Synthetic studies toward plakortide E: application of the Feldman oxygenation to synthesis of highly substituted 1,2-dioxolanes

Article abstract of DOI:10.1016/j.tet.2007.02.121

The Feldman radical oxygenation of vinylcyclopropanes is successfully applied to the synthesis of the highly substituted core of the 1,2-dioxolane natural product, plakortide E. The ratio of the desired cis-1,2-dioxolane can be enhanced by choice of cyclo

Full text of DOI:10.1016/j.tet.2007.02.121

Tetrahedron 63 (2007) 6296–6305
Synthetic studies toward plakortide E: application of the Feldman
oxygenation to synthesis of highly substituted 1,2-dioxolanes
Qiong Zhaoa and Henry N. C. Wonga,b,c,d,
*
aShanghai–Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry,
The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai, China
bDepartment of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
cCenter of Novel Functional Molecules, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
dInstitute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
Received 21 January 2007; revised 24 February 2007; accepted 27 February 2007
Available online 2 March 2007
Abstract—The Feldman radical oxygenation of vinylcyclopropanes is successfully applied to the synthesis of the highly substituted core of
the 1,2-dioxolane natural product, plakortide E. The ratio of the desired cis-1,2-dioxolane can be enhanced by choice of cyclopropane
substituents.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Bloodworth and co-workers prepared four non-natural
five-membered ring plakinic acids in racemic form via
sequential peroxymercuration and in situ reduction with
sodium borohydride.3 A recent article disclosed that Lewis
acid-mediated annulation reactions of alkenes with peroxy-
carbenium ions enable the preparation of 1,2-dioxolanes,
and triethylsilyl-protected peroxycarbenium ions are most
suitable for these reactions.4 Based on the elegant synthetic
routes developed in his laboratory,5 Dussault achieved for
the first time the asymmetric synthesis and configurational
assignment of plakinic acid A in 2006.5h A regio- and stereo-
selective opening of an enantiomerically enriched oxetane
by hydrogen peroxide led to a hydroperoxyalcohol, which
was elaborated into the 1,2-dioxolanic product (Scheme 1).
The chemistry of five-membered peroxides (1,2-dioxolanes)
has been rejuvenated in the last decades because some of the
naturally occurring five-membered peroxides isolated from
terrestrial or marine sources (such as the marine sponges
Plakortis sp.) exhibit remarkable bioactivities including
antimalarial, antifungal, antiviral, and cytotoxic properties.1
We have been interested in the synthesis of molecules
isolated from the Jamaican marine sponge Plakortis hali-
chondrioides of which plakortide E (1) is one of our targets.
Plakortide E presents challenging issues due to its unknown
absolute configuration, lack of stereochemical assignment
for C10, and the presence of the two tertiary peroxide centers
in the 1,2-dioxolane.1a
However, despite these and other approaches for the synthe-
sis of five-membered ring peroxides, no synthesis has been
reported for any member of the plakortide family, which
features tertiary, allylic, peroxide subunits. In this paper,
we describe the first synthesis of a cis-1,2-dioxolane con-
taining suitable substitution and functionality for elaboration
to plakortide E.
Et
Et
4
10
CO2H
6O
O
2
plakortide E (1)
Although many methods have been developed in the past to
construct the peroxide ring, most of them demand low
temperature operations and mild conditions, and the yields
are less than satisfactory because such products contain
a weak O–O bond.2 Recently, significant progress has been
made in the synthesis of five-membered cyclic peroxides.
2. Results and discussion
The salient feature in our strategy is a radical [3+2] oxygen-
ation of highly substituted vinylcyclopropanes, a reaction
that introduces two tertiary peroxide linkages in a single
step.6 The retrosynthetic pathway is depicted in Figure 1.
Keywords: Peroxide; Plakortide E; Feldman reaction; Radical; Five-
membered ring.
The key intermediate diethyl 1,2-diethyl-1,2-cyclopropane-
dicarboxylate (5) was prepared by the McCoy procedure
* Corresponding author. Tel.: +852 2609 6329; fax: +852 2603 5057;
e-mail: hncwong@cuhk.edu.hk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.121

Q. Zhao, H. N. C. Wong / Tetrahedron 63 (2007) 6296–6305
6297
OOH OH
Ph
8
:
O
a
+
Ph
OOH OH
1
Ph
OOH OH
OOTBS
c
b
Ph
Ph
O
O
O O
O O
O
OMe
d
Ph
Ph
SEt
O
O
O O
e
CO H
CO H
2
2
+
Ph
Ph
3.3 : 1
O
O
CO H
2
Ph
OOH OH
plakinic acid A
+
Ph
O
O
CO H
2
Ph
Scheme 1. Reagents and conditions: (a) Me3SiOTf, H2O2, Et2O, ꢀ78 ꢁC, 57%; (b) LiN(SiMe3)2, t-BuMe2SiCl, Dess–Martin periodinane, 80%; (c) HF,
MeOCH2CH2OH, two days, 88%; (d) TiCl4, H2C]C(OSiMe3)SEt, ꢀ50 to 0 ꢁC, 88%; (e) NaOMe, MeOH, LiOH, H2O2, THF, 92%.
Et
Et
Et
Et
10
X
CO2H
CO2H
6O
+
O 4
2
O
O
2
3
plakortide E (1)
Et
Et
Et
Et
CO2Et
EtO2C
CO2Et
5
4
Figure 1. Retrosynthetic analysis for plakortide E.
starting from ethyl a-chlorobutyrate (6) and ethyl a-ethyl-
acrylate (7).7 In the cyclopropanation, solvent exerts marked
effect on the isomer ratio, so we were able to synthesize
either of the two isomers in a stereoselective manner by
changing the solvent (Scheme 2).
and the subsequent Horner–Emmons reaction with triethyl
phosphonoacetate led to the unsaturated ester cis-11.10
Deprotection of cis-11 with 3 M HCl afforded cis-12,11
which was again submitted to Swern oxidation to give
cis-13. The expected product of olefination, cis-4 was not
isolated but instead underwent rapid Cope rearrangement
to furnish cycloheptadiene 14 (Scheme 3).
Because of the cis configuration of plakortide E, our syn-
thesis began with diethyl cis-1,2-diethyl-1,2-cyclopropane-
dicarboxylate (cis-5). After reduction with LiAlH4, we
obtained diol cis-8,8 which was monoprotected with
t-BuMe2SiCl.8 Swern oxidation of cis-9 generated cis-10,9
We therefore changed our strategy to focus on a trans-divinyl
cyclopropane as a precursor for the radical oxygenation.
trans-13, available from trans-5 (49%, six steps), underwent
Et
EtO2C
Et
Et
Et
NaH
Et
CO2Et
Et
CO2Et
+
EtO2C
CO2Et
20-30 °C
CO2Et
Cl
6
7
cis-5
trans-5
solvent
toluene
100/0
82
benzene/HMPA
cis/trans
yield(%)
1/2.5
80
Scheme 2.

6298
Q. Zhao, H. N. C. Wong / Tetrahedron 63 (2007) 6296–6305
Et
EtO2C
Et
Et
Et
Et
Et
a
c
b
HO
TBSO
CO2Et
OH
OH
ci s-5
cis-8
cis-9
Et
Et
Et
Et
Et
Et
d
e
O
TBSO
TBSO
HO
CO2Et
Et
CO2Et
Et
cis-10
cis-11
cis-12
Et
Et
Et
O
Et
g
f
CO2Et
CO2Et
CO2Et
14
cis-13
cis-4
Scheme 3. Reagents and conditions: (a) LiAlH4, Et2O, 0 ꢁC to reflux, 87%; (b) TBSCl, Et3N, CH2Cl2, 0 ꢁC, 78%; (c) (COCl)2, DMSO, CH2Cl2, ꢀ78 ꢁC, 81%;
(d) NaH, (EtO)2P(O)CH2CO2Et, THF, rt, 72%; (e) 3 M HCl, THF, 0 ꢁC to rt, 95%; (f) (COCl)2, DMSO, CH2Cl2, ꢀ78 ꢁC, 81%; (g) Ph3P+CH3Iꢀ, n-BuLi, THF,
0 ꢁC, 14%.
6 steps
49%
EtO2C
Et
Et
Et
O
Et
a
CO2Et
Et
Et
CO2Et
CO2Et
trans-13
trans-5
trans-4
Et
Et
Et
Et
b
CO2Et
CO2Et
Et
+
Et
O
O
O O
cis-15
CO2Et
trans-4
trans-15
Scheme 4. Reagents and conditions: (a) Ph3P+CH3Iꢀ, n-BuLi, THF, ꢀ78 ꢁC, 76%; (b) Ph2Se2, AIBN, O2, MeCN, 0 ꢁC, 88%.
olefination to furnish trans-4.10b Irradiation with a 300 W
sunlamp at 0 ꢁC under an atmosphere of O2 and in the pres-
ence of catalytic amounts of Ph2Se2 and AIBN furnished
1,2-dioxolane 15 in 88% yield (Scheme 4)6 and as a 1/7
mixtureofdiastereomers(1H, HPLC). Thetransconfiguration
of the major diastereomer was established by NOE studies
(Fig. 2).
outcome of this transformation depends primarily upon the
nature of the substituents.6e
To clarify the situation, we prepared a series of vinylcyclo-
propanes and subjected them to the peroxidation. A trans-
2-vinylcyclopropane carboxylic acid (trans-18), prepared
in three steps from trans-10 (Scheme 5), was converted
to an amide (trans-19),12 esters trans-2013 and trans-2114
(Scheme 6). In all three substrates, the acyl group is consid-
ered a radical-stabilizing substituent.
Thus the Feldman protocol entirely suits our purpose as we
have realized the construction of 1,2-dioxolanes with both
oxygen atoms linking to tertiary carbon centers. While
both experimental6a–d and computational results6e support
the notion that the cis-products should predominate in the
[3+2] radical addition, however, the major products from
the peroxidation of compound 4 have a trans configuration.
We sought to increase the proportion of cis-product, which
was desired as a precursor for plakortide E.
The peroxidation results are summarized in Table 1. As for
23 and 25, the peroxidation at 30–40 ꢁC for two days
cat. AIBN
O O
cat. Ph2Se2
R
+ O2
R
hv , 0°C
In the accepted mechanism for the peroxidation (Fig. 3),6c
the dioxolane stereochemistry is set during ring closure of
substituted 5-hexenylperoxy radical. The stereochemical
.
.
PhSe
PhSe
PhSe
R
O O
.
nOe
PhSe
R
.
Ha
Et
Hb
O
O
Et
.
.
O
O
.
O O
.
CO2Et
PhSe
R
PhSe
nOe
R
Figure 2. NOESY results of trans-15.
Figure 3.

Q. Zhao, H. N. C. Wong / Tetrahedron 63 (2007) 6296–6305
6299
Et
Et
a
O
Et
H
N
a
Et
OTBS
Et
trans-10
Et
OTBS
O
trans-19
Ph
trans-16
b
Et
CO2H
trans-18
Et
b
c
Et
Et
Et
Et
CO2Me
trans-20
Et
CO2H
trans-18
Et
c
Et
OH
Et
trans-17
Et
O
Scheme 5. Reagents and conditions: (a) Ph3P+CH3Iꢀ, n-BuLi, THF, 0 ꢁC to
rt, 95%; (b) p-TsOH, MeOH/CH2Cl2, 94%; (c) (COCl)2, DMSO, CH2Cl2,
ꢀ78 ꢁC; NaClO2, KHPO4, resorcinol, t-BuOH/H2O, 70%.
N
O
O
tra ns-21
Et
Et
d
Et
OH
furnished very high yields of 1,2-dioxolanes. To our disap-
pointment, the cis/trans ratios are lower than for the original
oxygenation to furnish 15, in fact, amide 19 reacted to only
furnish trans-23 in which the diastereoisomer ratio is 1/1.
These products were isolated and purified by standard
Ph
trans-17
trans-22
Scheme 6. Reagents and conditions: (a) (COCl)2, CH2Cl2, (R)-1-methyl-
benzyl amine, Et3N, CH2Cl2, rt, 65%; (b) CH2N2, Et2O, 0 ꢁC, 94%; (c)
(COCl)2, CH2Cl2, oxazolidin-2-one, n-BuLi, THF, ꢀ78 ꢁC, 75%; (d)
(COCl)2, DMSO, CH2Cl2, ꢀ78 ꢁC; Ph3P+CH2PhBrꢀ, n-BuLi, THF, 0 ꢁC
to rt, 71%.
1
methods, with cis/trans ratios determined by H NMR and
HPLC methods. The trans configurations of the major dia-
stereomers were all established by NOE studies. Peroxides
23, 24, and 25 are as stable as 15 upon prolonged storage
at room temperature.
The Feldman group performed a utilized ab initio compu-
tation at the MP2/6-31G*//UHF/6-31G* level to gain an
Table 1
Ph2Se2
AIBN,
Et
Et
Et
Et
R
hv, O2
R
Et
R
+
Et
MeCN,
0 °C or 25-40 °C
O
O O
O
Substrate
Products
Yield (%)
88
cis/trans
1/7
Et
Et
Et
Et
CO2Et
Et
CO2Et
Et
CO2Et
O O
cis-15
O O
trans-15
trans-4
O
O
Et
Et
Et
Et
N
H
Ph
Ph
N
H
Ph
Ph
O O
cis-23a
O O
trans-23a
Et
H
N
Et
+
quant
trans
Ph
O
trans-19
O
O
NH
Et
NH
Et
Et
Et
O O
cis-23b
O O
trans-23b
Et
Et
Et
Et
Et
CO2Me
CO2Me
CO2Me
Et
Et
75
1/22
1/13
O O
cis-24
O O
trans-20
trans-24
O
Et
O
O
Et
Et
Et
O
O
O
Et
N
N
N
O
quant
O O
O O
O
O
trans-21
trans-25
cis-25
Et
Et
Et
Et
Ph
Et
Ph
Et
82
1/2.8
Ph
O O
O
O
trans-26
trans-22
cis-26

6300
Q. Zhao, H. N. C. Wong / Tetrahedron 63 (2007) 6296–6305
W
W
SePh
D
O
O
D
O
O
O
O
O O
SePh
Chair-like
trans
Chair-like
cis
Figure 4.
3. Conclusion
HO
Et
Et
Et
Et
Et
O
Et
i, ii
Ph
OH
OH
HO
We have successfully synthesized the five-membered cyclic
peroxide fragment of plakortide E via a radical oxygenation
of cyclopropanes. By modification of the cyclopropane sub-
stituents, we improved the cis/trans ratio from 1/7 to 1/2.8,
and obtained the key synthetic precursor cis-27 from trans-
5 in eight steps with a 7% overall yield. Further linkage of
the side chain with the cis-peroxide and the total synthesis
of plakortide E are under investigation.
O
O
O
O
O
26(cis/trans=1/2.8)
trans-27
cis-27
Scheme 7. Reagents and conditions: (i) O3, CH2Cl2, ꢀ78 ꢁC; (ii) NaBH4,
ꢀ78 ꢁC to rt, 80%.
understanding of structural correlation for the cis/trans ratio
of the products.6e Their results indicate that in a favorable
chair-like transition state, an electron-withdrawing group
would prefer an axial disposition that leads to a trans-
product. On the other hand, electron-donating group will
occupy an equatorial position to give a cis-product (Fig. 4).
4. Experimental
4.1. General
Accordingly, we investigated oxygenation of trans-22,15
which contains an electron-rich styrenyl substituent
(Scheme 7). Radical oxygenation under similar conditions
as above furnished the 1,2-dioxolane 26 as an inseparable
1/2.8 mixture of cis/trans isomers. This was the best result
among the five substrates tested (Table 1). This result might
suggest that the aryl group plays an important role in the
stereocontrol process, possibly by p–p stacking with the
phenylseleno group in the radical intermediate (Fig. 5).
1H NMR spectra were recorded on a Bruker AM-300
(300 MHz) or on a Varian Mercury 300 (300 MHz) spec-
trometer. 13C NMR spectra were recorded on a Bruker
DPX-400 (100.4 MHz) or on a Varian Mercury 300
(75.3 MHz) spectrometer, in CDCl3 with tetramethylsilane
(TMS) as internal standard. The following abbreviations are
used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br s, broad singlet. Infrared (IR) spectra were measured on
a Bio-Rad FTS-185 spectrophotometer. Elemental analyses
were performed in an Elemantar Vario EL apparatus. High-
resolution mass spectra (MS) were measured on a Kratos
Concept 1H or on a Bruker Daltonics FTMS-7 instrument.
Solvents were dried and purified according to standard
procedures. Column chromatography was carried out with
Qingdao Haiyang silica gel (300–400 mesh).
The mixture was subjected to ozonolysis, which on reduc-
tive workup with NaBH4 gave two chromatographically
separable diols 27 (Scheme 7). The cis-27 is the key syn-
thetic precursor for plakortide E, which would be used in
the following linkage of the side chain and the peroxide
ring.
4.1.1. Diethyl cis-1,2-diethylcyclopropane-1,2-dicarboxyl-
ate (cis-5). A stirred suspension of sodium hydride (60%
suspension in mineral oil, 2.5 g, 63 mmol) in dry toluene
(10 mL) was treated under nitrogen with ethyl 2-chloro-
butyrate (7.5 g, 50 mmol) and ethyl 2-ethylacrylate (6.4 g,
50 mmol). The reaction temperature was maintained between
20 and 40 ꢁC. After the addition, the reaction was monitored
with TLC. At the end, residual sodium hydride was destroyed
by addition of a small amount of methanol. Sufficient water
(15 mL) was added to dissolve the sodium halide, and the
mixture was extracted with Et2O (20 mLꢂ3), washed with
water (50 mL) and brine (50 mL), dried over MgSO4, and
concentrated. The residual oil was distilled under reduced
pressure to give cis-5 as a colorless oil (9.9 g, 82%); bp:
1
130 ꢁC/10 torr; H NMR: d 4.07–4.14 (q, 4H, J¼7.5 Hz),
1.95–2.02 (m, 2H, J¼7.5 Hz), 1.87 (d, 1H, J¼4.5 Hz), 1.43–
1.50 (m, 2H, J¼7.5 Hz), 1.24 (t, 6H, J¼7.5 Hz), 1.01 (t, 6H,
J¼7.5 Hz), 0.66 (d, 1H, J¼4.5 Hz); 13C NMR: d 180.9,
66.1, 32.8, 29.8, 23.8, 21.2, 11.6; IR (film, cmꢀ1): 1726,
1380, 1328, 1246, 1189, 1149; m/z 242 (M+); HRMS
C13H22O4 (M+) required 242.1518, found 242.1516.
4.1.2. Diethyl trans-1,2-diethylcyclopropane-1,2-dicarb-
oxylate (trans-5). To a suspension of sodium hydride
Figure 5. Peroxy radical intermediate from trans-22 optimized with
UMPWB1K/6-31G* method (not complete).

Q. Zhao, H. N. C. Wong / Tetrahedron 63 (2007) 6296–6305
6301
(60% suspension in mineral oil, 12.2 g, 0.3 mol) in dry
HMPA (130 mL) under nitrogen was added a solution of 6
(38.7 g, 0.26 mmol) and 7 (33.6 g, 0.26 mmol) in benzene
(130 mL) dropwise. The reaction temperature was main-
tained between 20 and 40 ꢁC. At the end of the reaction, a
small amount of methanol was added, which was followed
by water (650 mL). The mixture was extracted with Et2O
(650 mLꢂ1, 400 mLꢂ2), and the combined organic extracts
were washed with water (1000 mL) and brine (1000 mL),
dried over MgSO4, filtered, and concentrated. The residual
oil was purified by flash chromatography (hexane/EtOAc,
20/1) to give firstly trans-5 (36 g, 57%) followed by cis-5
1H, J¼4.8 Hz), 0.21 (d, 1H, J¼4.8 Hz), 0.11 (s, 3H), 0.10
(s, 3H); 13C NMR: d 66.9, 66.2, 33.6, 32.4, 25.9, 24.0,
23.8, 20.9, 20.8, 18.2, 11.7, 11.7; IR (film, cmꢀ1): 3497,
1471, 1256, 1053, 838; m/z 272 (M+). Anal. Calcd for
C15H32O2Si: C 66.11, H 11.84. Found: C 66.15, H 11.93.
4.1.6. trans-1,2-Diethyl-2-(hydroxymethyl)-[(tert-butyl-
dimethylsiloxy)methyl]cyclopropane (trans-9). It was pre-
pared in the same manner as cis-9 in 82% yield; H NMR:
1
d 3.72 (d, 1H, J¼10.8 Hz), 3.67 (d, 1H, J¼10.5 Hz), 3.54
(d, 1H, J¼10.5 Hz), 3.41 (d, 1H, J¼10.8 Hz), 1.40–1.72
(m, 4H, J¼7.5 Hz), 0.98 (t, 3H, J¼7.5 Hz), 0.94 (t, 3H,
J¼7.5 Hz), 0.89 (s, 9H), 0.30 (d, 1H, J¼4.8 Hz), 0.28
(d, 1H, J¼4.8 Hz), 0.04 (s, 3H), 0.04 (s, 3H); IR (film,
cmꢀ1): 3364 (br s, OH), 1473, 1256, 1077. Anal. Calcd for
C15H32O2Si: C 66.11, H 11.84. Found: C 66.00, H 11.95.
1
(14.5 g, 23%); H NMR: d 4.13–4.25 (m, 4H, J¼7.5 Hz),
1.98–2.14 (m, 2H, J¼7.5 Hz), 1.33 (s, 2H), 1.28 (t, 6H,
J¼7.5 Hz), 1.07–1.20 (m, 2H, J¼7.5 Hz), 0.93 (t, 6H,
J¼7.5 Hz); 13C NMR: d 171.4, 60.7, 37.7, 23.3, 19.9, 14.1,
11.4; IR (film, cmꢀ1): 1729, 1458, 1234, 1182; m/z 242
(M+); HRMS C13H22O4 (M+) required 242.1518, found
242.1513.
4.1.7. cis-1,2-Diethyl-2-[(tert-butyldimethylsiloxyl)-
methyl]cyclopropanecarboxaldehyde (cis-10). A solution
of DMSO (0.13 mL, 1.85 mmol) in CH2Cl2 (2 mL) was
added to a solution of oxalyl chloride (0.07 mL, 0.74 mmol)
in CH2Cl2 (2 mL) at ꢀ78 ꢁC over 30 min, followed by
a solution of cis-9 (200 mg, 0.74 mmol) in CH2Cl2 (2 mL).
The resulting mixture was stirred at the same temperature
for 30 min, and then Et3N (0.5 mL, 3.7 mmol) was added.
After another 20 min, water (10 mL) and CH2Cl2 (10 mL)
were added, and the whole was partitioned. The aqueous
layer was extracted with CH2Cl2 (20 mLꢂ3). The combined
organic layers were successively washed with 1% HCl
(30 mL), H2O (30 mL), saturated NaHCO3 (30 mL), and
brine (30 mL), and dried over Na2SO4. After removal of
the solvents, the crude product was purified by column
chromatography (hexane/EtOAc, 40/1) to give cis-10 as a
4.1.3. cis-1,2-Diethyl-1,2-bis(hydroxymethyl)cyclopro-
pane (cis-8). To a stirred suspension of lithium aluminum
hydride (2.8 g, 74 mmol) in Et2O (70 mL) at 0 ꢁC was added
a solution of cis-5 (8.6 g, 35.5 mmol) in Et2O (30 mL). Upon
complete disappearance of cis-5, the reaction mixture was
quenched with water (2.8 mL), then 15% sodium hydroxide
(2.8 mL), and finally water (8.4 mL). The mixture was
filtered through Florisil and the filter cake was washed
with Et2O (20 mLꢂ3). The filtrate was dried over MgSO4
and evaporated by rotary evaporation. Further purification
by flash chromatography (hexane/EtOAc, 4/1) gave cis-8
1
as a colorless viscous oil (4.88 g, 87%); H NMR: d 4.02
(d, 2H, J¼12.0 Hz), 3.36 (d, 2H, J¼12.0 Hz), 2.90 (s, 2H),
1.75–1.90 (m, 2H, J¼7.5 Hz), 1.23–1.41 (m, 2H,
J¼7.5 Hz), 1.01 (t, 6H, J¼7.5 Hz), 0.33 (d, 1H, J¼4.8 Hz),
0.24 (d, 1H, J¼4.8 Hz); 13C NMR: d 66.0, 32.5, 23.6, 21.0,
11.6; IR (film, cmꢀ1): 3338 (br s, OH), 1467, 1207; HRMS
C9H18O2Na (M++Na) required 181.1199, found 181.1198.
1
colorless oil (0.16 g, 81%); H NMR: d 9.33 (s, 1H), 3.86
(d, 1H, J¼11.2 Hz), 3.42 (d, 1H, J¼11.2 Hz), 1.55–1.91
(m, 4H), 1.42 (d, 1H, J¼4.8 Hz), 0.98 (t, 3H, J¼7.5 Hz),
0.96 (t, 3H, J¼7.5 Hz), 0.84 (s, 9H), 0.70 (d, 1H,
J¼4.8 Hz), 0.01 (s, 3H), 0.01 (s, 3H); IR (film, cmꢀ1):
1711 (C]O), 1257, 1087, 838. Anal. Calcd for
C15H30O2Si: C 66.61, H 11.18. Found: C 67.04, H 11.06;
HRMS C15H31O2Si (M++H) required 271.2088, found
271.2101.
4.1.4. trans-1,2-Diethyl-1,2-bis(hydroxymethyl)cyclopro-
pane (trans-8). It was prepared in the same manner as
1
cis-8 in 88% yield; H NMR: d 3.8 (d, 2H, J¼11.4 Hz),
3.42 (d, 2H, J¼11.4 Hz), 2.44 (s, 2H), 1.74–1.89 (m, 2H,
J¼7.5 Hz), 1.35–1.50 (m, 2H, J¼7.5 Hz), 0.98 (t, 6H,
J¼7.5 Hz), 0.28 (s, 2H); 13C NMR: d 63.2, 32.8, 21.7, 19.0,
11.0; IR (film, cmꢀ1): 3333 (br s, OH), 1467, 1027; HRMS
C9H18O2Na (M++Na) required 181.1199, found 181.1195.
4.1.8. trans-1,2-Diethyl-2-[(tert-butyldimethylsiloxyl)-
methyl]cyclopropanecarboxaldehyde (trans-10). It was
prepared in the same manner as cis-10 in 87% yield; H
1
NMR: d 9.30 (s, 1H), 3.69 (d, 1H, J¼11.2 Hz), 3.60 (d,
1H, J¼11.2 Hz), 1.76–1.91 (m, 2H), 1.47–1.74 (m, 2H),
1.35 (d, 1H, J¼4.8 Hz), 0.96 (t, 3H, J¼7.5 Hz), 0.93 (t,
3H, J¼7.5 Hz), 0.90 (s, 9H), 0.87 (d, 1H, J¼4.8 Hz), 0.06
(s, 3H), 0.06 (s, 3H); IR (film, cmꢀ1): 1708 (C]O); m/z
270 (M+); HRMS C15H31O2Si (M++H) required 271.2088,
found 271.2090.
4.1.5. cis-1,2-Diethyl-2-(hydroxymethyl)-[(tert-butyl-
dimethylsiloxy)methyl]cyclopropane (cis-9). To a solution
of cis-8 (275 mg, 1.74 mmol) and triethylamine (0.5 mL,
3.6 mmol) in CH2Cl2 (2 mL) at 0 ꢁC was added tert-butyl-
dimethylsilyl chloride (263 mg, 1.74 mmol) in CH2Cl2
(2 mL). After 2 h at 0 ꢁC, a white precipitate formed. The
reaction mixture was washed with water (5 mL), dried
over Na2SO4, filtered, and concentrated to give a yellow
oil, which was purified by flash chromatography (hexane/
EtOAc, 40/1) to give cis-9 as a colorless oil (0.37 g, 78%);
1H NMR: d 4.04 (d, 1H, J¼11.4 Hz), 3.87 (d, 1H,
J¼12.0 Hz), 3.36 (d, 1H, J¼11.4 Hz), 3.33 (d, 1H,
J¼12.0 Hz), 1.8–1.95 (m, 1H, J¼7.5 Hz), 1.68–1.8 (m,
1H, J¼7.5 Hz), 1.2–1.40 (m, 2H, J¼7.5 Hz), 1.01 (t, 3H,
J¼7.5 Hz), 0.97 (t, 3H, J¼7.5 Hz), 0.91 (s, 9H), 0.30 (d,
4.1.9. Ethyl 3-[cis-1,2-diethyl-2-(tert-butyldimethylsiloxy-
methyl)cyclopropyl]acrylate (cis-11). To a 0 ꢁC sus-
pension of NaH (0.45 g, 11.4 mmol) in THF (20 mL) was
added a solution of ethyl diethylphosphonoacetate (2.55 g,
11.4 mmol) in THF (10 mL). After stirring for 0.5 h,
cis-10 (2.18 g, 8 mmol) in THF (20 mL) was added slowly.
The reaction mixture was warmed to room temperature,
stirred overnight, and quenched by slow addition of satu-
rated NH4Cl (40 mL). The mixture was extracted with

6302
Q. Zhao, H. N. C. Wong / Tetrahedron 63 (2007) 6296–6305
EtOAc (50 mLꢂ2). The combined extracts were washed
with water (50 mL) and brine (50 mL), dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography (hexane/EtOAc, 40/1) to furnish cis-11 as
4.1.13. Ethyl 3-(cis-1,2-diethyl-2-formylcyclopropyl)-
acrylate (cis-13). It was prepared in a similar manner as
cis-10. Swern oxidation of cis-12 (0.55 g, 2.4 mmol) fur-
nished, after flash chromatography (hexane/EtOAc, 20/1),
1
1
a colorless oil (1.96 g, 72% yield); H NMR: d 6.98 (d,
cis-13 (0.44 g, 82%); H NMR: d 9.06 (s, 1H), 6.93 (d,
1H, J¼16 Hz), 5.76 (d, 1H, J¼16 Hz), 4.15–4.22 (q, 2H,
J¼7.5 Hz), 3.67 (d, 1H, J¼10.5 Hz), 3.27 (d, 1H,
J¼10.5 Hz), 1.41–1.79 (m, 4H), 1.29 (t, 3H, J¼7.5 Hz),
0.97 (t, 3H, J¼7.5 Hz), 0.94 (t, 3H, J¼7.5 Hz), 0.85 (s,
9H), 0.84 (d, 1H, J¼4.8 Hz), 0.47 (d, 1H, J¼4.8 Hz), 0.00
(s, 3H), 0.00 (s, 3H); IR (film, cmꢀ1): 1720, 1259. Anal.
Calcd for C19H36O3Si: C 67.01, H 10.65. Found: C 66.83,
H 10.70.
1H, J¼15.6 Hz), 6.91 (d, 1H, J¼15.6 Hz), 4.16–4.23 (q,
2H, J¼7.2 Hz), 1.5–2.0 (m, 4H), 1.79 (d, 1H, J¼5.7 Hz),
1.30 (t, 3H, J¼7.2 Hz), 1.07 (d, 1H, J¼5.7 Hz), 0.99 (t,
6H, J¼7.5 Hz); 13C NMR: d 201.4, 166.2, 147.8, 123.0,
60.6, 45.4, 38.6, 25.8, 24.5, 20.6, 14.4, 12.1, 11.4; IR
(film, cmꢀ1): 3454, 1739. Anal. Calcd for C13H20O3: C
69.61, H 8.99. Found: C 69.41, H 9.13; m/z 224 (M+);
HRMS C13H20O3 (M+) required 224.1412, found 224.1375.
4.1.10. Ethyl 3-[trans-1,2-diethyl-2-(tert-butyldimethyl-
siloxymethyl)cyclopropyl]acrylate (trans-11). It was pre-
pared in the same manner as cis-11. The crude product
resulting from concentration was used without purification.
1H NMR: d 6.91 (d, 1H, J¼16.0 Hz), 5.74 (d, 1H,
J¼16.0 Hz), 4.12–4.17 (q, 2H, J¼7.5 Hz), 3.70 (d, 1H,
J¼10.5 Hz), 3.53 (d, 1H, J¼10.5 Hz), 1.41–1.73 (m, 4H),
1.26 (t, 3H, J¼7.5 Hz), 0.91 (t, 3H, J¼7.5 Hz), 0.86 (s,
9H), 0.85 (t, 3H, J¼7.5 Hz), 0.74 (d, 1H, J¼4.8 Hz), 0.61
(d, 1H, J¼4.8 Hz), 0.01 (s, 3H), 0.01 (s, 3H); 13C
NMR: d 166.8, 152.9, 119.7, 63.8, 59.9, 36.2, 33.2, 25.6,
24.2, 24.1, 23.7, 18.0, 14.1, 11.4, 10.9, ꢀ5.7, ꢀ5.7;
IR (film, cmꢀ1): 1720 (C]O), 1637, 1258, 1176. Anal.
Calcd for C19H36O3Si: C 67.01, H 10.65. Found: C 66.95,
H 10.74.
4.1.14. Ethyl 3-(trans-1,2-diethyl-2-formylcyclopropyl)-
acrylate (trans-13). It was prepared in the same manner as
cis-13 in 86% yield; H NMR: d 9.46 (s, 1H), 6.99 (d, 1H,
1
J¼15.9 Hz), 5.99 (d, 1H, J¼15.9 Hz), 4.21 (q, 2H,
J¼7.2 Hz), 1.58–1.91 (m, 4H), 1.65 (d, 1H, J¼5.1 Hz),
1.31 (t, 3H, J¼7.2 Hz), 1.26 (d, 1H, J¼5.1 Hz), 0.95 (t,
3H, J¼7.2 Hz), 0.92 (t, 3H, J¼7.2 Hz); 13C NMR:
d 201.3, 166.1, 148.3, 121.9, 60.3, 43.8, 39.3, 25.7, 23.7,
21.6, 14.1, 11.9, 11.7; IR (film, cmꢀ1): 1719, 1641, 1459,
1179; m/z 224 (M+); HRMS C13H20O3 (M+) required
224.1412, found 224.1374.
4.1.15. (2Z,5Z)-Ethyl 3,5-diethylcyclohepta-2,5-dienecarb-
oxylate (14). To a stirred suspension of methyltriphenyl-
phosphonium bromide (268 mg, 0.75 mmol) in THF
(2 mL) at 0 ꢁC was added n-BuLi (1.6 M in hexane,
0.38 mL, 0.6 mmol). After 0.5 h, a solution of cis-13
(112 mg, 0.5 mmol) in THF (2 mL) was added in one por-
tion. The reaction mixture was allowed to warm to room
temperature, stirred overnight, and poured into saturated
aqueous NH4Cl (5 mL), extracted with Et2O (10 mLꢂ2),
dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash chromatography (hexane/EtOAc,
4.1.11. Diethyl 3-(cis-1,2-diethyl-2-hydroxymethylcyclo-
propyl)acrylate (cis-12). To a solution of cis-11 (68 mg,
0.2 mmol) in THF (2 mL) at 0 ꢁC was added aqueous HCl
(3 M, 0.7 mL, 2 mmol). The reaction was warmed to room
temperature and stirred until the reactant disappeared
(TLC). The reaction mixture was extracted with EtOAc
(10 mLꢂ3) and washed with aqueous NaHCO3 (5%,
15 mL) and brine (15 mL). The solution was dried over
Na2SO4, filtered, and concentrated. The residue was purified
by flash chromatography (hexane/EtOAc, 3/1) to give cis-12
1
40/1) to give 14 as a colorless oil (16 mg, 14% yield); H
NMR: d 5.40 (d, 1H, J¼5.1 Hz), 5.31 (d, 1H, J¼5.1 Hz),
4.16 (q, 2H, J¼10.2 Hz), 3.49 (q, 2H, J¼10.2 Hz), 3.39–
3.46 (m, 1H), 2.93 (d, 1H, J¼17.7 Hz), 2.55 (d, 1H,
J¼17.7 Hz), 2.42 (t, 3H, J¼6.9 Hz), 1.94–2.09 (m, 4H),
1.01 (t, 3H, J¼7.2 Hz), 0.99 (t, 3H, J¼7.5 Hz); IR (film,
cmꢀ1): 1737, 1462, 1264; m/z 222 (M+); HRMS C14H22O2
(M+) required 222.1620, found: 222.1621.
1
as a colorless oil (43 mg, 95%); H NMR: d 6.98 (d, 1H,
J¼15.6 Hz), 5.82 (d, 1H, J¼15.6 Hz), 4.15–4.22 (q, 2H,
J¼7.5 Hz), 3.69 (d, 1H, J¼12.0 Hz), 3.43 (d, 1H, J¼12.0 Hz),
1.45–1.82 (m, 4H), 1.6–1.8 (1H), 1.29 (t, 3H, J¼7.5 Hz), 1.00
(t, 3H, J¼7.5 Hz), 0.94 (t, 3H, J¼7.5 Hz), 0.88 (d, 1H,
J¼4.8 Hz), 0.56 (d, 1H, J¼4.8 Hz); IR (film, cmꢀ1): 3443
(br s, OH), 1717, 1634, 1179. Anal. Calcd for C13H22O3:
C 68.99, H 9.80. Found: C 68.81, H 10.03.
4.1.16. Ethyl 3-(trans-1,2-diethyl-2-vinylcyclopropyl)-
acrylate (trans-4). It was prepared in 76% yield in the
same manner as 14 except that the initial temperature was
ꢀ78 ꢁC; 1H NMR: d 6.98 (d, 1H, J¼15.9 Hz), 5.80 (d, 1H,
J¼15.9 Hz), 5.89 (dd, 1H, J¼15.9, 10.8 Hz), 5.17 (dd, 1H,
J¼10.5, 1.8 Hz), 5.03 (dd, 1H, J¼10.5, 1.8 Hz), 4.20 (q,
2H, J¼7.2 Hz), 1.40–1.60 (m, 4H), 1.30 (t, 3H, J¼7.5 Hz),
0.96 (d, 1H, J¼4.8 Hz), 0.90 (d, 1H, J¼4.8 Hz), 0.88 (t,
3H, J¼7.5 Hz), 0.87 (t, 3H, J¼7.5 Hz); 13C NMR:
d 166.9, 152.1, 138.7, 120.4, 116.2, 60.1, 38.8, 34.7, 29.7,
26.7, 25.0, 23.7, 14.3, 11.5; IR (film, cmꢀ1): 1720, 1636,
1262; m/z 222 (M+); HRMS C14H22O2 (M+) required
222.1620, found: 222.1616.
4.1.12. Diethyl 3-(trans-1,2-diethyl-2-hydroxymethyl-
cyclopropyl)acrylate (trans-12). It was prepared in the
same manner as cis-12 in 91% yield (two steps); 1H NMR:
d 6.93 (d, 1H, J¼15.3 Hz), 5.80 (d, 1H, J¼15.3 Hz), 4.15–
4.22 (q, 2H, J¼7.5 Hz), 3.75 (d, 1H, J¼12.0 Hz), 3.69
(d, 1H, J¼12.0 Hz), 2.05 (s, 1H), 1.41–1.80 (m, 4H), 1.30
(t, 3H, J¼7.5 Hz), 0.94 (t, 3H, J¼7.5 Hz), 0.93 (t, 3H,
J¼7.5 Hz), 0.84 (d, 1H, J¼4.8 Hz), 0.69 (d, 1H,
J¼4.8 Hz); 13C NMR: d 166.8, 152.3, 119.9, 63.5, 60.0,
39.5, 33.4, 24.3, 24.0, 23.6, 14.0, 11.5, 10.9; IR (film,
cmꢀ1): 3449 (br s, OH), 1717, 1635, 1180. Anal. Calcd for
C13H22O3: C 68.99, H 9.80. Found: C 68.87, H 9.94; m/z
227 (M+); HRMS C13H22O3Na (M++Na) required
249.1461, found 249.1473.
4.1.17. Ethyl 3-(3,5-diethyl-5-vinyl-1,2-dioxolan-3-yl)-
acrylate (15). To a stirring solution of the vinylcyclopropane
trans-4 (222 mg, 1 mmol) in CH3CN (10 mL) at 0 ꢁC was

Q. Zhao, H. N. C. Wong / Tetrahedron 63 (2007) 6296–6305
6303
added diphenyl diselenide (32 mg, 0.1 mmol) and AIBN
(13 mg, 0.08 mmol). The reaction was placed under
a balloon of oxygen and irradiated with a 300 W sunlamp.
When starting material was consumed as shown by TLC,
the reaction mixture was concentrated in vacuo, and the resi-
due was purified by flash chromatography (hexane/EtOAc,
10/1) to afford 15 as a colorless oil (224 mg, 88%). The
cis/trans ratio was shown to be 1/7 by HPLC (Chiralcel
AD-H column, 210 nm, hexane/2-propanol, 99/1, flow
rate, 0.7 mL/min) tR¼9.28, 10.02, 11.13, 12.19 min; trans-
15: 1H NMR: d 6.86 (d, 1H, J¼15.9 Hz), 6.05 (d, 1H,
J¼15.9 Hz), 5.79 (dd, 1H, J¼15.9, 10.8 Hz), 5.26 (dd, 1H,
J¼10.5, 1.8 Hz), 5.17 (dd, 1H, J¼10.5, 0.9 Hz), 4.20 (q,
2H, J¼7.2 Hz), 2.59 (d, 1H, J¼12.3 Hz), 2.37 (d, 1H,
J¼12.3 Hz), 1.56–1.90 (m, 4H), 1.30 (t, 3H, J¼7.5 Hz),
0.92 (t, 3H, J¼7.5 Hz), 0.89 (t, 3H, J¼7.5 Hz); 13C NMR:
d 166.3, 148.4, 138.5, 120.6, 115.2, 88.6, 60.4, 53.4, 30.9,
30.8, 14.1, 8.7, 8.6; cis-15: 1H NMR: d 6.98 (d, 1H,
J¼15.9 Hz), 6.11 (d, 1H, J¼15.9 Hz), 5.87 (dd, 1H,
J¼17.1, 10.8 Hz), 5.29 (dd, 1H, J¼10.5, 0.9 Hz), 5.21 (dd,
1H, J¼10.5, 0.9 Hz), 4.21 (q, 2H, J¼7.5 Hz), 2.53 (d, 1H,
J¼12.3 Hz), 2.43 (d, 1H, J¼12.3 Hz), 1.56–1.90 (m, 4H),
1.31 (t, 3H, J¼7.5 Hz), 0.88 (t, 3H, J¼7.5 Hz), 0.86 (t,
3H, J¼7.5 Hz); 13C NMR: d 166.5, 149.3, 140.1, 120.0,
114.3, 87.6, 60.4, 52.6, 30.2, 30.2, 14.1, 8.6, 8.5; IR (film,
cmꢀ1): 1720, 1657, 1463, 1305; m/z 254 (M+); HRMS
C14H22O4 (M+) required 254.1518, found: 254.1545.
KH2PO4 (8 g), resorcinol (2.64 g, 24 mmol), and NaClO2
(2.16 g, 24 mmol). The mixture was stirred at room temper-
ature until all aldehyde was consumed. The aqueous layer
was saturated with NH4Cl and extracted with EtOAc
(50 mLꢂ2). The aqueous layer was adjusted to pH 4–5 with
10% HCl, and again extracted with EtOAc (50 mLꢂ2). The
combined organic extracts were dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash chroma-
tography (hexane/EtOAc, 5/1) to give trans-18 as a colorless
oil (1.89 g, 70%); 1H NMR: d 12.03 (br s, 1H), 5.87 (dd, 1H,
J¼10.5, 17.4 Hz), 5.21 (dd, 1H, J¼1.85, 10.5 Hz), 5.05 (dd,
1H, J¼1.5, 17.4 Hz), 1.99–2.96 (m, 1H), 1.60–1.76 (m, 1H),
1.42–1.56 (m, 1H), 1.11–1.29 (m, 1H), 1.34 (d, 1H,
J¼4.8 Hz), 0.97 (t, 3H, J¼7.5 Hz), 0.90 (t, 3H, J¼7.5 Hz),
0.88 (d, 1H, J¼4.8 Hz); 13C NMR: d 180.4, 137.7, 117.1,
38.6, 36.6, 25.0, 23.9, 20.9, 11.8, 11.0; IR (film, cmꢀ1):
3337, 1689; m/z 168 (M+); HRMS C10H16O2 (M+) required
168.1150, found: 168.1131.
4.1.21. trans-1,2-Diethyl-N-((R)-1-phenylethyl)-2-vinyl-
cyclopropanecarboxamide (trans-19). Oxalyl chloride
(0.11 mL, 1.3 mmol, 1.5 equiv) was added dropwise to
a solution of trans-18 (0.15 g, 0.89 mmol) in dry CH2Cl2
(15 mL). The resulting mixture was heated at reflux for 2 h,
cooled, and evaporated in vacuo to afford an acid chloride,
which was redissolved in dry CH2Cl2 (10 mL). To the solu-
tion was added Et3N (0.17 mL, 1.2 mmol) and (R)-1-methyl-
benzylamine (0.13 mL, 0.12 g, 1 mmol) under argon at
ambient temperature. After stirring for 20 h, the reaction
mixture was quenched with water (10 mL), and extracted
with CH2Cl2 (20 mLꢂ3). The combined extracts were
washed with 10% NaHCO3 (50 mL) and brine (100 mL).
The extracts were dried over Na2SO4, filtered, and concen-
trated. The residue was purified by flash chromatography
(hexane/EtOAc, 5/1) to afford trans-19 as a white powder
4.1.18. trans-1,2-Diethyl-1-(tert-butyldimethylsiloxy-
methyl)-2-vinylcyclopropane (trans-16). It was prepared
by a similar procedure as employed for 14, Wittig reaction
of trans-10 (4.7 g, 17.4 mmol) furnished, after flash chroma-
tography (hexane), trans-16 (4.44 g, 95%); 1H NMR: d 5.86
(dd, 1H, J¼10.5, 17.1 Hz), 5.07 (d, 1H, J¼1.8, 10.5 Hz),
4.94 (dd, 1H, J¼1.8, 17.1 Hz), 3.70 (d, 1H, J¼10.2 Hz),
3.55 (d, 1H, J¼10.2 Hz), 1.36–1.64 (m, 4H), 0.91 (t, 3H,
J¼7.5 Hz), 0.89 (s, 9H), 0.86 (t, 3H, J¼7.5 Hz), 0.57 (d,
1H, J¼4.8 Hz), 0.34 (d, 1H, J¼4.8 Hz), 0.04 (s, 6H); IR
(film, cmꢀ1): 1472, 1255, 1083; m/z 268 (M+). Anal. Calcd
for C16H32OSi: C 71.57, H 12.01. Found: C 71.74, H 11.82.
1
(0.158 g, 65%); H NMR: d 7.21–7.44 (m, 5H), 5.88 (d,
1H, J¼7.8 Hz), 5.82 (dd, 0.5H, J¼10.5, 17.1 Hz), 5.77
(dd, 0.5H, J¼10.5, 17.1 Hz), 5.13–5.26 (m, 2H), 5.00 (dd,
0.5H, J¼1.8, 17.1 Hz), 4.99 (dd, 0.5H, J¼1.8, 17.1 Hz),
1.72–1.95 (m, 1H), 1.57–1.73 (m, 1H), 1.51 (d, 1.5H,
J¼7.2 Hz), 1.50 (d, 1.5H, J¼7.2 Hz), 1.10–1.31 (m, 2H),
1.07 (d, 1H, J¼4.8 Hz), 0.94 (t, 3H, J¼7.5 Hz), 0.87 (t, 3H,
J¼7.5 Hz), 0.71 (d, 1H, J¼4.8 Hz); 13C NMR: d 171.4,
143.1, 138.0, 128.5 (128.5), 127.3 (127.2), 126.3 (126.2),
116.8, 48.6 (48.6), 39.2 (39.2), 35.6 (35.4), 26.2, 25.5,
25.3, 24.2, 21.4 (21.3), 18.9, 11.7 (11.2), 11.2 (11.1); IR
(film, cmꢀ1): 3302, 1635, 1536; m/z 271 (M+); HRMS
C18H25NO (M+) required 271.1936, found: 271.1944.
4.1.19. (trans-1,2-Diethyl-2-vinylcyclopropyl)methanol
(trans-17). To a solution of trans-16 (3.75 g, 13.7 mmol)
in CH2Cl2/MeOH (15/30 mL) was added p-TsOH (0.25 g,
1.4 mmol). The reaction was stirred at room temperature un-
til no starting material remained (TLC). After removal of the
solvents, the crude product was purified by column chroma-
tography (hexane/EtOAc, 5/1) to give trans-17 as a colorless
oil (1.99 g, 94%); 1H NMR: d 5.86 (dd, 1H, J¼10.5, 17.1 Hz),
5.11 (d, 1H, J¼1.8, 10.5 Hz), 4.97 (dd, 1H, J¼1.8, 17.1 Hz),
3.68 (q, 2H, J¼10.2 Hz), 2.09 (s, 1H), 1.57–1.92 (m, 1H),
1.32–1.57 (m, 3H), 0.93 (t, 3H, J¼7.5 Hz), 0.92 (t, 3H,
J¼7.5 Hz), 0.65 (d, 1H, J¼4.8 Hz), 0.42 (d, 1H, J¼4.8 Hz);
13C NMR: d 139.8, 115.1, 64.2, 34.6, 33.6, 25.7, 23.3, 20.7,
11.6, 11.1; IR (film, cmꢀ1): 3337; m/z 155 (M++H); HRMS
C10H16 (M+ꢀH2O) required 136.1252, found: 136.1244.
4.1.22. trans-Methyl 1,2-diethyl-2-vinylcyclopropanecarb-
oxylate (trans-20). An ethereal solution of diazomethane
was prepared by stirring a solution of N-methylnitrosourea
(0.62 g, 6 mmol, 2.0 equiv) in Et2O (10 mL) with 50%
KOH (10 mL) at 0 ꢁC for 30 min. The ethereal layer was
separated, dried over solid KOH, and was added dropwise
to a stirred solution of trans-18 (0.5 g, 3 mmol) in Et2O
(10 mL) at 0 ꢁC. The reaction mixture was stirred at this
temperature under nitrogen for 30 min before the excess of
diazomethane was decomposed by the dropwise addition
of HOAc. The reaction was then poured into water
(20 mL) and the mixture extracted with Et2O (30 mLꢂ2).
The combined ethereal extracts were washed with water
(30 mL), 5% NaHCO3 (30 mL), brine (30 mL), dried over
4.1.20. trans-1,2-Diethyl-2-vinylcyclopropanecarboxylic
acid (trans-18). By a similar procedure as employed for
cis-10, Swern oxidation of trans-17 (2.48 g, 16.1 mmol) fur-
nished a crude aldehyde (2.54 g) that was used without puri-
fication in the next step. To a solution of the crude aldehyde
(2.54 g, 16 mmol) in t-BuOH/H2O (215/80 mL) was added

6304
Q. Zhao, H. N. C. Wong / Tetrahedron 63 (2007) 6296–6305
1
Na2SO4, and concentrated. The residue was purified by flash
chromatography (hexane/EtOAc, 20/1) to yield trans-20 as
a colorless oil (520 mg, 96%); H NMR: d 5.83 (dd, 1H,
E/Z ratio is about 3/1 as a colorless oil (0.51 g, 71%); H
NMR: d 7.14–7.46 (m, 5H), 6.46 (d, 1H, J¼12 Hz), 5.90
(dd, 1H, J¼10.8, 17.1 Hz), 5.78 (d, 1H, J¼12 Hz), 5.16
(dd, 1H, J¼1.5, 10.8 Hz), 4.99 (dd, 1H, J¼1.5, 17.1 Hz),
1.14–1.74 (m, 4H), 1.26 (d, 1H, J¼4.8 Hz), 0.94 (t, 3H,
J¼7.5 Hz), 0.84 (t, 3H, J¼7.5 Hz), 0.40 (d, 1H,
J¼4.8 Hz); 13C NMR: d 139.4 (139.7), 137.0 (137.8),
133.3 (132.3), 131.6 (130.6), 129.0 (128.5), 127.8 (126.8),
126.6 (125.9), 115.4 (115.3), 36.6 (35.5), 32.8 (29.7), 27.2
(26.6), 26.5 (26.4), 24.6 (21.2), 12.2 (11.7), 11.6 (11.6); IR
(film, cmꢀ1): 1640, 1601, 1495, 1463, 1450. Anal. Calcd
for C17H22: C 90.20, H 9.80. Found: C 90.51, H 9.60; m/z
226 (M+); HRMS C17H22 (M+) required 226.1722, found:
226.1723.
1
J¼10.5, 17.1 Hz), 5.18 (dd, 1H, J¼1.5, 10.5 Hz), 5.02 (dd,
1H, J¼1.5, 17.1 Hz), 3.68 (s, 3H), 1.89–2.06 (m, 1H),
1.49–1.64 (m, 1H), 1.22–1.36 (m, 1H), 1.28 (d, 1H,
J¼5.1 Hz), 1.04–1.18 (m, 1H), 0.84 (t, 3H, J¼7.5 Hz),
0.89 (t, 3H, J¼7.5 Hz), 0.78 (d, 1H, J¼5.1 Hz); 13C NMR:
d 174.0, 137.9, 116.9, 51.6, 37.2, 25.6, 24.3, 20.4, 12.0,
11.0, 0.9; IR (film, cmꢀ1): 1725, 1459, 1261; m/z 182
(M+); HRMS C11H18O2 (M+) required 182.1307, found:
182.1314.
4.1.23.
trans-3-(1,2-Diethyl-2-vinylcyclopropane-
carbonyl)oxazolidin-2-one (trans-21). Oxalyl chloride
(0.13 mL, 1.5 mmol) was added dropwise to a solution of
18 (0.17 g, 1 mmol) in dry CH2Cl2 (15 mL). The mixture
was heated at reflux for 2 h, cooled, and evaporated in vacuo.
Repeated re-evaporation from dry THF afforded the crude
acid chloride as a gum. A solution of n-BuLi (1.6 M in hex-
ane, 1.3 mL, 2 mmol) was added dropwise over 10 min un-
der argon to a ꢀ70 ꢁC solution of oxazolidin-2-one (90 mg,
1 mmol) in dry THF (2 mL). The mixture was stirred at
ꢀ70 ꢁC for an additional 30 min prior to its addition over
10 min to a solution of the acid chloride obtained above in
dry THF (2 mL). Stirring was continued at ꢀ70 ꢁC for 1 h.
The mixture was then allowed to warm to room temperature
overnight (20 h) and concentrated. The residue was diluted
with water (10 mL), extracted with EtOAc (15 mLꢂ2) and
the combined extracts were washed with water (20 mL),
brine (20 mL), dried over MgSO4, and concentrated. The
residue was purified by flash chromatography (hexane/
Compounds 23–26 were prepared by a similar procedure
as 15.
4.1.25. trans-3,5-Diethyl-N-((R)-1-phenylethyl)-5-vinyl-
1,2-dioxolane-3-carboxamide (23). It was obtained as
a white powder (quantitative); H NMR: d 7.20–7.40 (m,
1
5H), 7.15 (d, 0.5H, J¼8.1 Hz), 7.10 (d, 0.5H, J¼8.1 Hz),
5.87 (dd, 0.5H, J¼10.5, 17.1 Hz), 5.83 (dd, 0.5H, J¼10.5,
17.1 Hz), 5.30 (dd, 0.5H, J¼0.9, 17.1 Hz), 5.29 (dd, 0.5H,
J¼0.9, 17.1 Hz), 5.20 (dd, 0.5H, J¼0.9, 10.5 Hz), 5.19
(dd, 0.5H, J¼0.9, 10.5 Hz), 5.08–5.19 (m, 1H), 2.99 (d,
0.5H, J¼12.9 Hz), 2.90 (d, 0.5H, J¼12.9 Hz), 2.49 (d,
0.5H, J¼12.9 Hz), 2.46 (d, 0.5H, J¼12.9 Hz), 1.93–2.12
(m, 1H), 1.45–1.83 (m, 3H), 1.52 (d, 1.5H, J¼6.6 Hz),
1.51 (d, 1.5H, J¼6.9 Hz), 0.91 (t, 1.5H, J¼7.5 Hz), 0.89 (t,
1.5H, J¼7.5 Hz), 0.78 (t, 1.5H, J¼7.5 Hz), 0.75 (t, 1.5H,
J¼7.5 Hz); 13C NMR: d 172.3 (172.3), 143.2 (143.0),
140.6 (140.4), 128.8 (128.5), 127.2 (127.1), 126.0 (125.8),
114.1 (141.0), 90.4 (90.4), 88.7 (88.6), 51.2 (50.9), 48.3
(48.4), 29.8 (29.7), 28.7 (28.6), 22.3 (21.7), 8.8 (8.7), 8.4
(8.4); IR (film, cmꢀ1): 1654, 1527, 1461; m/z 304 (M++H);
HRMS C18H25NO3Na (M++Na) required 326.1727, found:
326.1724.
1
EtOAc, 5/1) to afford trans-21 (176 mg, 75%); H NMR:
d 5.98 (dd, 1H, J¼10.5, 17.1 Hz), 5.22 (dd, 1H, J¼1.2,
10.5 Hz), 4.98 (dd, 1H, J¼1.5, 17.1 Hz), 4.37–4.45 (m,
2H), 3.95–4.10 (m, 2H), 2.00–2.17 (m, 2H), 1.70–1.85 (m,
2H), 1.11 (d, 1H, J¼5.7 Hz), 0.87 (t, 3H, J¼7.5 Hz), 0.85
(t, 3H, J¼7.5 Hz), 0.78 (d, 1H, J¼5.7 Hz); 13C NMR:
d 173.3, 152.1, 137.7, 117.1, 61.8, 43.0, 40.0, 37.5, 29.5,
26.7, 23.5, 11.9, 11.0; IR (film, cmꢀ1): 1790, 1778, 1682;
m/z 237(M+); HRMS C13H19NO3Na (M++Na) required
260.1257, found: 260.1257.
4.1.26. Methyl 3,5-diethyl-5-vinyl-1,2-dioxolane-3-
carboxylate (24). It was obtained as a colorless oil (75%);
1H NMR: d 5.82 (dd, 1H, J¼10.8, 17.4 Hz), 5.26 (dd, 1H,
J¼1.5, 17.7 Hz), 5.15 (dd, 1H, J¼1.5, 11.1 Hz), 3.77 (s,
3H), 2.99 (d, 1H, J¼12.9 Hz), 2.42 (d, 1H, J¼12.9 Hz),
1.82 (q, 2H, J¼7.5 Hz), 1.62 (q, 2H, J¼7.5 Hz), 0.85 (t,
3H, J¼7.5 Hz), 0.83 (t, 3H, J¼7.5 Hz); 13C NMR:
d 173.4, 140.2, 114.1, 89.6, 88.4, 52.4, 50.2, 29.6, 28.2,
8.7, 8.4; IR (film, cmꢀ1): 1737, 1461; HRMS C11H18O4Na
(M++Na) required 237.1097, found: 237.1100.
4.1.24. trans-(2-(1,2-Diethyl-2-vinylcyclopropyl)vinyl)-
benzene (trans-22). It was prepared by a similar procedure
as employed for cis-10. Swern oxidation of trans-17 (0.5 g,
3.2 mmol) furnished a crude aldehyde (0.45 g) that was used
without purification in the next step. Benzyltriphenylphos-
phonium bromide (1.73 mg, 4 mmol) was suspended in
anhydrous THF (15 mL) under nitrogen. n-BuLi (1.6 M in
hexane, 2.5 mL, 4 mmol) was added into the reaction flask
dropwise at 0 ꢁC. After warming to room temperature, the
resulting ylide mixture was allowed to stir for 30 min and
then cooled to 0 ꢁC again. A solution of the crude aldehyde
(0.45 g, 3 mmol) in THF (10 mL) was added dropwise into
the cooled reaction mixture, and was then allowed to
warm slowly to room temperature. After 20 h, saturated
NH4Cl (10 mL) was added to the mixture followed by
Et2O (30 mL). The organic layer was separated, and the
aqueous layer was extracted with Et2O (30 mLꢂ2). The
combined organic layers were dried over Na2SO4, filtered,
and concentrated. The crude product was purified by flash
chromatography (hexane) to afford trans-22 in which the
4.1.27. 3-(3,5-Diethyl-5-vinyl-1,2-dioxolane-3-carbonyl)-
oxazolidin-2-one (25). It was obtained as colorless crystals
(quantitative); HPLC (Chiralcel AD-H column, 214 nm,
hexane/2-propanol, 95/5, flow rate, 0.7 mL/min) tR¼21.87,
22.95, 24.43, 26.07 min; 1H NMR: d 5.84 (dd, 1H,
J¼10.8, 17.7 Hz), 5.30 (d, 1H, J¼17.1 Hz), 5.19 (dd, 1H,
J¼10.8 Hz), 4.44 (t, 2H, J¼7.5 Hz), 4.01–4.22 (m, 2H),
2.95 (d, 1H, J¼13.5 Hz), 2.72 (d, 1H, J¼13.5 Hz), 1.98–
2.22 (m, 2H), 1.60 (q, 2H, J¼7.2 Hz), 0.87 (t, 3H,
J¼7.5 Hz), 0.83 (t, 3H, J¼7.5 Hz); 13C NMR: d 172.1,
152.2, 140.2, 114.4, 91.5, 88.3, 62.4, 51.1, 44.0, 29.7,
26.3, 8.6, 8.5; IR (film, cmꢀ1): 1796, 1778, 1696, 1479,
1294; m/z 270 (M++H), 292 (M++Na); HRMS

Q. Zhao, H. N. C. Wong / Tetrahedron 63 (2007) 6296–6305
6305
C13H19NO5Na (M++Na) required 292.1155, found:
292.1153.
for a Shanghai Studentship. The authors would like to thank
Professors Li-Xin Dai, Xue-Long Hou, Xin-Xiang Xu,
Tse-Lok Ho, and Dr. Yu-Xue Li for helpful discussion.
4.1.28. 3,5-Diethyl-3-styryl-5-vinyl-1,2-dioxolane (26). It
was obtained as a colorless oil (82%), HPLC (Chiralcel
AD-H column, 230 nm, hexane/2-propanol, 99.5/0.5, flow
rate, 0.3 mL/min) tR¼16.68, 15.57, 18.81, 20.05 min;
cis-27: 1H NMR: d 7.18–7.46 (m, 5H), 6.60 (d, 1H,
J¼16.8 Hz), 6.19 (d, 1H, J¼16.8 Hz), 5.87 (dd, 1H,
J¼10.5, 17.1 Hz), 5.29 (d, 1H, J¼17.1 Hz), 5.17 (d,
1H, J¼10.5 Hz), 2.64 (d, 1H, J¼12 Hz), 2.38 (d, 1H,
J¼12 Hz), 1.58–1.91 (m, 4H), 0.96 (t, 3H, J¼7.5 Hz), 0.90
(t, 3H, J¼7.5 Hz); 13C NMR: d 142.3, 139.5, 130.9, 129.7,
128.5, 127.6, 126.4, 114.9, 88.6, 88.5, 54.0, 31.6, 31.0, 9.0,
References and notes
1. (a) Patil, A. D.; Freyer, A. J.; Bean, M. F.; Carte, B. K.; Westley,
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1
8.8; trans-27: H NMR: d 7.18–7.46 (m, 5H), 6.64 (d, 1H,
J¼16.8 Hz), 6.22 (d, 1H, J¼16.8 Hz), 5.89 (dd, 1H,
J¼10.5, 17.1 Hz), 5.31 (d, 1H, J¼17.1 Hz), 5.19 (d,
1H, J¼10.5 Hz), 2.52 (s, 2H), 1.58–1.91 (m, 4H), 0.93 (t,
3H, J¼7.5 Hz), 0.88 (t, 3H, J¼7.5 Hz); 13C NMR: d 140.3,
136.8, 131.9, 129.0, 128.6, 127.6, 126.5, 114.2, 88.7, 88.6,
53.4, 31.1, 30.6, 9.0, 8.8; IR (film, cmꢀ1): 1732, 1643,
1601, 1495, 1462, 1450; m/z 259 (M++H); HRMS
C17H23O2 (M++H) required 259.1693, found: 259.1705.
3. (a) Bloodworth, A. J.; Courtneidge, J. L. J. Chem. Soc., Perkin
Trans. 1 1982, 1807; (b) Bloodworth, A. J.; Chan, K. H.;
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A. J.; Curtis, R. J.; Mistry, N. J. Chem. Soc., Chem. Commun.
1989, 954; (d) Bloodworth, A. J.; Bothwell, B. D.; Collins,
A. N.; Maidwell, N. L. Tetrahedron Lett. 1996, 37, 1885.
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Trans. 1 2000, 3006; (d) Dussault, P. H.; Trullinger, T. K.;
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L. L. J. Org. Chem. 1960, 25, 2078; (c) McCoy, L. L. J. Am.
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4.1.29. (3,5-Diethyl-1,2-dioxolane-3,5-diyl)dimethanol
(27). To a ꢀ78 ꢁC solution of 26 (110 mg, 0.4 mmol) in
CH2Cl2 (4 mL) was bubbled O3. After the mixture turned
light blue and TLC analysis displayed little or no starting
material, ozonolysis was stopped and the ozone was
removed by passage of O2 or N2 through the solution.
NaBH4 (15 mg, 0.44 mmol) was added to the reaction mix-
ture at the same temperature and the reaction was slowly
(5 h) brought to room temperature. The reaction was diluted
with water (2 mL) and the mixture extracted with EtOAc
(15 mLꢂ2). The organic extracts were dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified
by flash chromatography (hexane/EtOAc, 2/1–1/1) to afford
firstly trans-27 (45 mg, 59%), followed by cis-27 (16 mg,
1
21%); trans-27: H NMR: d 3.72 (d, 2H, J¼11.7 Hz), 3.42
(d, 2H, J¼11.7 Hz), 2.22–2.58 (br s, 2H), 2.03 (s, 2H),
1.71–1.88 (m, 2H), 1.46–1.64 (m, 2H), 0.93 (t, 6H,
J¼7.5 Hz); 13C NMR: d 89.4, 64.3, 44.5, 24.9, 9.1; IR
(film, cmꢀ1): 3372 (br s), 1707, 1463, 1384, 1304; m/z 191
(M++H); HRMS C17H23O2 (M++Na) required 213.1097,
found: 213.1101; cis-27: 1H NMR: d 3.74 (d, 2H,
J¼11.7 Hz), 3.46 (d, 2H, J¼11.7 Hz), 2.6–3.2 (br s, 2H),
2.08 (s, 2H), 1.73–1.88 (m, 2H), 1.50–1.66 (m, 2H), 0.96
(t, 6H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3): d 89.4,
63.8, 44.0, 27.3, 8.6; IR (film, cmꢀ1): 3400 (br s), 1450;
m/z 191 (M++H); HRMS C9H18O4 (M++Na) required
213.1097, found: 213.1097.
Acknowledgements
€
€
14. Hubner, J.; Liebsche, J.; Patzel, M. Tetrahedron 2002, 58,
The work was supported by the Croucher Foundation (Hong
Kong). Q.Z. thanks the Croucher Foundation (Hong Kong)
10485.
15. Lin, Y. L.; Turos, E. J. Org. Chem. 2001, 66, 8751.