1 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 168.5, 166.3, 165.2, 159.5, 153.5, 134.5, 129.3,
121.2, 114.2, 113.8, 62.2, 62.0, 61.8, 55.3, 45.3, 42.9, 37.2,
30.5, 14.0, 13.7. HRMS (ESIꢀTOF, m/z) calcd for C20H24NO8
[M + H]+: 406.1496, found: 406.1497.
Diethyl
transꢀ2ꢀ(3ꢀchlorophenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (transꢀ3da). Puriꢀ
fied by column chromatography (petroleum ether/ethyl acetate
1
= 10/1) to afford a colorless oil in 80% yield (164 mg). H
NMR (500 MHz, CDCl3): δ 7.38 (s, 1H), 7.31–7.21 (m, 3H),
4.64 (d, J = 7.5 Hz, 1H), 4.48 (t, J = 8.1 Hz, 2H), 4.35–4.24
(m, 2H), 4.11–4.01 (m, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.65 (d,
J = 7.5 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz,
3H). 13C NMR (125 MHz, CDCl3): δ 168.2, 166.0, 165.0,
153.5, 135.1, 134.1, 129.6, 129.2, 128.0, 127.2, 62.3, 62.2,
62.1, 45.2, 42.8, 36.3, 30.5, 14.1, 13.8. HRMS (ESIꢀTOF, m/z)
calcd for C19H21ClNO7 [M + H]+: 410.1001, found: 410.1002.
Diethyl transꢀ2ꢀ(3,4ꢀdimethoxyphenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ
3ꢀcarbonyl)cyclopropaneꢀ1,1ꢀdicarboxylate (transꢀ3ia). Puriꢀ
fied by column chromatography (petroleum ether/ethyl acetate
1
= 8/1) to afford a colorless oil in 80% yield (174 mg). H
NMR (300 MHz, CDCl3): δ 6.98–6.87 (m, 2H), 6.81–6.72 (m,
1H), 4.62 (d, J = 7.4 Hz, 1H), 4.50–4.40 (m, 2H), 4.34–4.21
(m, 2H), 4.08–3.99 (m, 2H), 3.99–3.89 (m, 2H), 3.86 (s, 3H),
3.83 (s, 3H), 3.60 (d, J = 7.4 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H),
0.95 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 168.5,
166.4, 165.2, 153.6, 148.6, 148.4, 125.3, 121.1, 112.0, 110.7,
62.2, 62.0, 61.8, 55.9, 55.8, 45.3, 42.8, 37.0, 30.6, 14.0, 13.8.
Diethyl
transꢀ2ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (transꢀ3ea). Puriꢀ
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HRMS (ESIꢀTOF, m/z) calcd for C21H26NO9 [M + H]+:
436.1602, found: 436.1605.
to afford a colorless oil in 93% yield (162 mg). H NMR (500
MHz, CDCl3): δ 7.35 (d, J = 7.1 Hz, 2H), 7.32–7.20 (m, 3H),
4.48–4.38 (m, 2H), 4.08–3.94 (m, 2H), 3.85 (s, 3H), 3.82 (d, J
= 9.9 Hz, 1H), 3.66 (s, 3H), 3.47 (d, J = 9.9 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 169.4, 166.2, 165.9, 153.6, 131.6, 130.1,
127.8, 127.4, 62.2, 53.5, 52.6, 42.7, 41.0, 36.9, 32.1. HRMS
(ESIꢀTOF, m/z) calcd for C17H18NO7 [M + H]+: 348.1078,
found: 348.1078.
1
4
Diethyl
transꢀ2ꢀ(2ꢀoxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀ(3,4,5ꢀ
5
6
7
8
trimethoxyphenyl)cyclopropaneꢀ1,1ꢀdicarboxylate (transꢀ3ja).
Purified by column chromatography (petroleum ether/ethyl
acetate = 6/1) to afford a yellow solid in 79% yield (184 mg).
Mp: 125–126 ºC. 1H NMR (500 MHz, CDCl3): δ 6.65 (s, 2H),
4.62 (d, J = 7.4 Hz, 1H), 4.52–4.43 (m, 2H), 4.37–4.24 (m,
2H), 4.11–4.02 (m, 2H), 4.02–3.92 (m, 2H), 3.85 (s, 6H), 3.81
(s, 3H), 3.62 (d, J = 7.4 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 0.97
(t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.4,
166.4, 165.2, 153.6, 153.1, 137.6, 128.6, 106.1, 62.3, 62.1,
61.9, 60.8, 56.2, 45.3, 42.9, 37.6, 30.8, 14.1, 13.8. HRMS
(ESIꢀTOF, m/z) calcd for C22H28NO10 [M + H]+: 466.1708,
found: 466.1709.
9
Diethyl
cisꢀ2ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (cisꢀ3ba). Purified
by column chromatography (petroleum ether/ethyl acetate =
10/1) to afford a colorless oil in 87% yield (171 mg). 1H NMR
(500 MHz, CDCl3): δ 7.42–7.32 (m, 2H), 7.01–6.90 (m, 2H),
4.43 (t, J = 8.0 Hz, 2H), 4.34–4.23 (m, 2H), 4.18–4.08 (m, 2H),
4.06–3.94 (m, 2H), 3.77 (d, J = 9.8 Hz, 1H), 3.40 (d, J = 9.7
Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13
C
Diethyl
transꢀ2ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ3ꢀ(2ꢀ
NMR (125 MHz, CDCl3): δ 168.8, 165.2, 163.1, 162.1 (d, 1JC–
oxooxazolidineꢀ3ꢀcarbonyl)cyclopropaneꢀ1,1ꢀdicarboxylate
(transꢀ3ka). Purified by column chromatography (petroleum
ether/ethyl acetate = 7/1) to afford a colorless oil in 78% yield
2
F = 246.4 Hz), 153.5, 132.1, 127.4, 114.6 (d, JC–F = 21.4 Hz),
62.6, 62.2, 61.7, 42.7, 41.3, 35.8, 31.8, 14.0, 13.8. 19F NMR
(470 MHz, CDCl3): δ –115.0. HRMS (ESIꢀTOF, m/z) calcd
for C19H21FNO7 [M + H]+: 394.1297, found: 394.1299.
1
(164 mg). H NMR (500 MHz, CDCl3): δ 6.90–6.82 (m, 2H),
6.73 (d, J = 8.6 Hz, 1H), 5.93 (s, 2H), 4.60 (d, J = 7.4 Hz, 1H),
4.51–4.42 (m, 2H), 4.34–4.22 (m, 2H), 4.10–3.94 (m, 4H),
3.60 (d, J = 7.4 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.01 (t, J =
7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.5, 166.3,
165.2, 153.5, 147.6, 147.2, 126.7, 122.4, 109.4, 108.1, 101.1,
62.2, 62.0, 61.9, 45.4, 42.9, 37.0, 30.8, 14.1, 13.9. HRMS
(ESIꢀTOF, m/z) calcd for C20H22NO9 [M + H]+: 420.1289,
found: 420.1288.
Diethyl
cisꢀ2ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (cisꢀ3ca). Purified
by column chromatography (petroleum ether/ethyl acetate =
10/1) to afford a white solid in 88% yield (180 mg). Mp: 112–
1
113 ºC. H NMR (500 MHz, CDCl3): δ 7.32 (d, J = 8.3 Hz,
2H), 7.25–7.19 (m, 2H), 4.43 (t, J = 8.1 Hz, 2H), 4.34–4.24 (m,
2H), 4.20–4.07 (m, 2H), 4.05–3.93 (m, 2H), 3.79 (d, J = 9.8
Hz, 1H), 3.39 (d, J = 9.8 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H),
1.17 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.7,
166.3, 165.2, 153.5, 133.3, 131.7, 130.3, 127.8, 62.7, 62.2,
61.7, 42.7, 41.3, 35.8, 31.8, 14.0, 13.8. HRMS (ESIꢀTOF, m/z)
calcd for C19H21ClNO7 [M + H]+: 410.1001, found: 410.1004.
General Procedure for the Syntheses of Diethyl cisꢀ2ꢀ(2ꢀ
oxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀarylcyclopropaneꢀ1,1ꢀ
dicarboxylate (cisꢀ3). Under an argon atmosphere, to a stirred
solution of (Z)ꢀ3ꢀ(2ꢀbromoꢀ3ꢀarylacryloyl)oxazolidinꢀ2ꢀones
1a−k (0.5 mmol) and malonate 2a−b (1.5 mmol) in anhydrous
DMF (5 mL) was added Cs2CO3 (0.75 mmol) at –20 ºC. Stirꢀ
ring was continued until the reaction was finished (monitored
by TLC). Upon completion, the reaction mixture was diluted
with 5 mL of H2O and extracted with dichloromethane (3 × 10
mL). The combined organic layers were washed twice with
water, dried with anhydrous sodium sulfate, filtered, and conꢀ
centrated under reduced pressure to yield a crude product,
which was analyzed by 1H NMR to determine the diastereoseꢀ
lectivity (cis:trans). The crude product was purified by column
chromatography to provide the cisꢀ3.
Diethyl
cisꢀ2ꢀ(3ꢀchlorophenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (cisꢀ3da). Purified
by column chromatography (petroleum ether/ethyl acetate =
10/1) to afford a colorless oil in 90% yield (184 mg). 1H NMR
(500 MHz, CDCl3): δ 7.42 (s, 1H), 7.33–7.27 (m, 1H), 7.25–
7.16 (m, 2H), 4.44 (t, J = 8.0 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H),
4.22–4.11 (m, 2H), 4.08–3.94 (m, 2H), 3.79 (d, J = 9.8 Hz,
1H), 3.42 (d, J = 9.7 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.20 (t,
J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.6, 166.2,
165.1, 153.5, 133.8, 133.5, 130.4, 128.8, 128.7, 127.5, 62.7,
62.2, 61.8, 42.7, 41.3, 35.7, 31.7, 14.0, 13.8. HRMS (ESIꢀTOF,
m/z) calcd for C19H21ClNO7 [M + H]+: 410.1001, found:
410.1002.
Diethyl
cisꢀ2ꢀ(2ꢀoxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀ
phenylcyclopropane ꢀ1,1ꢀdicarboxylate (cisꢀ3aa). Purified by
column chromatography (petroleum ether/ethyl acetate = 10/1)
to afford a colorless oil in 92% yield (173 mg). H NMR (500
1
Diethyl
cisꢀ2ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
MHz, CDCl3): δ 7.37 (d, J = 7.1 Hz, 2H), 7.30–7.20 (m, 3H),
4.43 (t, J = 8.0 Hz, 2H), 4.35–4.26 (m, 2H), 4.18–4.09 (m, 2H),
4.06–3.95 (m, 2H), 3.79 (d, J = 9.8 Hz, 1H), 3.45 (d, J = 9.8
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (cisꢀ3ea). Purified
by column chromatography (petroleum ether/ethyl acetate =
10/1) to afford a white solid in 86% yield (195 mg). Mp: 109–
1
Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13
C
110 ºC. H NMR (500 MHz, CDCl3): δ 7.39 (d, J = 8.5 Hz,
NMR (125 MHz, CDCl3): δ 169.0, 166.3, 165.4, 153.5, 131.8,
130.3, 127.7, 127.3, 62.6, 62.2, 61.6, 42.7, 41.3, 36.6, 31.9,
14.0, 13.8. HRMS (ESIꢀTOF, m/z) calcd for C19H22NO7 [M +
H]+: 376.1391, found: 376.1394.
2H), 7.31–7.24 (m, 2H), 4.44 (t, J = 8.1 Hz, 2H), 4.35–4.24 (m,
2H), 4.19–4.09 (m, 2H), 4.06–3.94 (m, 2H), 3.80 (d, J = 9.7
Hz, 1H), 3.38 (d, J = 9.7 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H),
1.18 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.7,
166.2, 165.2, 153.5, 132.1, 130.8, 121.6, 62.7, 62.2, 61.8, 42.7,
41.3, 35.8, 31.7, 14.0, 13.8. HRMS (ESIꢀTOF, m/z) calcd for
C19H21BrNO7 [M + H]+: 454.0496, found: 454.0499.
Dimethyl
cisꢀ2ꢀ(2ꢀoxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀ
phenylcyclopro paneꢀ1,1ꢀdicarboxylate (cisꢀ3ab). Purified by
column chromatography (petroleum ether/ethyl acetate = 11/1)
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Page 8 of 12
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Diethyl
cisꢀ2ꢀ(2ꢀoxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀ(pꢀ
7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.9, 166.2,
tolyl)cyclo propaneꢀ1,1ꢀdicarboxylate (cisꢀ3fa). Purified by
column chromatography (petroleum ether/ethyl acetate = 10/1)
to afford a white solid in 91% yield (177 mg). Mp: 98–99 ºC.
1H NMR (500 MHz, CDCl3): δ 7.28–7.21 (m, 2H), 7.07 (d, J =
8.0 Hz, 2H), 4.43 (t, J = 8.1 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H),
4.19–4.10 (m, 2H), 4.07–3.94 (m, 2H), 3.78 (d, J = 9.8 Hz,
1H), 3.42 (d, J = 9.8 Hz, 1H), 2.30 (s, 3H), 1.32 (t, J = 7.1 Hz,
3H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
169.0, 166.3, 165.4, 153.5, 136.9, 130.1, 128.6, 128.4, 62.5,
62.1, 61.6, 42.7, 41.2, 36.4, 31.8, 21.1, 14.0, 13.8. HRMS
(ESIꢀTOF, m/z) calcd for C20H24NO7 [M + H]+: 390.1547,
found: 390.1548.
165.5, 153.5, 152.5, 137.4, 127.2, 107.8, 62.6, 62.2, 61.7, 61.5,
60.8, 56.1, 42.8, 41.4, 36.9, 32.6, 14.0, 13.9. HRMS (ESIꢀTOF,
m/z) calcd for C22H28NO10 [M + H]+: 466.1708, found:
466.1709.
3
4
5
6
7
8
9
Diethyl
cisꢀ2ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ3ꢀ(2ꢀ
oxooxazolidineꢀ3ꢀcarbonyl)cyclopropaneꢀ1,1ꢀdicarboxylate
(cisꢀ3ka). Purified by column chromatography (petroleum
ether/ethyl acetate = 7/1) to afford a colorless oil in 90% yield
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(189 mg). H NMR (500 MHz, CDCl3): δ 6.96–6.83 (m, 2H),
6.71 (d, J = 8.1 Hz, 1H), 5.92 (s, 2H), 4.44 (t, J = 8.0 Hz, 2H),
4.29 (q, J = 7.0 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 4.07–3.95
(m, 2H), 3.76 (d, J = 9.8 Hz, 1H), 3.39 (d, J = 9.8 Hz, 1H),
1.31 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 168.9, 166.3, 165.4, 153.5, 147.0, 146.8,
125.2, 123.9, 110.8, 107.6, 101.0, 62.6, 62.2, 61.7, 42.7, 41.3,
36.5, 31.9, 14.0, 13.9. HRMS (ESIꢀTOF, m/z) calcd for
C20H22NO9 [M + H]+: 420.1289, found: 420.1289.
Diethyl
cisꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (cisꢀ3ga). Purified
by column chromatography (petroleum ether/ethyl acetate =
1
9/1) to afford a colorless oil in 91% yield (184 mg). H NMR
(500 MHz, CDCl3): δ 7.30 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7
Hz, 2H), 4.43 (t, J = 8.1 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H),
4.18–4.10 (m, 2H), 4.07–3.95 (m, 2H), 3.82–3.73 (m, 4H),
3.40 (d, J = 9.8 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.18 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.0, 166.4,
165.4, 158.7, 153.5, 131.4, 123.5, 113.1, 62.5, 62.1, 61.6, 55.2,
42.7, 41.2, 36.2, 31.9, 14.0, 13.8. HRMS (ESIꢀTOF, m/z) calcd
for C20H24NO8 [M + H]+: 406.1496, found: 406.1494.
Dimethyl
cisꢀ2ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ3ꢀ(2ꢀ
oxooxazolidineꢀ3ꢀcarbonyl)cyclopropaneꢀ1,1ꢀdicarboxylate
(cisꢀ3kb). Purified by column chromatography (petroleum
ether/ethyl acetate = 8/1) to afford a colorless oil in 90% yield
(176 mg). 1H NMR (CDCl3, 500 MHz): δ 6.87 (s, 1H), 6.83 (d,
J = 8.1 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 5.92 (s, 2H), 4.44 (t,
J = 8.1 Hz, 2H), 4.09–3.94 (m, 2H), 3.83 (s, 3H), 3.77 (d, J =
9.8 Hz, 1H), 3.68 (s, 3H), 3.39 (d, J = 9.8 Hz, 1H). 13C NMR
(CDCl3, 125 MHz): δ 169.3, 166.2, 165.9, 153.6, 147.1, 146.9,
124.9, 123.7, 110.6, 107.7, 101.0, 62.2, 53.6, 52.8, 42.7, 40.9,
36.7, 32.1. HRMS (ESIꢀTOF, m/z) calcd for C18H18NO9 [M +
H]+: 392.0976, found: 392.0972.
Diethyl
cisꢀ2ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl) cyclopropaneꢀ1,1ꢀdicarboxylate (cisꢀ3ha). Purified
by column chromatography (petroleum ether/ethyl acetate =
9/1) to afford a white solid in 87% yield (176 mg). Mp: 123–
1
124 ºC. H NMR (500 MHz, CDCl3): δ 7.18 (t, J = 8.0 Hz,
1H), 7.01 (s, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.82–6.75 (m, 1H),
4.43 (t, J = 8.1 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.20–4.10
(m, 2H), 4.08–3.94 (m, 2H), 3.82–3.74 (m, 4H), 3.44 (d, J =
9.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ 168.9, 166.2, 165.4, 159.0,
153.5, 133.2, 128.6, 122.6, 116.3, 112.9, 62.6, 62.2, 61.6, 55.2,
42.7, 41.3, 36.6, 32.0, 14.0, 13.8. HRMS (ESIꢀTOF, m/z) calcd
for C20H24NO8 [M + H]+: 406.1496, found: 406.1506.
Procedure for the [3 + 2] Annulation of cisꢀ3kb With
Veratral/Piperonal. To a solution of cisꢀ3kb (196 mg, 0.5
mmol), veratral (831 mg, 5 mmol) or piperonal (751 mg, 5
mmol) in 5.0 mL of dichloromethane was added AlCl3 (67 mg,
0.5 mmol). The reaction mixture was stirred at 30 °C and
monitored by TLC. Upon completion, the reaction mixture
was cooled down to room temperature followed by the addiꢀ
tion of 2.0 mL of H2O. Then the mixture was extracted with
ethyl acetate (3 × 10 mL), and the combined organic layers
were washed twice with brine (2 × 10 mL), dried with anhyꢀ
drous Na2SO4, filtered, and concentrated in vacuo. The crude
products were purified by flash chromatography (petroleum
ether/ethyl acetate = 1/1) to give the pure products 4.
Diethyl cisꢀ2ꢀ(3,4ꢀdimethoxyphenyl)ꢀ3ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl)cyclopropaneꢀ1,1ꢀdicarboxylate (cisꢀ3ia). Purified
by column chromatography (petroleum ether/ethyl acetate =
1
8/1) to afford a colorless oil in 93% yield (202 mg). H NMR
(500 MHz, CDCl3): δ 7.04 (d, J = 2.0 Hz, 1H), 6.95–6.86 (m,
1H), 6.75 (d, J = 8.4 Hz, 1H), 4.48–4.38 (m, 2H), 4.34–4.25
(m, 2H), 4.21–4.08 (m, 2H), 4.06–3.94 (m, 2H), 3.85 (s, 3H),
3.84 (s, 3H), 3.73 (d, J = 9.8 Hz, 1H), 3.41 (d, J = 9.8 Hz, 1H),
1.31 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 169.0, 166.3, 165.5, 153.5, 148.2, 148.0,
124.0, 122.5, 114.0, 110.4, 62.5, 62.1, 61.6, 55.83, 55.75, 42.7,
41.3, 36.5, 32.2, 14.0, 13.9. HRMS (ESIꢀTOF, m/z) calcd for
C21H26NO9 [M + H]+: 436.1602, found: 436.1604.
Dimethyl
5ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ2ꢀ(3,4ꢀ
dimethoxyphenyl)ꢀ4ꢀ(2ꢀoxooxazolidineꢀ3ꢀ
carbonyl)dihydrofuranꢀ3,3(2H)ꢀdicarboxylate (4a). Colorless
1
oil, 91% yield (256 mg). H NMR (CDCl3, 500 MHz): δ 7.21
(d, J = 1.3 Hz, 1H), 7.18–7.09 (m, 2H), 6.97 (dd, J = 7.9, 1.4
Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H),
5.98 (s, 2H), 5.72 (s, 1H), 5.55 (d, J = 8.9 Hz, 1H), 5.22 (d, J =
9.0 Hz, 1H), 4.42–4.27 (m, 2H), 4.03–3.91 (m, 2H), 3.90 (s,
3H), 3.87 (s, 3H), 3.73 (s, 3H), 3.29 (s, 3H). 13C NMR (CDCl3,
125 MHz): δ 171.7, 168.8, 168.4, 152.6, 149.1, 148.4, 148.2,
148.1, 131.7, 128.5, 121.2, 120.0, 110.53, 110.46, 108.2,
107.8, 101.2, 85.1, 84.6, 70.3, 61.7, 55.93, 55.88, 52.84, 52.80,
42.9. HRMS (ESIꢀTOF, m/z) calcd for C27H31N2O12 [M +
NH4]+: 575.1872, found: 575.1871.
Diethyl
cisꢀ2ꢀ(2ꢀoxooxazolidineꢀ3ꢀcarbonyl)ꢀ3ꢀ(3,4,5ꢀ
trimethoxy phenyl)cyclopropaneꢀ1,1ꢀdicarboxylate (cisꢀ3ja).
Purified by column chromatography (petroleum ether/ethyl
acetate = 6/1) to afford a colorless oil in 90% yield (209 mg).
1H NMR (500 MHz, CDCl3): δ 6.71 (s, 2H), 4.49–4.38 (m,
2H), 4.36–4.26 (m, 2H), 4.24–4.15 (m, 1H), 4.15–4.08 (m,
1H), 4.07–3.94 (m, 2H), 3.82 (s, 9H), 3.69 (d, J = 9.8 Hz, 1H),
3.41 (d, J = 9.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.18 (t, J =
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Dimethyl
2,5ꢀbis(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ4ꢀ(2ꢀ
umn chromatography (petroleum ether/dichloromethane = 1/1)
to afford the pure product 6a or 6b.
oxooxazolidineꢀ3ꢀcarbonyl)dihydrofuranꢀ3,3(2H)ꢀ
1
dicarboxylate (4b). Colorless oil, 92% yield (249 mg). H
NMR (CDCl3, 500 MHz): δ 7.19 (d, J = 1.5 Hz, 1H), 7.12–
7.02 (m, 2H), 6.96 (dd, J = 8.0, 1.6 Hz, 1H), 6.82–6.74 (m,
2H), 5.98 (s, 2H), 5.94 (dd, J = 3.6, 1.4 Hz, 2H), 5.68 (s, 1H),
5.50 (d, J = 8.8 Hz, 1H), 5.21 (d, J = 8.9 Hz, 1H), 4.41–4.27
(m, 2H), 4.02–3.88 (m, 2H), 3.73 (s, 3H), 3.36 (s, 3H). 13C
NMR (CDCl3, 125 MHz): δ 171.7, 168.7, 168.4, 152.7, 148.2,
148.1, 147.6, 147.2, 131.7, 129.7, 121.2, 121.0, 108.2, 108.0,
107.8, 101.2, 101.0, 85.0, 84.5, 70.3, 61.7, 56.1, 52.9, 52.8,
42.9. HRMS (APCIꢀTOF, m/z) calcd for C26H27N2O12 [M +
NH4]+: 559.1559, found: 559.1566.
4
5
6
7
8
9
Methyl
5ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ2ꢀ(3,4ꢀ
dimethoxyphenyl)ꢀ4ꢀ(hydroxymethyl)tetrahydrofuranꢀ3ꢀ
carboxylate (6a). Colorless oil in 69% yield (92 mg). 1H NMR
(CDCl3, 500 MHz): δ 7.18 (d, J = 1.5 Hz, 1H), 7.02–6.89 (m,
3H), 6.86–6.76 (m, 2H), 5.97 (s, 2H), 5.19 (d, J = 8.7 Hz, 1H),
4.66 (d, J = 9.1 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.81–3.73
(m, 1H), 3.72–3.63 (m, 1H), 3.48 (dd, J = 8.7, 7.0 Hz, 1H),
3.23 (s, 3H), 2.95–2.82 (m, 1H). 13C NMR (CDCl3, 125 MHz):
δ 172.9, 148.6, 148.5, 148.0, 147.6, 133.8, 130.8, 120.8, 119.1,
110.6, 109.9, 108.1, 107.5, 101.1, 82.9, 81.7, 61.5, 55.91,
55.88, 53.7, 52.4, 51.6. HRMS (ESIꢀTOF, m/z) calcd for
C22H23O7 [M + H – H2O]+: 399.1438, found: 399.1437.
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Procedure for the Reduction of 4 to 5 Using LiBH4. In a
glovebox, to a solution of the cyclopropane 4a (240 mg, 0.43
mmol) or 4b (233 mg, 0.43 mmol) in anhydrous THF (5.0 mL)
was added LiBH4 (9.4 mg, 0.43 mmol) at rt and the resulting
mixture was stirred for 8 hours. Then the reaction was
quenched with saturated NH4Cl solution (2 mL). The reaction
mixture was extracted with ethyl acetate (3 × 10 mL) and the
combined organic layers were washed twice with brine (2 × 10
mL), dried with anhydrous sodium sulfate, filtered, and conꢀ
centrated under reduced pressure to yield a crude product. The
residue was purified by flash chromatography (petroleum
ether/ethyl acetate = 1/1) to afford the pure product 5a or 5b.
Methyl
(hydroxymethyl)tetra
2,5ꢀbis(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ4ꢀ
hydrofuranꢀ3ꢀcarboxylate (6b).
1
Colorless oil in 68% yield (89 mg). H NMR (CDCl3, 500
MHz): δ 7.16 (s, 1H), 6.97 (dd, J = 7.9, 1.2 Hz, 1H), 6.90 (s,
1H), 6.86 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.77 (d,
J = 8.0 Hz, 1H), 5.98 (s, 2H), 5.94 (s, 2H), 5.17 (d, J = 8.8 Hz,
1H), 4.65 (d, J = 9.1 Hz, 1H), 3.84–3.74 (m, 1H), 3.73–3.63
(m, 1H), 3.47 (dd, J = 8.6, 7.3 Hz, 1H), 3.29 (s, 3H), 2.92–
2.82 (m, 1H), 1.53–1.45 (m, 1H). 13C NMR (CDCl3, 125
MHz): δ 172.7, 148.0, 147.7, 147.4, 147.2, 133.6, 132.1, 120.8,
120.2, 108.2, 107.9, 107.5, 107.3, 101.1, 101.0, 82.8, 81.6,
61.5, 53.7, 52.4, 51.7. HRMS (APCIꢀTOF, m/z) calcd for
C21H19O7 [M + H – H2O]+: 383.1125, found: 383.1118.
Methyl
1ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ3ꢀ(3,4ꢀ
dimethoxyphenyl)ꢀ4ꢀoxohexahydrofuro[3,4ꢀc]furanꢀ3aꢀ
1
carboxylate (5a). Colorless oil, 71% yield (135 mg). H NMR
Procedure for the Reduction of 6 to 7 Using LiAlH4.
LiAlH4 (31 mg, 0.84 mmol) was added slowly to a solution of
compound 6a (90 mg, 0.21 mmol) or 6b (89 mg, 0.22 mmol)
in anhydrous THF (10 mL) at 0 °C under an argon atmosphere.
After completion of the reaction, the mixture was diluted with
water (5 mL) and extracted with ethyl acetate (3 × 10 mL).
The combined organic layers were washed with brine (2 × 10
mL), dried with anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (petroleum ether/ethyl acetate = 1/2) to afford
the pure product 7a or 7b.
(CDCl3, 500 MHz): δ 7.12–7.04 (m, 2H), 7.01 (d, J = 1.8 Hz,
1H), 6.95 (dd, J = 7.9, 1.5 Hz, 1H), 6.90–6.82 (m, 2H), 6.01 (s,
2H), 5.34 (s, 1H), 4.63 (d, J = 9.6 Hz, 1H), 4.39 (dd, J = 10.0,
6.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 3.92 (s, 3H), 3.89 (s,
3H), 3.63 (dd, J = 9.4, 5.8 Hz, 1H), 3.30 (s, 3H). 13C NMR
(CDCl3, 125 MHz): δ 173.4, 166.3, 149.2, 148.7, 148.43,
148.36, 131.3, 129.0, 120.7, 119.5, 110.7, 110.1, 108.4, 106.9,
101.4, 86.5, 85.2, 67.8, 67.4, 56.0, 55.9, 53.5, 53.0. HRMS
(APCIꢀTOF, m/z) calcd for C23H26NO9 [M + NH4]+: 460.1602,
found: 460.1605.
Methyl
1,3ꢀbis(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ4ꢀ
2ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ5ꢀ(3,4ꢀ
oxohexahydrofuro[3,4ꢀc]furanꢀ3aꢀcarboxylate (5b). Colorless
dimethoxyphenyl)tetrahydro furanꢀ3,4ꢀdiyl)dimethanol (7a).
Brown oil, 91% yield (74 mg). 1H NMR (CDCl3, 500 MHz): δ
7.02 (d, J = 1.4 Hz, 1H), 6.97–6.87 (m, 3H), 6.84 (d, J = 8.2
Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 5.97 (s, 2H), 5.11 (d, J = 8.6
Hz, 1H), 4.47 (d, J = 9.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H),
3.79–3.70 (m, 1H), 3.66–3.56 (m, 1H), 3.41–3.29 (m, 1H),
1
oil, 71% yield (130 mg). H NMR (CDCl3, 500 MHz): δ 7.07
(s, 1H), 7.04–6.98 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.85 (d, J
= 7.9 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.02 (s, 2H), 5.97 (d, J
= 1.5 Hz, 2H), 5.31 (s, 1H), 4.60 (d, J = 9.6 Hz, 1H), 4.38 (dd,
J = 10.0, 6.0 Hz, 1H), 4.28 (d, J = 10.0 Hz, 1H), 3.61 (dd, J =
9.5, 5.9 Hz, 1H), 3.36 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ
173.4, 166.2, 148.42, 148.38, 147.8, 147.5, 131.1, 130.3,
120.8, 120.7, 108.4, 108.0, 107.4, 106.9, 101.4, 101.2, 86.4,
85.0, 67.8, 67.3, 53.5, 53.0. HRMS (APCIꢀTOF, m/z) calcd for
C22H22NO9 [M + NH4]+: 444.1289, found: 444.1282.
3.17–3.08 (m, 1H), 2.64–2.54 (m, 1H), 2.27–2.16 (m, 1H). 13
C
NMR (CDCl3, 125 MHz): δ 148.9, 148.5, 148.0, 147.5, 134.0,
131.3, 120.5, 118.7, 111.0, 109.7, 108.2, 107.0, 101.2, 82.6,
81.2, 63.8, 63.0, 55.9, 55.3, 55.2, 50.8. HRMS (ESIꢀTOF, m/z)
calcd for C21H23O6 [M + H – H2O]+: 371.1489, found:
371.1488.
Procedure for the Decarboxylation of 5 to 6. A mixture of
compound 5a (142 mg, 0.32 mmol) or 5b (140 mg, 0.33 mmol)
and NaCl (150 mg, 2.56 mmol) in DMSO (10 mL) and water
(1 mL) was heated at 100 °C for 24 h under an argon
atmosphere. Then the mixture was cooled down to room temp,
diluted with water (10 mL) and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with brine (30
mL), dried with anhydrous Na2SO4, filtered, and concentrated
under reduced pressure, and the residue was purified by colꢀ
2,5ꢀBis(benzo[d][1,3]dioxolꢀ5ꢀyl)tetrahydrofuranꢀ3,4ꢀ
diyl)dimeth anol (7b). Colorless oil, 92% yield (81 mg). H
1
NMR (CDCl3, 500 MHz): δ 7.00 (d, J = 1.5 Hz, 1H), 6.94–
6.86 (m, 2H), 6.85–6.76 (m, 3H), 5.97 (s, 2H), 5.96 (s, 2H),
5.08 (d, J = 8.6 Hz, 1H), 4.45 (d, J = 9.4 Hz, 1H), 3.74 (dd, J =
10.5, 4.0 Hz, 1H), 3.60 (dd, J = 10.3, 8.7 Hz, 1H), 3.35 (dd, J
= 10.6, 4.7 Hz, 1H), 3.16 (t, J = 10.1 Hz, 1H), 2.62–2.52 (m,
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1H), 2.24–2.15 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 148.0,
147.8, 147.6, 147.1, 134.0, 133.9, 132.6, 120.5, 119.8, 108.25,
108.18, 107.0, 101.2, 101.1, 82.6, 81.2, 63.8, 63.0, 55.4, 50.7.
HRMS (APCIꢀTOF, m/z) calcd for C20H21O7 [M + H]+:
373.1282, found: 373.1278.
oxabicyclo[3.1.0]hexaneꢀ1ꢀcarboxylate (11). H NMR (CDCl3,
500 MHz): δ 7.41–7.29 (m, 5H), 4.39 (dd, J = 10.0, 5.3 Hz,
1H), 4.11 (d, J = 10.0 Hz, 1H), 3.90 (s, 3H), 3.61 (d, J = 8.5
Hz, 1H), 3.06 (dd, J = 8.5, 5.2 Hz, 1H). 13C NMR (CDCl3, 125
MHz): δ 169.3, 167.6, 130.5, 129.2, 129.1, 128.4, 63.8, 53.2,
36.1, 34.8, 33.3. HRMS (ESIꢀTOF, m/z) calcd for C13H13O4
[M + H]+: 233.0808, found: 233.0804.
Procedure for the Methylation of 7 to 8 Using MeI.
Under an argon atmosphere, to an iceꢀcooled solution of diol
7a (30 mg, 0.077 mmol) or 7b (81 mg, 0.2 mmol) in anhyꢀ
drous THF (10 mL) was added NaH (31 mg, 0.77 mmol for 7a;
80 mg, 2 mmol for 7b, 60% dispersion in mineral oil). The
resultant suspension was stirred for 30 min before the dropꢀ
wise addition of CH3I (0.48 mL, 0.77 mmol for 7a; 1.01 mL, 2
mmol for 7b). The resulting reaction solution was stirred at
room temperature for 2.5 h before the addition of 5.0 mL of
H2O. After concentration of the reaction mixture, the residue
was dissolved in 20 mL of CH2Cl2 and 20 mL of H2O and the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with brine (2 × 10 mL),
dried with anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chroꢀ
matography (petroleum ether/ethyl acetate = 10/1) to afford
the pure product 8a or 8b.
Procedure for the [3 + 2] Annulation of 11 with Benzalꢀ
dehyde. To a solution of the γꢀbutyrolactone fused cycloproꢀ
pane 11 (85 mg, 0.37 mmol), benzaldehyde (43 mg, 0.41
mmol) in 5.0 mL of dichloromethane was added Sc(OTf)3 (4.5
mg, 0.0092 mmol). The reaction mixture was stirred at 70 °C
for 72 h. Upon completion (monitored by TLC), the reaction
mixture was cooled down to room temperature followed by
the addition of 2.0 mL H2O. Then the mixture was extracted
with ethyl acetate (3 × 10 mL), and the combined organic layꢀ
ers were washed with brine (2 × 10 mL), dried with anhydrous
Na2SO4, filtered, and concentrated in vacuo. The crude prodꢀ
uct was purified by flash chromatography (petroleum
ether/ethyl acetate = 10/1) to give the pure product 5c as a
colorless oil in 21% yield (26 mg). Methyl 4ꢀoxoꢀ1,3ꢀ
diphenylhexahydrofuro[3,4ꢀc]furanꢀ3aꢀcarboxylate (5c). 1H
NMR (CDCl3, 500 MHz): δ 7.60–7.51 (m, 4H), 7.50–7.30 (m,
6H), 5.44 (s, 1H), 4.74 (d, J = 9.6 Hz, 1H), 4.44–4.32 (m, 2H),
3.73–3.65 (m, 1H), 3.22 (s, 3H). 13C NMR (CDCl3, 125 MHz):
δ 173.4, 166.2, 137.6, 136.7, 129.2, 129.1, 128.7, 128.2, 127.0,
126.7, 86.8, 85.3, 68.2, 67.4, 53.7, 52.8. HRMS (ESIꢀTOF,
m/z) calcd for C20H22NO5 [M + NH4]+: 356.1492, found:
356.1496.
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10
11
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14
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5ꢀ(3,4ꢀDimethoxyphenyl)ꢀ3,4ꢀbis(methoxymethyl)ꢀ
tetrahydrofuranꢀ2ꢀyl)benzo[d][1,3]dioxole (8a). Brown oil,
92% yield (29.5 mg). 1H NMR (CDCl3, 500 MHz): δ 7.04 (d, J
= 1.3 Hz, 1H), 6.99–6.90 (m, 3H), 6.84 (d, J = 8.1 Hz, 1H),
6.80 (d, J = 7.9 Hz, 1H), 5.96 (s, 2H), 5.09 (d, J = 7.3 Hz, 1H),
4.71 (d, J = 8.1 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.58–3.46
(m, 2H), 3.36 (s, 3H), 3.07 (s, 3H), 3.04 (d, J = 9.0 Hz, 1H),
2.97–2.89 (m, 1H), 2.66–2.57 (m, 1H), 2.35–2.25 (m, 1H). 13C
NMR (CDCl3, 125 MHz): δ 148.6, 148.1, 147.8, 147.0, 135.6,
131.4, 120.1, 118.6, 110.7, 109.8, 108.1, 107.0, 101.0, 82.7,
81.5, 73.2, 73.0, 59.1, 58.7, 55.9, 51.2, 46.6. HRMS (APCIꢀ
TOF, m/z) calcd for C23H29O7 [M + H]+: 417.1908, found:
417.1899.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Xꢀray crystallographic data and structures for cisꢀ3ha and 1a,
copies of 1H, 13C NMR spectra for all new compounds (PDF)
Xꢀray crystallographic data for cisꢀ3ha (CIF)
1
(±)ꢀUrinaligran (8b). Dark red oil, 93% yield (75 mg). H
NMR (CDCl3, 500 MHz): δ 7.02 (d, J = 1.5 Hz, 1H), 6.97–
6.89 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.82–6.75 (m, 2H),
6.02–5.90 (m, 4H), 5.04 (d, J = 7.3 Hz, 1H), 4.69 (d, J = 8.0
Hz, 1H), 3.57–3.45 (m, 2H), 3.35 (s, 3H), 3.08 (s, 3H), 3.07–
3.01 (m, 1H), 3.01–2.93 (m, 1H), 2.64–2.52 (m, 1H), 2.33–
2.21 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 147.8, 147.4,
147.0, 146.6, 135.6, 132.7, 120.0, 119.6, 108.1, 107.9, 107.1,
107.0, 101.0, 100.9, 82.6, 81.4, 73.2, 73.0, 59.1, 58.6, 51.4,
46.5. HRMS (APCIꢀTOF, m/z) calcd for C22H25O7 [M + H]+:
401.1595, found: 401.1594.
Xꢀray crystallographic data for 1a (CIF)
AUTHOR INFORMATION
Corresponding Author
*gshyang@mail.ahnu.edu.cn
Notes
The authors declare no competing financial interest
.
ACKNOWLEDGMENT
Financial support of this project from the NNSFC (Nos. 21672005,
21472001, 21172002) and the Natural Science Research Fund for
Universities in Anhui Province (KJ2017A709) is gratefully appreꢀ
ciated.
Procedure for the Conversion of cisꢀ3ab to 11. In a
glovebox, to a solution of the cyclopropane cisꢀ3ab (240 mg,
0.69 mmol) in anhydrous THF (5.0 mL) was added LiBH4 (7.5
mg, 0.35 mmol) at rt and the resulting mixture was stirred for
8 hours. Then the reaction was quenched with saturated NH4Cl
solution (2 mL). The reaction mixture was extracted with ethyl
acetate (3 × 10 mL) and the combined organic layers were
washed with brine (2 × 10 mL), dried with anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure to
yield a crude product. The residue was purified by flash chroꢀ
matography (petroleum ether/ethyl acetate = 10/1) to afford
the γꢀbutyrolactone fused cyclopropane 11 as a colorless oil in
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53%
yield
(85
mg).
Methyl
2ꢀoxoꢀ6ꢀphenylꢀ3ꢀ
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Ibrahem, I.; Zhao, G.ꢀL; Rios, R.; Vesely, J.; Sundén, H.;
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