Asymmetric [2,3]-Wittig rearrangement of the dienolates of chiral secondary alcohol-substituted β-pyrrolidinyl-γ-allyloxyl-α,β-unsaturated esters: total synthesis of (+)-eldanolide

Article abstract of DOI:10.1016/j.tetasy.2009.07.028

The asymmetric [2,3]-Wittig rearrangement of the dienolates of various chiral β-pyrrolidinyl-γ-allyloxyl-α,β-unsaturated esters was investigated using different chiral secondary alcohol substitutions. When (1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2,2,1]he

Full text of DOI:10.1016/j.tetasy.2009.07.028

Tetrahedron: Asymmetry 20 (2009) 1854–1863
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric [2,3]-Wittig rearrangement of the dienolates of chiral
secondary alcohol-substituted b-pyrrolidinyl-c-allyloxyl-a,b-unsaturated
esters: total synthesis of (+)-eldanolide
a
b
Yu-Jang Li a, , Guo-Ming Ho , Pin-Zu Chen
*
a Department of Applied Chemistry, National Chiayi University, 300 University Road, Chiayi City 600, Taiwan
b Departmet of Applied Chemistry, Chaoyang University of Technology, Wufeng, Taichung County 413, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric [2,3]-Wittig rearrangement of the dienolates of various chiral b-pyrrolidinyl-
,b-unsaturated esters was investigated using different chiral secondary alcohol substitutions. When
(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2,2,1]heptane-1-carboxylic acid diisopropylamide was used
as chiral auxiliary, it provided the best enantioselectivity in the rearrangement. When various -allyloxy
c-allyloxyl-
Received 10 June 2009
Accepted 15 July 2009
Available online 2 September 2009
a
c
substitutions underwent temperature and additive studies, 1,1-dimethylpropenoxy substitution was
found to give the best enantioselectivity. The methodology was applied to the total synthesis of (+)-
eldanolide.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
With the unsaturated esters 5a–5e in hand, compounds 5a–5e
were first subjected to rearrangement studies in order to test their
Recently, we have reported studies of the [2,3]-Wittig rear-
behaviors and efficacies in the [2,3]-Wittig rearrangement. When
reactions were carried out by deprotonation with lithium diisopro-
pylamine (2 equiv) at ꢀ78 °C and then slowly warmed up to room
temperature within a 5-h period, rearrangement of the dienolate of
rangement involving the use of dienolates of achiral b-pyrrolidi-
nyl-
cyclized products could be transformed into
monosubstituted
-lactones,2,3 which are potentially important
c-allyloxyl-a
,b-unsaturated esters.1 Since the resulting
a
,b-unsaturated c-
c
5d provided b-pyrrolidinyl-c-allyl-a,b-unsaturated c-lactone 7 in
starting materials for the synthesis of a variety of natural products,
studies on the asymmetric [2,3]-Wittig rearrangement involving
the chiral version of the unsaturated ester would be of interest.4
Herein, we report our investigation on the asymmetric [2,3]-Wittig
rearrangement related to the use of various chiral second-
48% enantiomeric excess, with the best enantioselectivity among
the rearrangements of dienolates of 5a–e (Scheme 2).
The unsaturated lactone 7 was presumably obtained through a
three-step sequence; the first step, involved the LDA deprotona-
tion; the second step, a [2,3]-Wittig rearrangement, which was
an enantioselection-determining step; and finally, the cyclization
of resulting lithium alkoxides (S)-8 and (R)-8, which were en route
to unsaturated lactones (S)-7 and (R)-7 (Scheme 3). Since the
chemical yield and enantioselectivity of the resulting unsaturated
lactones were highly susceptible to the reaction conditions, espe-
cially temperature changes, the enantioselectivity of the rearrange-
ment of 5d was further optimized through detailed temperature
and additive studies, as shown in Table 1.6 When 5d was reacted
at constant temperature throughout the reaction without the addi-
tion of LiBr (entries 1, 2, 5, and 8), enantioselectivities were found
to decrease when increasing the temperature. Although lower tem-
perature conditions increased the enantioselectivities of the rear-
rangements, temperatures at or below ꢀ40 °C were found to not
be efficient for the rearrangement and the subsequent cyclizations
(entry 1). When LiBr was added for the rest of studies, the enanti-
oselectivities dramatically increased, presumably due to the per-
turbation of lithium aggregation,7 subsequently biasing the
formation of one enantiomer over the other. The temperature of
ary alcohol-substituted b-pyrrolidinyl-c-allyloxyl-a,b-unsaturated
esters.
2. Results and discussion
Our studies commenced with the synthesis of various chiral
secondary alcohol-substituted simple b-pyrrolidinyl- -allyloxyl-
,b-unsaturated esters, as shown in Scheme 1. Reactions of 2-(allyl-
c
a
oxy)acetyl chloride 1 with Meldrum’s acid provide 2 in 95% yield,
and the subsequent treatment of 2 with various chiral secondary
alcohols 3a–3e in refluxing toluene generated chiral ketoesters
4a–4e in 75–86% yields, respectively.5 Finally, condensation of
4a–4e with pyrrolidine successfully provided 5a–5e in 92–97%
yields, respectively (Scheme 1).
* Corresponding author. Tel.: +886 5 2717745; fax: +886 5 2717901.
E-mail address: yjli@mail.ncyu.edu.tw (Y.-J. Li).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.028

Y.-J. Li et al. / Tetrahedron: Asymmetry 20 (2009) 1854–1863
1855
O
O
O
O
O
O
O
O
R*OH 3a-e
O
O
O
O
Cl
O
Toluene
75-86%
Et3N
95%
2
1
OR*
O
O
pyrrolidine
N
O
OR*
PhH
O
92-97%
4a-e
5a-e
OH
O
OH
N
O
R*OH=
OH
Ph
N
OH
3b
O
OH
3a
3c
3d
3e
N
OH
Ph
Scheme 1.
OR*
OR*
O-
O
O
O
2.0 eq LDA
Li+
O
N
N
N
º
-78 C
O
7
6
5a-e
5a, 78%, 18% e.e.
5b, 68%, 40% e.e.
5c, 25%, 18% e.e.
5d, 70%, 48% e.e.
5e, 70%, 45% e.e.
Scheme 2.
OR*
O-
OR*
O
[2,3]-Wittig rearrangement
O
Li+
O
cyclization
O
N
OLi
N
N
N
OR*
H
H
H
H
H
O
TS*A
7
(S)-
8
(S)-
LDA
N
O
OR*
N
OR*
º
-78 C
[2,3]-Wittig rearrangement
O
O-
Li+
cyclization
O
OLi
O
5d
O
N
H
(R)-8
TS*A'
(R)-7
Scheme 3.
ꢀ30 °C was effective for the rearrangement and cyclization (entry
3), which provided a reasonable 86% enantiomeric excess. When
reactions were performed at higher temperatures, similar to cases
without LiBr, the enantioselectivities of the rearrangement deteri-
orated with increasing temperature (entries 6, 7, 9, and 10).
After the completion of studies using simple allyloxyl substitu-
tion, substituted propenoxyl groups such as 2-methyl, 1,1-dimethyl,
and 3,3-dimethyl were used to study their rearrangement. Although
2-methyl-substituted 12 was straightforwardly synthesized, similar
to the synthesis of 5d as shown in Scheme 4, the synthesis of 1,1-di-
methyl and 3,3-dimethyl substitution proved to be more difficult,
partially due to the early introduction of these sensitive alkene
groups. Therefore a synthetic strategy involving the introduction
of these alkenes at a later stage was designed to overcome this prob-
lem. Ketoester 13 was first synthesized in 94% yield by refluxing 3d
with Meldrum’s acid, and then by treating 13 with bromine to afford
bromoketoester 14 in a satisfactory 88% yield. The reaction of so-
dium alkoxide of 15a–b with 14 generated 16a–b in 75–79% yields.
Finally, 17a–b were obtained with the condensation of pyrrolidine
under refluxing benzene conditions in 96–98% yields (Scheme 5).
gem-Dimethyl-substituted 17a was used to study the rear-
rangement, as shown in Scheme 6 and Table 2. While studies indi-
cated that the rearrangement cannot occur efficiently at ꢀ30 °C
(entries 1 and 2), it reacted smoothly to provide unsaturated lac-
tone 18 in good enantoselectivities,8 when reactions were per-
formed at ꢀ20 °C or ꢀ15 °C (entries 4–10). Similar to previous
studies, the addition of LiBr also improved the enantioselectivity,
though less dramatically than in the case of 5d, increasing from

1856
Y.-J. Li et al. / Tetrahedron: Asymmetry 20 (2009) 1854–1863
Table 1
Rearrangement studies of 5d
OR*
O
O
Temp 1a
Temp 2b
eec (%)
Yieldd (%)
2.0 eq LDA
Entry
LiBr (equiv)
O
N
1
2
3
4
0.0
0.0
1.0
1.0
ꢀ40
ꢀ30
ꢀ40
ꢀ30
ꢀ30
ꢀ15
45
48
86
85
26
90
92
92
º
N
-78 C to Temp 1
(S)
O
quenched at Temp 2
17a
18
5
6
7
0.0
1.0
1.0
ꢀ20
ꢀ15
ꢀ20
ꢀ20
ꢀ15
ꢀ15
ꢀ15
ꢀ10
31
74
74
91
93
92
Scheme 6.
Table 2
Rearrangement studies of 17a
8
9
10
0.0
1.0
1.0
30
57
57
92
94
95
Entry
LiBr (equiv)
Temp 1a
Temp 2b
eec (%)
Yieldd (%)
a
b
c
Reaction temperature after LDA deprotonation (3 h).
Quenched temperature.
Enantiomeric excesses of 7 were determined by HPLC column using a chiral
1
2
3
4
5
6
7
8
9
1.0
1.0
0.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
ꢀ30
ꢀ30
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ30
ꢀ25
ꢀ20
ꢀ20
ꢀ10
ꢀ5
N.D.e
N.D.
77
93
95
93
90
87
90
Trace
Trace
86
88
93
90
88
93
90
stationary phase (Chiralpak AD-H, n-hexane/methanol 17:1).
d
Isolated yields.
ꢀ15
ꢀ10
ꢀ5
77% to 93% enantiomeric excess (entry 3 vs entry 4). According to
these studies, the rearrangement of 17a seems to be more stereo-
selective, even without LiBr addition, and also more tolerable over
a broader temperature range. This is presumably due to the exis-
tence of a bulky gem-dimethyl group, which constrained the rota-
tional degree of freedom, therefore rendering steric bias in favor of
one diastereomeric transition state over the other.
10
0
88
92
a
b
c
Reaction temperature after LDA deprotonation (3 h).
Quenched temperature.
Enantiomeric excesses of 18 were determined by HPLC column using a chiral
stationary phase (Chiralpak AD-H, n-hexane/methanol 17:1).
d
Isolated yields.
Not determined.
e
When vinyl methyl-substituted compounds such as 12 and 17b
were used in the reaction studies as shown in Scheme 7, the rear-
rangement of 12 at temperatures above ꢀ20 °C generated 19 in
70–73% yields with moderate enantioselectivities (53–60% ee,
Table 3). In contrast, the rearrangement of 17b did not provide
O
O
O
O
O
O
O
O
R*OH
O
O
O
O
Cl
Toluene 79%
Et3N
92%
10
9
OR*
O
O
O
OH
O
N
OR*=
pyrrolidine
N
O
OR*
O
PhH
98%
11
12
Scheme 4.
O
O
O
OH
3d
O
O
O
O
Br2, CHCl3
88%
N
N
O
O
xylene, 94%
13
OR*
OR*
O
R3
O
R3
O
R4
R4
N
Br
NaH
O
H
O
N
N
O
O
benzene
O
R1
O
or
R2
R1
R2
Dean-Stark
14
HO
HO
16a 79%
16b 75%
17a 96%
17b 98%
15a
15b
Scheme 5.

Y.-J. Li et al. / Tetrahedron: Asymmetry 20 (2009) 1854–1863
1857
OR*
approach,9b upon treatment of 28 with dimethyl cuprate in the pres-
ence of trimethylsilyl chloride gave (+)-eldanolide 21 in 85% yield
and 93% enantioselectivity. Synthetic (+)-21 possessed spectroscopic
O
O
R4
R3
2.0 eq LDA
O
R5
data {e.g., 300 MHz 1H and 75 MHz 13C; ½a 2D6
¼ þ46:5 (c 1.02, MeOH)
ꢁ
N
º
-78 C to Temp 1
N
[lit.9b
pheromone.
½
a 2D0
ꢁ
¼ þ51:5 (c 1.15, MeOH)]} identical to the natural
quenched at Temp 2
O
R4 R5
R3
12
R4=R5=H, R3=Me
R4=R5=Me, R3=H
19
20
17b
3. Conclusion
Scheme 7.
In conclusion, we have demonstrated that chiral second-
ary alcohol-substituted b-pyrrolidinyl-
esters can successfully undergo asymmetric [2,3]-Wittig rear-
rangement to provide -monosubstituted ,b-unsaturated lactone
c-allyloxyl-a,b-unsaturated
Table 3
Rearrangement studies of 12
c
a
in good enantioselectivity. (+)-Eldanolide was successfully synthe-
sized to demonstrate this methodology. Applications of this study
for the synthesis of other natural products are currently in progress
in our laboratory.
Entry
LiBr (equiv)
Temp 1a
Temp 2b
eec (%)
Yieldd(%)
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
ꢀ30
ꢀ30
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ15
ꢀ15
ꢀ15
ꢀ25
ꢀ20
ꢀ20
ꢀ15
ꢀ10
ꢀ5
N.D.e
N.D.
60
65
55
53
44
44
43
Trace
Trace
70
73
72
70
77
72
77
4. Experimental
ꢀ15
ꢀ10
0
Melting points were determined on a Fisher-Jones melting point
apparatus and are uncorrected. Optical rotations were measured at
ambient temperature on a Jasco P-1010 polarimeter using a NaD
(586 nm) lamp quartz cell with a path length of 0.1 dm; abs values
were corrected for the rotation of cell with solvent.
a
b
c
Reaction temperature after LDA deprotonation (3 h).
Quenched temperature.
Enantiomeric excesses of 19 were determined by HPLC column using a chiral
stationary phase (Chiralpak AD-H, n-hexane/methanol 17:1).
1H NMR was recorded at 300 MHz on a Varian Mercury-300 nu-
clear magnetic resonance spectrometer. Chemical shift is reported
in ppm (d) from tetramethylsilane with the solvent resonance of
CDCl3 (7.24 ppm) as the internal standard. Data are reported as fol-
lows: chemical shift (multiplicity {s = singlet, d = doublet, t = trip-
let, q = quartet, br = broad, m = multiplet}, integration, coupling
constant (Hz), and assignment.) (J) refers to the observed coupling
constant(s) in hertz. The chemical shift difference in hertz between
the signals for protons A and B of an AB quartet is Du. As described
in Silverstein, Bassler, and Morririll’s text, a four-line two-spin pat-
tern was analyzed as shown in the figure below and by using the
equation; (a–c) = [(Du)2 + JAB2]0.5. Letting (a–c) = x and rearranging
the equation solves for Du = [(x)2 ꢀ JAB2]0.5. For those examples
where multiples were recognized as the A and B protons of ABmx
pattern, the chemical shift is reported as the midpoint of the
multiplet.
d
Isolated yields.
Not determined.
e
meaningful enantioselectivity, presumably hampered by the exis-
tence of a bulky vinyl gem-dimethyl group at the reacting center,
which prevented the rearrangement from occurring in an orderly
fashion (Table 4).
Table 4
Rearrangement studies of 17b
Entry
LiBr (equiv)
Temp 1a
Temp 2b
eec (%)
Yieldd (%)
1
2
3
1.0
1.0
1.0
ꢀ30
ꢀ20
ꢀ15
ꢀ20
ꢀ5
25
ꢀ11
ꢀ13
40
40
68
ꢀ5
a
b
c
Reaction temperature after LDA deprotonation (3 h).
Quenched temperature.
Enantiomeric excesses of 20 were determined by HPLC column using a chiral
Chemical shift of 13C NMR spectra was also recorded on the Var-
ian Mercurry-200 NMR instrument (50 MHz) using the solvent res-
onance of CDCl3 (d 77.0 ppm) as the internal standard.
stationary phase (Chiralpak AD-H, n-hexane/methanol 17:1).
d
Isolated yields.
Infrared spectra were recorded on a Perkin–Elmer 1600 series
Fourier transform infrared spectrometer. Infrared frequencies are
reported in reciprocal centimeters (cmꢀ1).
Analytical HPLC analyses were performed with a Jasco PU-980
and LDC spectrometer Jasco UV-975 detector using 5um silica col-
umns supplied by HypersilÒ with 250 ꢂ 4.6 mm column. The UV
spectra were recorded with a Jasco V-530 UV/VIS spectrophotom-
eter. Chiral compounds were analyzed using Chiralcel OJ or OD col-
umns supplied by Chiral Technologies Inc.Ò Gmax and gs mean
maximum and shoulder, respectively.
Mass spectra were recorded on a VG-7035 mass spectrometer at
an ionizing voltage of either 70 or 20 eV; alternatively, samples
were analyzed by the Instrumental center of National Science Con-
sul at National Chung Hsing University. Mass spectra are reported
as m/z values for the parent peak M+ and/or the major fragments.
The values in parentheses refer to the relative peak intensities.
Microanalyses were carried out by Instrumental center of National
Science Consul at National Chung Hsing University.
Reaction progress was monitored by analytical thin-layer chro-
matography on Analtech 250 nm hard layer Silica Gel 60 F-250
plates cut into 1 cm ꢂ 5 cm sections. Visualization was effected
Since the rearrangement of 17a was able to achieve reasonable
enantioselectivity, the resulting unsaturated lactone 18 can be
transformed into butenolide and serve as a valuable starting build-
ing block for various natural product syntheses. Eldanolide 21, the
pheromone of the male African sugar stem borer, with a very
similar structure, can be easily synthesized to demonstrate our
methodology.9,10 Since (+)-eldanolide possesses a prenyl group
with the (R)-absolute stereochemistry, (1R,2S,4S)-2-hydroxy-7,7-
dimethylbicyclo[2,2,1]heptane-1-carboxylic acid diisopropylamide
22 was chosen as a chiral auxiliary to start the synthesis. Unsatu-
rated ester 26 was synthesized following the previously designed
protocol, as shown in Scheme 8.
When 26 was deprotonated with LDA at ꢀ78 °C, and then warmed
to ꢀ20 °C for 3 h,
c-prenyl-substituted unsaturated lactone 27 was
obtained in 90% yield with 93% enantiomeric excess. Subsequent
treatment of 27 with lithium in liquid ammonia, followed by the
Cope elimination using metachloroperbenzoic acid provided c-pre-
nyl-substituted butenolide 28 {½a D26
ꢁ
¼ ꢀ125:2 (c 1.15, MeOH) [lit.9b
½
a 2D0
ꢁ
¼ ꢀ130 (c 0.80, MeOH)]}, in two steps in 72% yield (93% ee).
Final introduction of the methyl group, as in Vigneron’s final

1858
Y.-J. Li et al. / Tetrahedron: Asymmetry 20 (2009) 1854–1863
O
O
CON(iPr)2
CON(iPr)2
OH
O
O
O
Br2, CHCl3
85%
xylene, 94%
H
22
H
O
23
O
OR*
OR*
CON(iPr)2
O
O
O
N
H
NaH
Br
O
N
H
O
O
benzene
Dean-Stark
98%
O
Me
O
Me
HO
O
Me
Me
79%
26
24
25
15a
O
Me2CuLi
1) Li/NH3, t-BuOH
LDA
O
O
(R)
N
85% (93% e.e.)
90% (93% e.e.)
2) mCPBA
72% (93% e.e.)
(R)
27
28
O
O
Synthetic [α]25D = +46.5
Natural [α]25D = +51.5
Me
(R)
21 (+)-Eldanolide
Scheme 8.
by ultraviolet light (254 nm), followed by dipping the plate into the
appropriate stain and then charring on a hot plate. [15% (w/v) sol-
vent of phosphoromolybdic acid and 95% ethanol (PMA); or 1.8%
(w/v) solution of anisaldehyde, 2.5% concentrated sulfuric acid,
0.07% acetic acid, and 95% ethanol (Anisaldehyde); or 0.6% (w/v)
solution of potassium permanganate, 6.1% potassium carbonate,
1.5% of 5% aq NaOH, and water (permanganate)].
cyclohexane for infrared spectra, HPLC analyses, and optical rota-
tions were labeled as spectroscopic grade by the manufacturer.
Reagents were purchased from the Aldrich Chemical Company,
Fluka, and Lancaster Synthesis.
4.2. General procedure for the synthesis of ketoesters
Flash chromatography was performed on silica gel 230–400
mesh, eluted with appropriate solvents.
4.2.1. Synthesis of 4-allyloxy-3-oxo-butyric acid (1S,2R)-1,7,7-
trimethyl-bicyclo[2.2.1]hept-2-yl ester 4a
Reactions requiring heating were immersed in thermostat-
controlled silicon-oil baths. The low temperature baths were
dry ice/acetone (ꢀ78 °C), dry ice/CCl4 (ꢀ20 °C), and ice water
(0 °C). Reactions, which were maintained at low temperature
for extended periods of time, were kept in Neslab thermostat-
controlled Cryobath with stirrer. Reactions other than those in
which water was present as a solvent, reagent or by-product
were normally performed under a slight positive pressure of
nitrogen in vessels, which had been flame-dried under a slow
nitrogen flow and sealed with rubber septa. The nitrogen gas
was dried by passing it through a drying tube filled with Drie-
riteÒ. Additions of liquid to the vessels were made via a syringe
or a cannula through septa. Solid was added through open septa.
All reactions were stirred with Teflon-coated magnetic stir bars.
Removal of solvents was normally accomplished using a Jasco ro-
tary evaporator connected to a vacuum pump. The flask was
heated, if necessary, by a warm water bath. Samples were lyoph-
ilized on a labconco Freeze dryer at a pressure of approximately
0.03 mm Hg.
(1S)-endo-(ꢀ)-Borneol (1.1 g, 7.4 mmol) and 2 (1.8 g, 7.4 mmol)
in 25 mL round-bottomed flask with xylene (12 mL) were heated at
reflux under Dean–Stark apparatus. After being refluxed for 3 h,
the xylene was removed under vacuo, and then the crude material
was purified by flash chromatography (n-hexane/ethyl acetate,
10:1) to afford 1.7 g of 4a in 78% yield. 1H NMR (300 MHz, CDCl3)
d 5.93–5.80 (m, 1H), 5.27 (dd, J = 15.5, 1.7 Hz, 1H), 5.20 (dd,
J = 10.4, 1.7 Hz, 1H), 4.92 (ddd, J = 10.0, 3.5, 2.2 Hz, 1H), 4.09 (s,
2H), 4.03 (d, J = 5.6 Hz, 2H), 3.52 (s, 2H), 2.39–0.81 (m, 7H), 0.88
(s, 3H), 0.85 (s, 3H), 0.82 (s, 3H); 13C NMR (50 MHz, CDCl3) d
201.6, 167.1, 133.5, 117.9, 81.1, 74.7, 72.3, 48.8, 47.8, 46.2, 44.8,
36.4, 27.9, 27.0, 19.6, 18.7, 13.3; HRMS-EI calcd for C17H26O4,
294.1831 found 294.1833; MS-EI 294 (M+, 2), 137 (100), 95 (88),
81 (70); ½a 2D6
¼ ꢀ26:4 (c 0.39, CH2Cl2).
ꢁ
4.2.2. Synthesis of 4-allyloxy-3-oxo-butyric acid (1R,2R)-1-
(hydroxy-diphenyl-methyl)-7,7-dimethyl-bicyclo[2.2.1]hept-2-
yl ester 4b
According to the general procedure in 75% yield. 1H NMR
(300 MHz, CDCl3) d 7.69 (d, J = 7.9 Hz, 2 H), 7.54 (d, J = 7.9 Hz,
2H), 7.24–7.01 (m, 6H), 5.83 (m, 1H), 5.28–5.16 (m, 2H), 5.14 (m,
1H), 3.94 (d, J = 5.7 Hz, 2H), 3.87 (s, 2H), 3.60 (s, 2H), 2.29–0.98
(m, 7H), 1.14 (s, 3H), 0.57 (s, 3H); 13C NMR (50 MHz, CDCl3) d
201.3, 164.3, 149.2, 143.3, 133.3, 128.5 (2C), 128.0 (2C), 126.8
(2C), 126.5, 126.1, 126.0 (2C), 118.4, 82.7, 74.6, 72.4, 59.1, 51.4,
47.7, 45.2, 38.3, 31.3, 29.7, 26.9, 24.4, 22.5; HRMS-EI calcd for
C29H34O5, 462.2406 found 462.2411; MS-EI 462 (M+, 1), 183
4.1. Reagents and solvents
The following solvents were distilled directly before use, under
a slightly positive pressure of nitrogen. Diethyl ether and tetrahy-
drofuran were distilled from sodium benzophenone ketyl, and pyr-
idine was distilled from calcium hydride. Methanol was distilled
from magnesium methoxide and methylene chloride was distilled
from calcium hydride. Chloroform, isopropyl alcohol, hexane, and
(100), 123 (20), 105 (56); ½a D26
¼ þ63:6 (c 1.4, CH2Cl2).
ꢁ

Y.-J. Li et al. / Tetrahedron: Asymmetry 20 (2009) 1854–1863
1859
4.2.3. Synthesis of 4-allyloxy-3-oxo-butyric acid (1R,2R)-1-
diethylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl ester 4c
According to the general procedure in 82% yield. 1H NMR
(300 MHz, CDCl3) d 5.90–5.77 (m, 1H), 5.25 (dd, J = 17.3, 1.5 Hz,
1H), 5.19 (dd, J = 10.3, 1.5 Hz, 1H), 5.15 (m, 1H), 4.01 (s, 2H), 3.99
(d, J = 5.6 Hz, 2H), 3.59–3.52 (m, 2H), 3.44 (d, J = 1.0 Hz, 1H, ABq),
3.43 (d, J = 1.0 Hz, 1H, ABq), 3.06 (br, 2H), 2.06–0.61 (m, 7H), 1.29
(s, 3H), 1.11 (s, 3H), 1.04 (t, J = 6.5 Hz, 6H); 13C NMR (50 MHz, CDCl3)
d 201.3, 169.8, 166.1, 133.4, 117.9, 79.5, 74.7, 72.2, 58.7, 51.2, 44.7,
40.5 (2C), 39.5, 29.2, 26.8, 22.5, 21.5, 21.4, 13.9 (2C); HRMS-EI calcd
for C21H33NO5, 379.2359 found 379.2354; MS-EI 379 (M+, 3), 222
1H, ABq), 3.27 (sep, J = 6.7 Hz, 1H), 2.25 (s, 3H), 2.09–0.99 (m,
7H), 1.39 (d, J = 6.7 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.32 (s, 3H),
1.15 (s, 3H), 1.12 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H); 13C
NMR (50 MHz, CDCl3) d 200.1, 169.5, 166.2, 80.3, 59.4, 51.5, 49.8,
47.3, 46.4, 44.8, 44.7, 40.1, 30.6, 29.8, 26.8, 21.8, 21.6, 21.1, 20.6,
20.5; HRMS-EI calcd for C20H33NO4, 351.2410 found 351.2403;
MS-EI 351 (M+, 3), 206 (37), 167 (49), 149 (39), 139 (100), 121
(39), 85 (71); ½a D26
¼ ꢀ16:9 (c 0.19, CH2Cl2).
ꢁ
4.2.8. Synthesis of 4-bromo-3-oxo-butyric acid (1R,2R)-1-
diisopropylcarbamoyl-7, 7-dimethyl-bicyclo[2.2.1] hept-2-yl
ester 14
(94), 139 (72), 72 (100), 58 (80); ½a D26
¼ ꢀ20:3 (c 0.37, CH2Cl2).
ꢁ
To 13 (6.2 g, 17.6 mmol) in 100 mL round-bottomed three-
necked flask with CHCl3 (50 mL) at 0 °C was added dropwise a solu-
tion of bromine (0.9 mL, 17.6 mmol) in CHCl3 (10 mL) through an
addition funnel. After stirring for 30 min at 0 °C, the reaction was al-
lowed to warm to room temperature and then stirred for additional
16 h. Next, H2O (100 mL) was added to quench the reaction, after
which the organic layer was separated and washed by saturated
aqueous sodium bicarbonate until the pH reached neutral 7.0. The
organic layer was washed with brine, dried over anhydrous sodium
sulfate, and then concentrated in vacuo to give a crude material. The
crude material was purified by flash chromatography (n-hexane/
ethyl acetate, 10:1) to afford 6.7 g of product 14 in 88% yield. 1H
NMR (300 MHz, CDCl3) d 5.10 (dd, J = 7.6, 3.5 Hz, 1H), 4.17 (sep,
J = 6.6 Hz, 1H), 4.03 (d, J = 12.8 Hz, 1H, ABq), 3.99 (d, J = 12.8 Hz,
1H, ABq), 3.69 (d, J = 16.0 Hz, 1H, ABq), 3.63 (d, J = 16.0 Hz, 1H,
ABq), 3.27 (sep, J = 6.7 Hz, 1H), 2.09–0.99 (m, 7H), 1.39 (d,
J = 6.7 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.31 (s, 3H), 1.14 (s, 3H),
1.12 (d, J = 6.6 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H); 13C NMR (50 MHz,
CDCl3) d 194.4, 169.5, 165.6, 80.7, 59.4, 51.6, 47.4, 46.5, 45.6, 44.7,
40.0, 34.1, 29.7, 26.8, 21.8, 21.7, 21.1, 20.7, 20.5, 20.4; HRMS-EI calcd
for C20H32BrNO4, 429.1515 found 428.0959; MS-EI 428 (M+, 1), 167
4.2.4. Synthesis of 4-allyloxy-3-oxo-butyric acid (1R,2R)-1-
diisopropylcarbamoyl-7,7-dimethyl-bicyclo-[2.2.1]hept-2-yl
ester 4d
According to the general procedure in 80% yield. 1H NMR
(300 MHz, CDCl3) d 5.84 (m, 1H), 5.34–5.18 (m, 2H), 5.05 (dd,
J = 7.1, 3.9 Hz, 1H), 4.16 (sep, J = 6.6 Hz, 1H), 4.05 (s, 2H), 4.01 (d,
J = 5.5 Hz, 2H), 3.49 (s, 2H), 3.25 (sep, J = 6.7 Hz, 1H), 2.10–0.86
(m, 7H), 1.37 (d, J = 6.6 Hz, 6H), 1.30 (s, 3H), 1.14 (s, 3H), 1.10 (d,
J = 6.7 Hz, 3H), 1.05 (d, J = 6.7 Hz, 3H); 13C NMR (50 MHz, CDCl3)
d 201.6, 169.5, 166.4, 133.4, 118.2, 80.4, 74.8, 72.3, 59.3, 51.5,
47.2, 46.3, 45.5, 44.7, 40.0, 29.8, 29.7, 26.8, 21.8, 21.6, 21.1, 20.6,
20.5; HRMS-EI calcd for C23H37NO5, 407.2672 found 407.2678;
MS-EI 407 (M+, 4), 149 (60), 141 (88), 121 (58), 86 (100); ½a 2D6
¼
ꢁ
ꢀ35:0 (c 0.5, CH2Cl2).
4.2.5. Synthesis of 4-allyloxy-3-oxo-butyric acid (1R,2R)-1-
dicyclohexylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl
ester 4e
According to the general procedure in 86% yield. 1H NMR
(300 MHz, CDCl3) d 5.95–5.77 (m, 1H), 5.29 (dd, J = 17.0, 1.8 Hz,
1H), 5.24 (dd, J = 10.2, 1.8 Hz, 1H), 5.08 (dd, J = 7.2, 3.5 Hz, 1H),
4.08 (s, 2H), 4.03 (d, J = 5.4 Hz, 2H), 3.67 (br, 2H), 3.50 (s, 2H),
2.82–2.70 (m, 4H), 2.60–2.50 (m, 4H), 2.10–0.81 (m, 7H), 2.03–
2.02 (m, 12H), 1.30 (s, 3H), 1.14 (s, 3H); 13C NMR (50 MHz, CDCl3)
d 201.4, 169.6, 166.2, 133.4, 118.0, 80.5, 74.7, 72.2, 60.3, 59.5, 56.9,
56.3, 51.4, 45.5, 44.7, 39.9, 31.6, 31.4, 29.9, 29.8, 26.8, 26.7 (2C),
25.8 (2C), 25.2 (2C), 21.8, 21.5; HRMS-EI calcd for C29H45NO5,
487.3298 found 487.3301; MS-EI 487 (M+, 10), 329 (60), 247
(34), 139 (100), 121 (38), 84 (33); ½a D26
¼ ꢀ20:9 (c 0.2, CH2Cl2).
ꢁ
4.2.9. Synthesis of 4-(1,1-dimethyl-allyloxy)-3-oxo-butyric acid
(1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]
hept-2-yl ester 16a
To NaH (0.19 g, 60%, 4.7 mmol, pre-washed with n-hexane) in a
50 mL round-bottomed three-necked flask with THF (20 mL) at
0 °C was added dropwise a solution of compound 14 (1.0 g,
2.33 mmol) in THF (3 mL). The reaction mixture was stirred for
30 min at 0 °C, after which a solution of 2-methyl-3-buten-2-ol
15a (0.3 mL, 2.33 mmol) in THF (2 mL) was added dropwise into
the reaction, and then allowed to warm to room temperature
slowly, and stirred for additional 6 h at room temperature. The
reaction was quenched by the slow addition of water (20 mL),
the reaction mixture was acidified with aqueous HCl (1 M) to pH
4.0, and then extracted with EtOAc (10 mL ꢂ 2). The combined or-
ganic layer was washed with brine, then dried over anhydrous so-
dium sulfate, and concentrated to give crude material. The crude
material was purified by flash chromatography (n-hexane/ethyl
acetate, 10:1) to afford 0.80 g of product 16a in 79% yield. 1H
NMR (300 MHz, CDCl3) d 5.71 (dd, J = 17.3, 11.0 Hz, 1H), 5.10 (dd,
J = 17.3, 1.6 Hz, 1H), 5.09 (dd, J = 11.0, 1.6 Hz, 1H), 5.06 (dd,
J = 7.3, 4.0 Hz, 1H), 4.19 (sep, J = 6.6 Hz, 1H), 3.91 (s, 2H), 3.57 (d,
J = 16.3 Hz, 1H, ABq), 3.47 (d, J = 16.3 Hz, 1H, ABq), 3.27 (sep,
J = 6.7 Hz, 1H), 2.09–0.99 (m, 7H), 1.39 (d, J = 6.7 Hz, 3H), 1.38 (d,
J = 6.7 Hz, 3H), 1.31 (s, 3H), 1.28 (s, 6H), 1.15 (s, 3H), 1.11 (d,
J = 6.6 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3)
d 202.6, 169.4, 166.6, 142.2, 115.2, 80.2, 76.4, 68.8, 59.2, 51.4,
47.2, 46.2, 45.6, 44.7, 40.0, 29.7, 26.8, 25.5, 25.3, 21.9, 21.5, 21.1,
20.6, 20.5, 20.4; HRMS-EI calcd for C25H41NO5, 435.2985 found
435.2990; MS-EI 435 (M+, 1), 206 (78), 149 (100), 86 (67), 84
(100), 181 (54), 138 (57); ½a D26
¼ ꢀ19:8 (c 0.3, CH2Cl2).
ꢁ
4.2.6. Synthesis of 4-(1-methyl-allyloxy)-3-oxo-butyric acid (1R,
2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-
yl ester 11
According to the general procedure in 79% yield. 1H NMR
(300 MHz, CDCl3) d 5.04 (dd, J = 7.5, 3.7 Hz, 1H), 4.91 (dd, J = 7.0,
0.9 Hz, 2H), 4.17 (sep, J = 6.7 Hz, 1H), 4.03 (d, J = 14.0 Hz, 1H,
ABq), 3.98 (d, J = 14.0 Hz, 1H, ABq), 3.89 (s, 2H), 3.48 (s, 2H), 3.24
(sep, J = 6.7 Hz, 1H), 2.06–0.97 (m, 7H), 1.69 (s, 3H), 1.36 (d,
J = 6.7 Hz, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.28 (s, 3H), 1.12 (s, 3H),
1.08 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H); 13C NMR (50 MHz,
CDCl3) d 201.6, 169.4, 166.3, 140.8, 113.2, 80.4, 75.2, 74.6, 59.2,
51.4, 47.2, 46.3, 45.5, 44.7, 40.0, 29.7, 26.8, 21.8, 21.5, 21.1, 20.6,
20.5, 20.4, 19.3.
HRMS-EI calcd for C24H39NO5, 421.2828 found 421.2822; MS-EI
421(M+, 4), 167(49), 139 (97), 55(100); ½a 2D6
¼ ꢀ37:9(c0.21,CH2Cl2).
ꢁ
4.2.7. Synthesisof 3-oxo-butyric acid(1R,2R)-1-diisopropylcarba-
moyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl ester 13
According to the general procedure in 94% yield. 1H NMR
(300 MHz, CDCl3) d 5.09 (dd, J = 7.6, 3.5 Hz, 1H), 4.18 (sep,
J = 6.6 Hz, 1H), 3.43 (d, J = 15.5 Hz, 1H, ABq), 3.37 (d, J = 15.5 Hz,
(46); ½a 2D6
¼ ꢀ29:0 (c 0.47, CH2Cl2).
ꢁ

1860
Y.-J. Li et al. / Tetrahedron: Asymmetry 20 (2009) 1854–1863
4.2.10. Synthesis of 4-(3-methyl-but-2-enyloxy)-3-oxo-butyric
acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo
[2.2.1] hept-2-yl ester 16b
idine (0.34 mL, 4.1 mmol) and tert-butyl alcohol (0.2 mL). The
reaction mixture was heated to reflux at 100 °C for 40 min using
Dean-Stark apparatus to remove water. After removal of benzene
under vacuo, 1.2 g of 5a was obtained in 98% yield and then
used in the next reaction without further purifications. 1H NMR
(300 MHz, CDCl3) d 5.99–5.86 (m, 1H), 5.28 (dd, J = 17.3, 1.6 Hz,
1H), 5.22 (dd, J = 10.4, 1.6 Hz, 1H), 4.89 (d, J = 11.3 Hz, 1H, ABq),
4.81 (d, J = 11.3 Hz, 1H, ABq), 4.86 (m, 1H), 4.55 (s, 1H), 4.06 (d,
J = 5.7 Hz, 2H), 3.30 (br, 4H), 2.37–0.94 (m, 7H), 1.90 (br, 4H),
0.89 (s, 3H), 0.84 (s, 3H), 0.81 (s, 3H); 13C NMR (50 MHz, CDCl3)
d 169.0, 156.3, 134.7, 117.0, 86.5, 77.5, 71.3, 64.2, 48.6, 47.8,
47.6 (2C), 45.0, 37.0, 28.0, 27.2, 25.1 (2C), 19.7, 18.8, 13.5;
HRMS-EI calcd for C21H33NO3, 347.2460 found 347.2468; MS-EI
Following the same procedure as in the preparation of com-
pound 16a in 75% yield. 1H NMR (300 MHz, CDCl3) d 5.27 (t,
J = 8.5 Hz, 1H), 5.04 (dd, J = 7.2, 3.5 Hz, 1H), 4.16 (sep, J = 6.6 Hz,
1H), 4.00 (s, 2H), 3.98 (d, J = 8.5 Hz, 2H), 3.47 (s, 2H), 3.24 (sep,
J = 6.7 Hz, 1H), 2.07–0.99 (m, 7H), 1.72 (s, 3H), 1.63 (s, 3H), 1.37
(d, J = 6.7 Hz, 3H), 1.36 (d, J = 6.7 Hz, 3H), 1.29 (s, 3H), 1.13 (s,
3H), 1.09 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H); 13C NMR
(50 MHz, CDCl3) d 201.9, 169.4, 166.4, 138.4, 119.9, 80.3, 74.6,
67.7, 51.5, 47.2, 46.3, 45.6, 44.7, 40.0, 29.8, 26.8, 25.7, 21.9, 21.5,
21.1, 20.6, 20.5, 20.4, 20.3, 18.0; HRMS-EI calcd for C25H41NO5,
435.2985 found 435.2981; MS-EI 435 (M+, 1), 206 (78), 149
347 (M+, 12), 194 (100), 139 (71), 95 (58), 81 (56); ½a 2D6
¼
ꢁ
(100), 86 (56); ½a D26
ꢁ
¼ ꢀ26:5 (c 0.6, CH2Cl2).
ꢀ34:7 (c 0.4, CH2Cl2).
4.2.11. Synthesis of 3-oxo-butyric acid (1S,2S)-1-diisopropylcar-
bamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-yl ester 23
4.3.2. Synthesis of 4-allyloxy-3-pyrrolidin-1-yl-but-2-enoic acid
(1R,2R)-1-(hydroxy-diphenyl-methyl)-7,7-dimethyl-
bicyclo[2.2.1] hept-2-yl ester 5b
According to the general procedure in 94% yield. 1H NMR
(300 MHz, CDCl3) d 5.09 (dd, J = 7.6, 3.5 Hz, 1H), 4.18 (sep, J =
6.6 Hz, 1H), 3.43 (d, J = 15.5 Hz, 1H, ABq), 3.37 (d, J = 15.5 Hz, 1H,
ABq), 3.27 (sep, J = 6.7 Hz, 1H), 2.25 (s, 3H), 2.09–0.99 (m, 7H), 1.39
(d, J = 6.7 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.32 (s, 3H), 1.15 (s, 3H),
1.12 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H); 13C NMR (50 MHz,
CDCl3) d 200.1, 169.5, 166.2, 80.3, 59.4, 51.5, 49.8, 47.3, 46.4, 44.8,
44.7, 40.1, 30.6, 29.8, 26.8, 21.8, 21.6, 21.1, 20.6, 20.5;
According to the general procedure in 92% yield. 1H NMR
(300 MHz, CDCl3) d 7.76 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 7.9 Hz, 2H),
7.26–7.02 (m, 6H), 5.93–5.80 (m, 1H), 5.22 (dd, J = 17.3, 1.6 Hz,
1H), 5.14 (dd, J = 10.4, 1.6 Hz, 1H), 5.08 (dd, J = 7.8, 3.8 Hz, 1H),
4.76 (d, J = 11.7 Hz, 1H, ABq), 4.56 (s, 1H), 4.50 (d, J = 11.7 Hz, 1H,
ABq), 3.84 (d, J = 5.7 Hz, 2H), 3.78–3.22 (br, 4H), 2.39–0.85 (m,
7H), 1.86 (br, 4H), 1.53 (s, 3H), 0.55 (s, 3H); 13C NMR (50 MHz,
CDCl3) d 165.8, 157.2, 149.2, 144.0, 134.7, 128.4 (2C), 127.6 (2C),
126.8 (2C), 126.4, 126.0, 116.9, 85.0, 81.4, 79.5, 70.8, 63.8, 59.0,
51.1, 47.8 (2C), 39.2, 39.0, 30.8, 29.7, 27.2, 25.1, 24.6 (2C), 22.7,
16.6; HRMS-EI calcd for C33H41NO4, 515.3036 found 515.3030;
½
a 2D6
ꢁ
¼ þ16:8 (c 0.38, CH2Cl2).
4.2.12. Synthesis of 4-bromo-3-oxo-butyric acid (1S,2S)-1-
diisopropylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1] hept-2-yl
ester 24
MS-EI 515 (M+, 12), 247 (100), 181 (27); ½a 2D6
¼ ꢀ48:2 (c 0.14,
ꢁ
Following the same procedure as in the preparation of com-
pound 14 in 85% yield. 1H NMR (300 MHz, CDCl3) d 5.10 (dd,
J = 7.6, 3.5 Hz, 1H), 4.17 (sep, J = 6.6 Hz, 1H), 4.03 (d, J = 12.8 Hz,
1H, ABq), 3.99 (d, J = 12.8 Hz, 1H, ABq), 3.69 (d, J = 16.0 Hz, 1H,
ABq), 3.63 (d, J = 16.0 Hz, 1H, ABq), 3.27 (sep, J = 6.7 Hz, 1H),
2.09–0.99 (m, 7H), 1.39 (d, J = 6.7 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H),
1.31 (s, 3H), 1.14 (s, 3H), 1.12 (d, J = 6.6 Hz, 3H), 1.06 (d,
J = 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 194.4, 169.5, 165.6,
80.7, 59.4, 51.6, 47.4, 46.5, 45.6, 44.7, 40.0, 34.1, 29.7, 26.8, 21.8,
CH2Cl2).
4.3.3. Synthesis of 4-allyloxy-3-pyrrolidin-1-yl-but-2-enoic acid
(1R,2R)1-diethylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-2-
yl ester 5c
According to the general procedure in 96% yield. 1H NMR
(300 MHz, CDCl3) d 5.95–5.82 (m, 1H), 5.22 (dd, J = 17.2, 1.6 Hz,
1H), 5.12 (dd, J = 10.3, 1.6 Hz, 1H), 5.07 (dd, J = 7.6, 4.0 Hz, 1H),
4.86 (d, J = 11.4 Hz, 1H, ABq), 4.70 (d, J = 11.4 Hz, 1H, ABq), 4.40
(s, 1H), 4.01 (d, J = 5.7 Hz, 2H), 3.61–3.49 (m, 2H), 3.01 (br, 2H),
2.01–0.96 (m, 7H), 1.85 (br, 4H), 1.33 (s, 3H), 1.11 (s, 3H), 1.01 (t,
J = 6.9 Hz, 6H); 13C NMR (50 MHz, CDCl3) d 170.9, 167.6, 156.7,
134.6, 117.0, 85.9, 76.8, 71.2, 64.1, 58.8, 50.9, 47.9 (2C), 45.0,
40.2, 40.1 (2C), 30.3, 27.0, 24.9 (2C), 21.8, 21.7, 14.0 (2C); HRMS-
EI calcd for C25H40N2O4, 432.2988 found 432.2984; MS-EI 432
21.7, 21.1, 20.7, 20.5, 20.4; ½a D26
¼ þ20:7 (c 0.32, CH2Cl2).
ꢁ
4.2.13. Synthesis of 4-(1,1-dimethyl-allyloxy)-3-oxo-butyric
acid (1S,2S)-1-diisopropylcarbamoyl-7,7-dimethyl-bicyclo
[2.2.1]hept-2-yl ester 25
Synthesis starting from 24, following the same procedure as in
the preparation of compound 16a in 79% yield. 1H NMR (300 MHz,
CDCl3) d 5.75 (dd, J = 17.4, 11 Hz, 1H),5.18 (d, J = 17.4 Hz, 1H), 5.13
(d, J = 11 Hz, 1H), 5.06 (dd, J = 7.3, 4.0 Hz, 1H), 4.19 (sep, J = 6.6 Hz,
1H), 3.91 (s, 2H), 3.57 (d, J = 16.3 Hz, 1H, ABq), 3.47 (d, J = 16.3 Hz,
1H, ABq), 3.27 (sep, J = 6.7 Hz, 1H), 2.09–0.99 (m, 7H), 1.39 (d, J =
6.7 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.31 (s, 3H), 1.28 (s, 6H), 1.15
(s, 3H), 1.11 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H); 13C NMR
(50 MHz, CDCl3) d 202.6, 169.4, 166.6, 142.2, 115.2, 80.2, 76.4,
68.8, 59.2, 51.4, 47.2, 46.2, 45.6, 44.7, 40.0, 29.7, 26.8, 25.5, 25.3,
21.9, 21.5, 21.1, 20.6, 20.5, 20.4; HRMS-EI calcd for C25H41NO5,
435.2985 found 435.2990; MS-EI 435 (M+, 1), 206 (78), 149
(M+, 20), 222 (76), 194 (66), 139 (96), 58 (100); ½a 2D6
¼ ꢀ48:0 (c
ꢁ
0.8, CH2Cl2).
4.3.4. Synthesis of 4-allyloxy-3-pyrrolidin-1-yl-but-2-enoic acid
(1R,2R)-1-diisopropylcarbamoyl-7,7-di-methyl-bicyclo[2.2.1]he-
pt-2-yl ester 5d
According to the general procedure in 97% yield. 1H NMR
(300 MHz, CDCl3) d 5.95–5.82 (m, 1H), 5.23 (dd, J = 17.3, 1.6 Hz,
1H), 5.12 (dd, J = 10.4, 1.6 Hz, 1H), 5.00 (d, J = 11.3 Hz, 1H, ABq),
4.97 (dd, J = 7.8, 3.7 Hz, 1H), 4.61 (d, J = 11.3 Hz, 1H, ABq), 4.44 (s,
1H), 4.22 (sep, J = 6.7 Hz, 1H), 4.02 (dt, J = 5.7, 1.5 Hz, 2H), 3.53
(br, 2H), 3.51 (sep, J = 6.7 Hz, 1H), 3.09 (br, 2H), 2.37–1.09 (m,
7H), 1.87 (br, 4H), 1.36 (d, J = 6.7 Hz, 6H), 1.32 (s, 3H), 1.13 (s,
3H), 1.05 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H); 13C NMR
(50 MHz, CDCl3) d 170.4, 167.8, 156.7, 134.6, 117.0, 85.9, 77.6,
71.2, 64.1, 59.4, 51.2, 47.8 (2C), 47.0, 46.0, 45.0, 40.5, 30.0, 27.0,
25.4 (1C), 24.6 (1C), 22.0, 21.7, 21.1, 20.7, 20.5, 20.3; HRMS-EI calcd
for C27H44N2O4, 460.3301 found 460.3296; MS-EI 460 (M+, 20), 194
(100), 86 (67), 84 (46); ½a D26
¼ þ29:0 (c 0.52, CH2Cl2).
ꢁ
4.3. General procedure for the synthesis of vinylogous
urethanes
4.3.1. Synthesis of 4-Allyloxy-3-pyrrolidin-1-yl-but-2-enoic
acid (1S,2R)-1,7,7-trimethyl-bicyclo[2.2.1]hept 2-yl ester 5a
To a solution of 4a (1.0 g, 3.4 mmol) in a 10 mL round-bot-
tomed flask with benzene (10 mL) as solvent were added pyrrol-
(91), 152 (80), 139 (100), 55 (40),; ½a D26
¼ ꢀ15:9 (c 0.1, CH2Cl2).
ꢁ

Y.-J. Li et al. / Tetrahedron: Asymmetry 20 (2009) 1854–1863
1861
4.3.5. Synthesis of 4-allyloxy-3-pyrrolidin-1-yl-but-2-enoic acid
(1R,2R)-1-dicyclohexylcarbamoyl-7,7-dimethyl-bicyclo[2.2.1]hept-
2-yl ester 5e
4.3.9. Synthesis of 4-(1,1-dimethyl-allyloxy)-3-pyrrolidin-1-yl-
but-2-enoic acid (1S,2S)-1-diisopropylcar-bamoyl-7,7-dimethyl-
bicyclo [2.2.1]hept-2-yl ester 26
According to the general procedure in 98% yield. 1H NMR
(300 MHz, CDCl3) d 6.02–5.83 (m, 1H), 5.27 (dd, J = 17.3, 1.7 Hz,
1H), 5.24 (dd, J = 10.3, 1.7 Hz, 1H), 5.10–5.04 (m, 1H), 5.07 (d,
J = 11.4 Hz, 1H, ABq), 4.58 (d, J = 11.4 Hz, 1H, ABq), 4.47 (s, 1H),
4.05 (d, J = 5.8 Hz, 2H), 3.76 (br, 2H), 3.50 (br, 4H), 3.16 (br, 4H),
2.81–2.52 (m, 8H), 2.17–0.84 (m, 7H), 1.96–1.12 (m, 12H), 1.34
(s, 3H), 1.15 (s, 3H); 13C NMR (50 MHz, CDCl3) d 170.8, 167.7,
156.6, 134.7, 128.3, 117.1, 86.1, 71.2, 64.1, 59.8, 56.8, 56.1, 51.2,
48.0 (2C), 45.1, 40.5, 31.8, 31.4, 31.3, 31.0, 29.9, 27.0, 26.8 (2C),
25.9 (2C), 25.3 (4C), 22.1, 21.8; HRMS-EI calcd for C33H52N2O4,
540.3927 found 540.3921; MS-EI 540 (M+, 6), 250 (49), 167 (60),
According to the general procedure in 98% yield. 1H NMR
(300 MHz, CDCl3) d 5.89 (dd, J = 17.6, 10.7 Hz, 1H), 5.16 (dd,
J = 17.6, 1.2 Hz, 1H), 5.12 (dd, J = 10.7, 1.2 Hz, 1H), 4.98 (dd, J = 7.8,
3.2 Hz, 1H), 4.90 (d, J = 10.4 Hz, 1H, ABq), 4.49 (d, J = 10.4 Hz, 1H,
ABq), 4.41 (d, J = 10.0 Hz, 1H, ABq), 4.39 (s, 1H), 4.24 (sep,
J = 6.6 Hz, 1H), 3.52 (br, 2H), 3.22 (sep, J = 6.7 Hz, 1H), 3.09 (br,
2H), 2.02–0.99 (m, 7H), 1.88 (br, 4H), 1.38 (d, J = 6.7 Hz, 3H), 1.36
(d, J = 6.7 Hz, 3H), 1.31 (s, 3H), 1.32 (s, 6H), 1.14 (s, 3H), 1.06 (d,
J = 6.6 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) d
170.5, 167.6, 158.1, 143.3, 114.1, 84.9, 77.4, 75.8, 59.5, 57.6, 51.2,
48.1 (2C), 47.1, 46.0, 45.0, 40.4, 30.0, 27.0, 25.8, 25.5, 24.7 (2C),
22.1, 21.8, 21.2, 20.8, 20.5, 20.4; HRMS-EI calcd for C29H48N2O4,
139 (100), 83 (65); ½a D26
¼ ꢀ40:9 (c 0.15, CH2Cl2).
ꢁ
488.3614 found 488.3615; ½a D26
¼ þ23:8 (c 0.21, CH2Cl2).
ꢁ
4.3.6. Synthesis of 4-(1-methyl-allyloxy)-3-pyrrolidin-1-yl-but-
2-enoic acid (1R,2R)-1-diisopropylcarbamo-yl-7,7-dimethyl-
bicyclo[2.2.1]hept-2-yl ester 12
4.4. General procedure for the [2,3]-Wittig rearrangement of
vinylogous urethanes 5a–e
According to the general procedure in 98% yield. 1H NMR
(300 MHz, CDCl3) d 5.02 (d, J = 11.6 Hz, 1H, ABq), 4.99 (dd, J = 8.1,
3.7 Hz, 1H), 4.95 (dd, J = 2.05, 0.9 Hz, 2H), 4.62 (d, J = 11.6 Hz, 1H,
ABq), 4.46 (s, 1H), 4.24 (sep, J = 6.6 Hz, 1H), 3.94 (s, 2H), 3.60 (br,
2H), 3.22 (sep, J = 6.7 Hz, 1H), 3.13 (br, 2H), 2.04–0.94 (m, 7H),
1.58 (br, 4H), 1.71 (s, 3H), 1.39 (d, J = 6.7 Hz, 3H), 1.38 (d,
J = 6.7 Hz, 3H), 1.34 (s, 3H), 1.15 (s, 3H), 1.07 (d, J = 6.6 Hz, 3H),
1.02 (d, J = 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 170.5, 167.9,
156.8, 142.2, 112.0, 85.9, 77.6, 74.2, 64.1, 59.5, 51.2, 47.9 (2C),
47.1, 46.1, 45.0, 40.5, 30.0, 27.0, 25.4, 24.7, 22.1, 21.8, 21.2, 20.8,
20.5, 20.4, 19.6; HRMS-EI calcd for C28H46N2O4, 474.3458 found
474.3453; MS-EI 474 (M+, 17), 250 (81), 154 (90), 152 (100), 138
4.4.1. Synthesis of 5-allyl-4-pyrrolidin-1-yl-5H-furan-2-one 7
To compound 5d (50.0 mg, 0.1 mmol) with THF (1 mL) at ꢀ78 °C
in a 30 mL round-bottomed flask was added a solution of LDA
(0.25 mL, 0.25 mmol, 1 N in THF/n-hexane), which was then allowed
to warm to room temperature over a period of 6 h. The reaction was
quenched by the addition of aqueous ammonium chloride solution
(1 M, 2 mL), the reaction mixture was extracted with EtOAc
(5 mL ꢂ 2), dried over anhydrous sodium sulfate, and then concen-
trated to give crude material. The crude material was purified by
flash chromatography (n-hexane/acetone, 4:1) to afford 14.7 mg
of product 7 in 70% yield with 48% ee. [HPLC Chiralpak AD-H,
n-hexane/methanol 17:1; 0.5 mL/min; tR = 67.8 min (minor), tR =
80.6 min (major)]. 1H NMR (300 MHz, CDCl3) d 5.91–5.70 (m, 1H),
5.19 (dd, J = 9.0, 1.2 Hz, 1H), 5.15 (dd, J = 15.2, 1.2 Hz, 1H), 4.91 (dd,
J = 6.8, 3.0 Hz, 1H), 4.52 (s, 1H), 3.33 (br, 4H), 2.71 (dd, J = 6.8,
3.0 Hz, 1H), 2.43 (dd, J = 15.2, 9.0 Hz, 2H), 2.08–1.90 (br, 4H); 13C
NMR (50 MHz, CDCl3) d 174.1, 168.2, 131.0, 118.4, 81.2, 78.0, 49.5,
48.2, 35.8, 25.7, 24.3; HRMS-EI calcd for C11H15NO2, 193.1103 found
193.1100.
(70); ½a 2D6
¼ ꢀ44:8 (c 0.2, CH2Cl2).
ꢁ
4.3.7. Synthesis of 4-(1,1-dimethyl-allyloxy)-3-pyrrolidin-1-yl-
but-2-enoic acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-
bicyclo [2.2.1]hept-2-yl ester 17a
According to the general procedure in 96% yield. 1H NMR
(300 MHz, CDCl3) d 5.89 (dd, J = 17.6, 10.7 Hz, 1H), 5.16 (dd,
J = 17.6, 1.2 Hz, 1H), 5.12 (dd, J = 10.7, 1.2 Hz, 1H), 4.98 (dd, J = 7.8,
3.2 Hz, 1H), 4.90 (d, J = 10.4 Hz, 1H, ABq), 4.49 (d, J = 10.4 Hz, 1H,
ABq), 4.39 (s, 1H), 4.24 (sep, J = 6.6 Hz, 1H), 3.52 (br, 2H), 3.22 (sep,
J = 6.7 Hz, 1H), 3.09 (br, 2H), 2.02–0.99 (m, 7H), 1.88 (br, 4H), 1.38
(d, J = 6.7 Hz, 3H), 1.36 (d, J = 6.7 Hz, 3H), 1.31 (s, 3H), 1.32 (s, 6H),
1.14 (s, 3H), 1.06 (d, J = 6.6 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H); 13C
NMR (50 MHz, CDCl3) d 170.5, 167.6, 158.1, 143.3, 114.1, 84.9,
77.4, 75.8, 59.5, 57.6, 51.2, 48.1 (2C), 47.1, 46.0, 45.0, 40.4, 30.0,
27.0, 25.8, 25.5, 24.7 (2C), 22.1, 21.8, 21.2, 20.8, 20.5, 20.4; HRMS-
EI calcd for C29H48N2O4, 488.3614 found 488.3617; MS-EI 488 (M+,
4.5. General procedure for [2,3]-Wittig rearrangement of 5d
with LiBr addition
To 5d (50 mg, 0.11 mmol) in a 5 mL round-bottomed flask with
THF (1 mL) was added a solution of LiBr (0.1 mL, 1.0 M THF) at room
temperature. After the reaction mixture was cooled to ꢀ78 °C, LDA
(1.0 M, 0.25 mL, 0.25 mmol) was added and allowed to warm to
ꢀ30 °C and stirred for an additional 3 h. After being warmed to
ꢀ15 °C, the reaction was quenched by the addition of aqueous
ammonium chloride (1 M, 3 mL), and then the reaction mixture
was extracted with ethyl acetate (5 mL ꢂ 3). The combined organic
layer was washed with brine then dried over anhydrous sodium sul-
fate, and concentrated to give crude material. The crude material
was purified by flash chromatography (n-hexane/acetone, 2:1) to af-
ford 24.5 mg of product 16 in 92% yield with 85% ee [HPLC Chiralpak
AD-H, n-hexane/methanol 17:1; 0.5 mL/min; tR = 71.7 min (minor),
tR = 86.8 min (major)].
30), 250 (56), 154 (100), 153 (88), 137 (84), 86 (47); ½a D26
¼ ꢀ23:7
ꢁ
(c 0.2, CH2Cl2).
4.3.8. Synthesis of 4-(3-methyl-but-2-enyloxy)-3-pyrrolidin-1-yl-
but-2-enoic acid (1R,2R)-1-diisopropylcarbamoyl-7,7-dimethyl-
bicyclo[2.2.1]hept-2-yl ester 17b
According to the general procedure in 98% yield. 1H NMR
(300 MHz, CDCl3) d 5.39 (t, J = 7.0 Hz, 1H), 5.05 (d, J = 11.3 Hz, 1H,
ABq), 5.04 (dd, J = 7.6, 3.8 Hz, 1H), 4.65 (d, J = 11.3 Hz, 1H, ABq),
4.50 (s, 2H), 4.28 (sep, J = 6.6 Hz, 1H), 4.05 (d, J = 7.0 Hz, 2H), 3.58
(br, 2H), 3.27 (sep, J = 6.7 Hz, 1H), 3.15 (br, 2H), 2.08–0.98 (m, 7H),
1.92 (br, 4H), 1.76 (s, 3H), 1.69 (s, 3H), 1.43 (d, J = 6.7 Hz, 3H), 1.42
(d, J = 6.7 Hz, 3H), 1.38 (s, 3H), 1.19 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H),
1.07 (d, J = 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 170.5, 167.9,
157.0, 137.5, 120.9, 85.9, 77.7, 66.6, 64.1, 59.5, 51.2, 47.7 (2C),
47.1, 46.1, 45.1, 40.6, 30.1, 27.1, 25.8, 24.5 (2C), 22.1, 21.8, 21.2,
20.8, 20.5, 20.4, 17.9; HRMS-EIcalcdfor C29H48N2O4, 488.3614found
4.5.1. Synthesis of 5-(3-methyl-but-2-enyl)-4-pyrrolidin-1-yl-
5H-furan-2-one 18
To 17a (50 mg, 0.1 mmol) in a 5 mL round-bottomed flask with
THF (1 mL) was added a solution of LiBr (0.1 mL, 1.0 M THF) at
room temperature. After the reaction mixture was cooled to
ꢀ78 °C, LDA (1.0 M, 0.25 mL, 0.25 mmol) was added and then
allowed to warm to ꢀ20 °C, and stirred for an additional 3 h. After
warming to ꢀ10 °C, the reaction was quenched by the addition of
488.3610; ½a 2D6
¼ ꢀ32:1 (c 0.18, CH2Cl2).
ꢁ

1862
Y.-J. Li et al. / Tetrahedron: Asymmetry 20 (2009) 1854–1863
aqueous ammonium chloride (1 N, 3 mL), and then the reaction
mixture was extracted with ethyl acetate (5 mL ꢂ 3). The com-
bined organic layer was washed with brine, then dried over anhy-
drous sodium sulfate, and concentrated to give a crude material.
The crude material was purified by flash chromatography
(n-hexane/acetone, 2:1) to afford 24.5 mg of product 18 in 93%
yield with 95% ee [HPLC Chiralpak AD-H, n-hexane/methanol
17:1; 0.5 mL/min; tR = 45.1 min (minor), tR = 58.6 min (major)].
was quenched by saturated sodium bicarbonate (5 mL) and then
the reaction mixture was extracted with CH2Cl2 (5 mL ꢂ 3). Com-
bined organic layers were washed with brine then dried over anhy-
drous sodium sulfate, and concentrated in vacuo to give crude
material. The crude material was purified by flash chromatography
(n-hexane/ethyl acetate, 6:1) to afford 49.5 mg of product 28, two
steps in 72% yield. 1H NMR (300 MHz, CDCl3) d 7.43 (dd, J = 5.9,
1.6 Hz, 1H), 6.06 (dd, J = 5.9, 1.9 Hz, 1H), 5.03 (dq, J = 5.9, 14 Hz,
1H), 4.97 (t, J = 6.3, 1H), 2.40 (m, 2H), 1.66 (s, 3H), 1.56 (s, 3H);
13C NMR (50 MHz, CDCl3) d 172.9, 156.1, 136.4, 121.4, 116.1, 82.9,
1H NMR (300 MHz, CDCl3)
d 5.18–5.11 (m, 1H), 4.86 (ddd,
J = 3.2 Hz, 1H), 4.51 (s, 1H), 3.34 (br, 4H), 2.76–2.66 (br, 2H), 2.01
(br, 4H), 1.70 (s, 3H), 1.62 (s, 3H); 13C NMR (50 MHz, CDCl3) d
174.2, 168.5, 135.3, 116.8, 81.82, 77.9, 49.5, 48.2, 30.6, 25.8, 25.5,
24.4, 17.8; HRMS-EI calcd for C13H19NO2, 221.1416 found
31.6, 25.5, 17.7; ½a D26
¼ ꢀ125:2 (c 1.15, MeOH).
ꢁ
4.6.3. Synthesis of (4S, 5R)-(+)-eldanolide 21
221.1415; ½a 2D6
¼ þ24:1 (c 0.33, CH2Cl2).
ꢁ
To CuI (186 mg, 0.98 mmol) in ether (10 mL) in a 25 mL three-
necked round-bottomed flask at ꢀ20 °C under an Ar atmosphere
was added a solution of MeLi (1.5 N, 1.3 mL, 1.95 mmol), then al-
lowed to warm to 0 °C. To the reaction mixture pre-cooled to
ꢀ78 °C was added TMSCl (186 mg, 0.98 mmol) and then compound
20 (49.5 mg, 0.33 mmol) in ether (5 mL). After being stirred for 4 h
at ꢀ78 °C, the reaction mixture was warmed to ꢀ30 °C, then the
reaction was quenched with saturated aqueous ammonium chlo-
ride (10 mL), and the reaction mixture was allowed to warm to
room temperature and extracted with CH2Cl2 (5 mLꢂ3). The com-
bined organic layer was washed with brine, then dried over anhy-
drous sodium sulfate, and concentrated in vacuo to give crude
material. The crude material was purified by flash chromatography
(n-hexane/ethyl acetate, 6:1) to afford 46.5 mg of product 21, two
steps in 85% yield. 1H NMR (300 MHz, CDCl3) d 5.18 (tq, J = 5.9,
14.0 Hz, 1H), 4.03 (dt, J = 6.1, 5.9 Hz, 1H), 2.61 (dd, J = 9.0, 5.9 Hz,
2H), 2.35–2.40 (m, 1H), 2.15–2.35 (m, 1H), 2.15 (dd, J = 16.2,
8.8 Hz, 1H), 1.66 (s, 3H), 1.57 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H); 13C
NMR (50 MHz, CDCl3) d 176.5, 135.3, 117.8, 87.0, 37.0, 35.0, 32.1,
4.5.2. Synthesis of 5-(2-methyl-allyl)-4-pyrrolidin-1-yl-5H-
furan-2-one 19
According to the similiar procedure as in the preparation of 18
in 73% yield with 65% ee [HPLC Chiralpak AD-H, n-hexane/metha-
nol 17:1; 0.5 mL/min; tR = 52.7 min (minor), tR = 64.4 min (major)].
1H NMR (200 MHz, CDCl3) d 4.94 (dd, J = 8.3, 2.5 Hz, 1H), 4.88 (d,
J = 1.3 Hz, 1H), 4.84 (d, J = 1.3 Hz, 1H), 4.51 (s, 1H), 3.32 (br, 4H),
2.67 (dd, J = 14.7, 2.5 Hz, 1H), 2.26 (dd, J = 14.7, 8.3 Hz, 1H), 2.32–
1.92 (br, 4H), 1.81 (s, 3H); 13C NMR (50 MHz, CDCl3) d 174.3,
168.9, 140.2, 114.2, 82.2, 77.6, 49.4 (br, 2C), 40.7, 25.4 (br, 2C),
22.7; HRMS-EI: (C12H17NO2) Calcd, 207.1259; found, 207.1254.
4.5.3. Synthesis of 5-(1,1-dimethyl-allyl)-4-pyrrolidin-1-yl-5H-
furan-2-one 20
According to the similiar procedure as in the preparation of 18
in 40% yield with 25% ee [HPLC Chiralpak AD-H, n-hexane/metha-
nol 17:1; 0.25 mL/min; tR = 86.1 min (minor), tR = 92.2 min (ma-
jor)]. 1H NMR (200 MHz, CDCl3) d 5.90 (dd, J = 17.4, 10.6 Hz, 1H),
5.11 (d, J = 17.4 Hz, 1H), 5.08 (d, J = 10.6 Hz, 1H), 4.67 (s, 1H),
4.62 (s, 1H), 3.24–3.22 (br, 4H), 2.00–1.65 (br, 4H), 1.21 (s, 3H),
1.03 (s, 3H); 13C NMR (50 MHz, CDCl3) d 174.2, 169.3, 143.7,
113.6, 85.1, 84.6, 51.3 (2C), 42.7, 25.2 (2C), 20.6 (2C); HRMS-EI:
(C13H19NO2) Calcd, 221.1416; found, 221.1411.
25.8, 17.9, 17.6; ½a D26
¼ þ46:5 (c 1.02, MeOH).
ꢁ
Acknowledgments
We thank the National Science Council (NSC-93-2113-M-415-
003) for generous financial support. The data base service of NCHC
and partial support from the Mass spectrometer facility provided
by National Chung-Hsing University and the support of X-ray
facility by National Taiwan University are also acknowledged.
4.6. Synthesis of (+)-eldanolide
4.6.1. Synthesis of 5(R)-(3-methyl-but-2-enyl)-4-pyrrolidin-1-
yl-5H-furan-2-one 27
References
According to the procedure in the preparation of 18 in 90% yield
with 93% ee [HPLC Chiralpak AD-H, n-hexane/methanol 17:1;
0.5 mL/min; tR = 45.1 min (major), tR = 57.8 min (minor)]. 1H NMR
(300 MHz, CDCl3) d 5.12 (dd, J = 7.4, 7.2 Hz, 1H), 4.84 (dd, J = 13.7,
3.2 Hz, 1H), 4.49 (s, 1H), 3.35 (br, 4H), 2.72–2.68 (m, 1H), 2.34–
2.32 (m, 1H), 2.04–1.93 (m, 4H), 1.68 (s, 3H), 1.60 (s, 3H); 13C
NMR (50 MHz, CDCl3) d 174.5, 168.6, 135.5, 116.8, 82.0, 49.6,
1. Li, Y.-J.; Lee, P.-T.; Yang, C.-M.; Chang, Y.-K.; Weng, Y.-C.; Liu, Y.-H. Tetrahedron
Lett. 2004, 45, 1865–1868.
2. Transformation of b-pyrrolidinyl-a,b-unsaturated c-lactone to tetronic acids or
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c
Guerenu, A. M. Synth. Commun. 1993, 23, 459–472; (b) Nishide, K.; Aramata, A.;
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48.2, 30.7, 26.0, 25.7, 17.9; ½a D26
¼ ꢀ25:8 (c 0.42, CH2Cl2).
ꢁ
4.6.2. Synthesis of 5(R)-(3-methyl-but-2-enyl)-5H-furan-2-one
28
3. Synthesis of tetronic acid via other methods, see: (a) Svendsen, A.; Boll, P. M.
Tetrahedron 1973, 29, 4251–4258; (b) Bloomer, J. L.; Kappler, F. E. J. Org. Chem.
1974, 39, 113; (c) Damon, R. E.; Luo, T.; Schlessinger, R. H. Tetrahedron Lett.
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(e) Ireland, R. E.; Thompson, W. J. J. Org. Chem. 1979, 44, 3041–3052; (f) Krepski,
L. R.; Lynch, L. E.; Heilman, S. M.; Rasmussen, J. K. Tetrahedron Lett. 1985, 26,
981–984; (g) Booth, P. M.; Fox, C. M. J.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1
1987, 121–129; (h) Witiak, D.; Tehim, A. K. J. Org. Chem. 1990, 55, 1112–1114;
(i) Duffield, J. J.; Regan, A. C. Tetrahedron: Asymmetry 1996, 7, 663–666; (j) Ge,
P.; Kirk, K. L. J. Org. Chem. 1996, 61, 8671–8673; (k) Effenberder, F.; Syed, J.
Tetrahedron: Asymmetry 1998, 817–825; (l) Langer, P.; Eckardt, T. Synlett 2000,
844–846; (m) Mitosis, C. A.; Zografos, A. L.; Igglessi-Markopoulou, O. J. Org.
Chem. 2000, 65, 5852–5853; (n) Pevet, I.; Meyer, C.; Cossy, J. Tetrahedron Lett.
2001, 42, 5215–5218.
To lithium (31 mg, 4.5 mmol) in 30 mL liquid ammonia at
ꢀ78 °C, was added a solution of 27 (100 mg, 0.45 mmol) and tert-
butyl alcohol in 2 mL THF. The reaction mixture was stirred for
3 h and then the reaction was quenched by the addition of isoprene
(0.5 mL). The ammonia was allowed to evaporate off after which
the reaction mixture was diluted with saturated aqueous ammo-
nium chloride (10 mL) and extracted with ethyl acetate (5 mL ꢂ
3). The organic layers were combined, dried over anhydrous sodium
sulfate, and the solvent was removed in vacuo to give 86 mg of
crude material. To the crude material dissolved in CH2Cl2 (5 mL)
at 0 °C was added m-CPBA (114 mg, 0.46 mmol), and the reaction
was followed by TLC until it reached completion. The reaction
4. For reviews of [2,3]-Wittig rearrangement see: (a) Nakai, T.; Mikami, K. Chem.
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1863
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8. Absolute stereochemistry at C4 was assigned as (S)-by comparison of the
specific rotation of a degraded
compound in Ref. 9b.
a,b-unsaturated lactone with the authentic
9. Separation of (+)-eldanolide see: (a) Kunesch, G.; Zagatti, P.; Lallemand, J. Y.;
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see: Chu, Y.-Y.; Yu, C.-S.; Chen, C.-J.; Yang, K.-S.; Lain, J.-C.; Lin, C.-H.; Chen, K. J.
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6. The absolute stereochemistry of the major enantiomer of the rearrangement
product of 5d was confirmed by comparison of the specific rotation of the
degradation product of 7 with the reported compound, and assigned to be (S).
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Hasegawa, Y.; Kawasaki, H.; Koga, K. Tetrahedron Lett. 1993, 34, 1963–1966; (c)