Asymmetric multicomponent reactions: convenient access to acyclic stereocenters and functionalized cyclopentenoids

Article abstract of DOI:10.1016/j.tetasy.2008.04.005

Asymmetric multicomponent reactions of optically active phenyl dihydrofuran, keto ester or N-tosyl imino ester, and allylsilane provided functionalized phenyl tetrahydrofurans with multiple stereogenic centers diastereoselectively. Cleavage of the resulting substituted tetrahydrofurans readily provided acyclic derivatives with three contiguous asymmetric centers via an acyloxycarbenium ion intermediate. Ring closing olefin metathesis, using Grubbs catalyst, afforded functionalized cyclopentene derivatives in optically active form. A one-pot tandem tetrahydrofuran ring cleavage followed by ring closing olefin metathesis also provided functionalized cyclopentenes in good yield.

Full text of DOI:10.1016/j.tetasy.2008.04.005

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1020–1026
Asymmetric multicomponent reactions: convenient access to acyclic
stereocenters and functionalized cyclopentenoids
Arun K. Ghosh,* Sarang S. Kulkarni, Chun-Xiao Xu and Khriesto Shurrush
Department of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA
Received 17 March 2008; accepted 2 April 2008
Abstract—Asymmetric multicomponent reactions of optically active phenyl dihydrofuran, keto ester or N-tosyl imino ester, and allyl-
silane provided functionalized phenyl tetrahydrofurans with multiple stereogenic centers diastereoselectively. Cleavage of the resulting
substituted tetrahydrofurans readily provided acyclic derivatives with three contiguous asymmetric centers via an acyloxycarbenium
ion intermediate. Ring closing olefin metathesis, using Grubbs catalyst, afforded functionalized cyclopentene derivatives in optically
active form. A one-pot tandem tetrahydrofuran ring cleavage followed by ring closing olefin metathesis also provided functionalized
cyclopentenes in good yield.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
purity, and a Lewis acid-catalyzed cleavage of the substi-
tuted tetrahydrofurans via an acyloxycarbenium ion inter-
mediate to provide acyclic derivatives with three
contiguous asymmetric centers. The acyclic precursors
can be converted to functionalized cyclopentene derivatives
in an optically active form by a ring closing metathesis
using Grubbs catalyst. We have also demonstrated a one-
pot tandem Lewis acid-catalyzed cleavage followed by ring
closing olefin metathesis to afford functionalized cyclopen-
tene derivatives in good yield. Such functionalized cyclo-
pentenoids are often structural features of a variety of
bioactive natural products.4
Recently, we reported the syntheses of a variety of substi-
tuted tetrahydrofurans and tetrahydropyrans with the cre-
ation of multiple stereogenic centers in a single operation
by novel multicomponent coupling reactions.1 The overall
protocol is practical, efficient, and provided rapid access to
functionalized heterocycles. Subsequently, we have shown
that multicomponent reactions of optically active phenyl
dihydrofuran, N-tosyl imino ester, and carbon nucleophiles
can provide stereocontrolled synthesis of unnatural opti-
cally active heterocyclic amino acids with multiple stereo-
centers.2 To broaden the scope and utility of this reaction
further, we envisioned the cleavage of such functionalized
phenyl tetrahydrofuran derivatives to provide access to
acyclic derivatives with multiple stereocenters in optically
active form. Also, for all previous investigation, we synthe-
sized optically active 2-phenyl-2,3-dihydrofuran using the
Hayashi–Heck3 reaction of aryl triflate and dihydrofuran
in 80–88% ee. While the methodology provided enantio-
enriched phenyldihydrofuran in a single step, operational
complexity, low enantiomeric excess, and lack of generality
led us to explore alternative synthesis of optically active
dihydrofuran. Herein, we report an alternative synthesis
of optically active phenyl dihydrofuran, its conversion to
functionalized tetrahydrofurans in high diastereomeric
2. Results and discussion
The synthesis of optically active phenyldihydrofuran was
carried out as outlined in Scheme 1. The known c-lactone
1 was prepared in multigram quantity using an enantio-
selective CBS-reduction as the key step.5,6 The reduction
of 1 by DIBAL-H provided the corresponding lactol. Reac-
tion of the resulting lactol with mesyl chloride and triethyl-
amine at ꢀ50 °C provided the mesylate. Heating of the
mesylate at 42 °C furnished phenyldihydrofuran 2 in 60%
yield. The protocol is convenient and both enantiomers
of phenyldihydrofuran 2 can be prepared in high enantio-
meric purity (93–94% ee).7
*
An asymmetric multicomponent reaction was then carried
Corresponding author. Tel.: +1 765 494 5323; fax: +1 765 496 1612;
e-mail: akghosh@purdue.edu
out with this optically active phenyl dihydrofuran 2.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.005

A. K. Ghosh et al. / Tetrahedron: Asymmetry 19 (2008) 1020–1026
1021
R
HO
H
R
O
CO2Et
Cu(OTf)2
(5 mol%)
CO2Et
3
1. DIBAL-H, CH2Cl2
Ph
Ph
Ph
2. MsCl, Et3N, -50 ˚C
then reflux
Ac2O, PhMe,
O
O
O
TiCl4, CH2Cl2
TMS
O
110 ο
C
H
2
1
4a R = Me (dr 99:1)
4b R = CH2CH2OCH3 (dr 3:1)
OAc
OAc
OAc
AcO
R
R
H
R
H
-H+
CO2Et
CO2Et
CO2Et
Ph
Ph
O
O
H
O
H
O
Ph
CH3
CH3
5
6a R = Me (dr 99:1)
6b R = CH2CH2OCH3 (dr 3:1)
Scheme 1.
Table 1. Optimization of conditions of ring opening reaction
As described, the reaction of 2-phenyl-2,3-dihydrofuran 2
(1.2 equiv) and ethyl pyruvate 3a (R = Me, 1 equiv) in the
presence of TiCl4 (1 M solution in CH2Cl2, 1.1 equiv) at
ꢀ78 °C for 1 h, followed by the addition of trimethylsilane
(3 equiv) at ꢀ78 °C and warming up the reaction to 23 °C
for 1 h. The reaction was quenched with saturated NaHCO3
solution, standard work up and flash chromatography over
silica gel provided the single condensation product 4a in
Entry
Lewis acid
Equivalents
Solventa
Yieldb (%)
1
2
3b
4
5
6
7
8
ZnCl2
ZnCl2
0.06
0.20
1.00
0.20
0.10
0.20
0.20
0.05
Ac2O
25
—
79
75
75
73
85
82
Ac2O/toluene
Ac2O/toluene
Ac2O/toluene
Ac2O/toluene
Ac2O/toluene
Ac2O/toluene
Ac2O/toluene
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Sc(OTf)3
Cu(OTf)2
Cu(OTf)2
1
75% yield as a single diastereomer (by H and 13C NMR
analysis). We have also carried out multicomponent
reaction with ethyl 4-methoxy-2-oxobutanoate which was
prepared according to published procedure.8 Multicompo-
nent reaction of 2 with ethyl 4-methoxy-2-oxobutanoate
3b (R = CH2CH2OCH3), as described above, furnished
product 4b as a 3:1 inseparable mixture of diastereomers
in 67% yield. These multicomponent reactions afforded
highly functionalized tetrahydrofuranyl derivatives 4a and
4b diastereoselectively with efficient construction of three
contiguous asymmetric centers including a quaternary car-
bon center. Conceivably, the appropriate cleavage of the tet-
rahydrofuran ring would provide access to stereocontrolled
acyclic derivatives in optically active form. As it turned out,
the 2-phenyltetrahydrofuran is suitably positioned to be
cleaved by an acyloxycarbenium ion mediated ring opening
reaction. Unsubstituted phenyltetrahydrofuran was known
to react with excess of metal halide in acetic anhydride to
provide 4-acetoxy-1-phenylbut-1-ene.9 Cleavage of a more
substituted phenyltetrahydrofuran has been carried out by
us recently using a catalytic amount of ZnCl2 in acetic anhy-
dride at 120 °C. We elected to utilize this protocol. Thus, 2-
phenyl tetrahydrofuran derivative 4a was exposed to the
above reaction conditions for 4 h. This has afforded the
styryl derivative 6a in 25% yield. The reaction proceeded
first by Lewis acid-catalyzed formation of the acetate (mon-
itored by TLC and by 1H NMR) followed by the formation
of a possible acyloxycarbenium ion intermediate 5, then
stable benzylic carbonium ion and loss of a proton to pro-
vide 6a.10 To further improve the reaction yield, we have
examined a number of Lewis acids under a variety of reac-
tion conditions. The results are shown in Table 1. Entry 8
provided the optimum result.
a Reaction temperature of 110 °C.
b Isolated yield after silica gel chromatography.
Thus, the reaction of 4a with a catalytic amount of
Cu(OTf)2 in a mixture (10:1) of toluene and acetic anhy-
dride at reflux provided acyclic derivative 6a in 85% yield
as a single diastereomer. Similarly, phenyltetrahydrofuran
4b afforded acylic derivative 6b in 83% yield as a 3:1 insep-
arable mixture of diastereomers. Thus, the asymmetric
multicomponent reaction followed by acyloxycarbenium
ion mediated ring opening afforded 6a and 6b (major prod-
uct) containing multiple stereocenters in an optically active
form. Both these derivatives are also suitable precursors for
the synthesis of substituted cyclopentene derivatives by a
ring closing olefin metathesis.11 Thus, the exposure of 6a
to Grubbs II catalyst (3 mol %) in CH2Cl2 at 23 °C for
4 h afforded cyclopentene derivative 7a in optically active
form (Scheme 2).12 We then attempted to carry out Lewis
acid-catalyzed ring opening and ring closing metathesis in
one operation. Indeed, treatment of 4a with a catalytic
amount (20 mol %) of Zn(OTf)2 in the presence of acetic
anhydride in toluene at 110 °C for 12 h followed by expo-
sure of the resulting ring opening product to 3% Grubbs
catalyst at 23 °C for 4 h afforded cyclopentene 7a in 58%
yield. Treatment of 4a with 20 mol % Zn(OTf)2 and
5 mol % Grubbs II catalyst at 110 °C for 12 h afforded only
a trace amount of 7a with starting material mostly
unchanged.
Exposure of 6b and its diastereomer to Grubbs II catalyst
(3 mol %) in CH2Cl2 at 23 °C furnished cyclopentenes 7b

1022
A. K. Ghosh et al. / Tetrahedron: Asymmetry 19 (2008) 1020–1026
AcO OAc
R
Ts
NH
Grubbs II catalysis
(3 mol%)
H
H
6a or, 6b
CO2Et
CO2Et
Ts-N
CO2Et
CH2Cl2, 23 o
C
9
TiCl4, CH2Cl2
TMS
2
Ph
10
7a R = Me
O
7b R = CH2CH2OCH3
H
1. LiOH, H2O/THF
2. Ac2O, DMAP
1. CaCl2, NaBH4
2. (COCl2)3, Py
O
O
+
O
O
O
O
AcO OAc
H
CH2CH2OCH3
CO2Et
Ts
Ts
N
H
Me
OCH3
N
O
O
H
H
Zn(OTf)2
(20 mol%)
H
H
Ph
Ph
11
8b (Major)
7c (Minor)
Ac2O, PhMe,
110 oC
AcO
O
H
12
H
O
O
1. LiOH, H2O/THF
2. Ac2O, DMAP
O
H
O
H
Me
OCH3
O
O
Ts
AcO
Ts
N
H
AcO
N
Grubbs' II
(3 mol%)
O
H
H
O
8c (Minor)
CH2Cl2, 23 o
C
H
H
Scheme 2.
13
Ph
Scheme 3.
and 7c. The isomers were separated by flash column chro-
matography. The stereochemistry of the cyclopentenes was
determined based on the NOESY studies on the corre-
sponding bicyclic lactones 8b and 8c.
excess of compound 13 was determined by the reduction
of this compound with Dibal-H in CH2Cl2 at ꢀ78 °C fol-
lowed by the conversion of the alcohol to the Mosher ester.
The 19F NMR analysis of the Mosher ester established
enantiomeric excess of 10 as 87% ee.16
We had previously reported that the multicomponent reac-
tion of N-tosyl imino ester2a with 2-phenyldihydrofuran 2
in the presence of TiCl4 with allyltrimethylsilane as a nucle-
ophile provided the single diastereomer 10 in 72% yield
(Scheme 3). To determine the cyclic stereochemistry in an
acyclic form, we attempted acycloxycarbenium ion medi-
ated ring opening of tosylamine derivative 9 as described
above for phenyltetrahydrofuran derivatives 4a and 4b.
However, the above reaction conditions failed to provide
any ring opening product, even in presence of 3 equiv of
Lewis acid. The starting material remained mostly un-
changed. The formation of the acyloxycarbenium ion was
possibly retarded due to sequestering of the Lewis acid
by the tosylamide functionality.14 Therefore, ethyl ester
10 was reduced using NaBH4 in the presence of CaCl2
and resulting alcohol was treated with triphosgene in pyri-
dine to provide oxazolidinone 11 in 61% yield (over two
steps).15 Oxazolidinone 11 was then treated with a catalytic
amount (5 mol %) of Cu(OTf)2 which gave the expected
ring opening product 12 in 67% yield, and increasing the
catalyst loading to 10 mol % resulted in the improvement
of isolated yield to 73%. Exposure of oxazolidinone 11 to
a catalytic amount (20 mol %) of Zn(OTf)2 in presence of
excess acetic anhydride in toluene however, provided the
ring opening product 12 in 81% isolated yield. All three
asymmetric centers in acyclic derivative 12 were con-
structed diastereoselectively during the multicomponent
reaction. Diene 12 is set to form a functionalized cyclopen-
tene derivative 13. Thus, treatment of 12 with Grubbs cat-
alyst (3 mol %) in CH2Cl2 at 23 °C for 4 h afforded
cyclopentene in optically active form. The enantiomeric
3. Conclusions
In conclusion, the asymmetric multicomponent reaction
diastereoselectively constructed functionalized tetrahydro-
furan derivatives containing multiple stereocenters. Lewis
acid-catalyzed cleavage of phenyltetrahydrofuran ring via
acyloxycarbenium ion intermediate provided useful access
to acyclic derivatives with three contiguous asymmetric
centers. Acyclic derivatives were converted to functional-
ized cyclopentene derivatives in optically active form by
ring closing olefin metathesis.
4. Experimental
4.1. General
All melting points were recorded on a melting point appa-
ratus and are uncorrected. Anhydrous solvents were
obtained as follows: THF and diethyl ether by distillation
from sodium and benzophenone; pyridine and dichloro-
methane from CaH2. All other solvents were reagent grade.
All moisture-sensitive reactions were carried out in flame-
dried flask under nitrogen atmosphere. Column chromato-
graphy was performed with 240–400 mesh silica gel under
low pressure of 3–5 psi. TLC was carried out with Silica

A. K. Ghosh et al. / Tetrahedron: Asymmetry 19 (2008) 1020–1026
1023
Gel 60-F-254 plates. The title a-N-tosyl imino ester was
made from ethyl glyoxylate and N-toluenesulfonylisocya-
nate by Weinreb’s procedure.13 Ethyl 4-methoxy-2-oxobut-
anoate 3b was prepared according to the reported
procedure.8
4.1.3. (S)-Ethyl2-((2R,3S,5R)-2-allyl-5-phenyltetrahydrofu-
ran-3-yl)-2-hydroxy-4-methoxybutanoate 4b. The proce-
dure described for 3a was used for 3b. Accordingly,
ethyl-4-methoxy-2-oxobutanoate 1 (160 mg, 1 mmol), (R)-
2,3-dihydro-2-phenylfuran 1 (175 mg, 1.2 mmol), TiCl4
(1 M in CH2Cl2, 1.2 mmol) and allyltrimethylsilane (345
mg, 3 mmol) afforded furan 4b (230 mg, 66% yield) as a
4.1.1. (R)-2-Phenyl-2,3-dihydrofuran 2. To a stirred solu-
tion of lactone 1 (0.5 g, 3 mmol) in CH2Cl2 (10 mL) at
ꢀ78 °C was added a solution of DIBAL-H (1 M in
CH2Cl2, 3.7 mmol). After stirring at ꢀ78 °C for 1 h, the
reaction was quenched with saturated aqueous potassium
sodium tartrate. The mixture was diluted with CH2Cl2
and vigorously stirred at room temperature for 2 h. The
aqueous layer was extracted twice with CH2Cl2. The com-
bined organic layers were dried over anhydrous Na2SO4
and concentrated in vacuo to provide the crude lactol as
a colorless oil, which was immediately used in the next
reaction without further purification.
3:1 mixture of inseparable diastereomers, Rf = 0.36 (hex/
23
EtOAc = 4:1), ½aꢁD ¼ ꢀ15:3 ðc 1:2; CHCl3Þ; 1H NMR
(500 MHz, CDCl3): d 1.29 (t, J = 7 Hz, 3H, major), 1.34
(t, J = 7.5 Hz, minor), 1.76–1.97 (m, 2H), 1.98–2.11 (m,
2H), 2.17–2.23 (m, minor), 2.39–2.47 (m, 2H), 2.58–2.63
(m, 1H), 3.26 (s, minor), 3.27 (s, 3H, major), 3.41–3.46
(m, 1H), 3.49–3.56 (m, 1H), 3.75 (s, minor), 3.91 (s, 1H,
major), 4.01–4.05 (m, minor), 4.16–4.30 (m, 3H), 4.87–
4.92 (m, 1H), 5.09–5.20 (m, 2H), 5.92–6.04 (m, 1H),
7.21–7.36 (m, 5H); 13C NMR (125 MHz, CDCl3): d 14.1
(minor), 14.2 (major), 31.2 (minor), 37.0 (major), 37.2
(minor), 37.7 (minor), 37.9 (major), 39.5 (minor), 41.2 (ma-
jor), 50.3 (major), 50.5 (minor), 58.9 (major), 61.2 (major),
68.4 (minor), 68.5 (major), 117.3 (minor), 117.4 (major),
126 (major), 126.1 (minor), 127.3 (major), 128.2 (major),
128.5 (minor), 134.7 (minor), 134.8 (major), 141.9 (major),
142.4 (minor), 175.6 (major), 175.9 (minor); FT-IR (film,
NaCl) 3493, 2362, 1724 cmꢀ1. HRMS (CI) [M+H]+ calcd
for C20H28O5 349.2015, found 349.2018.
To a stirred solution of the above lactol in CH2Cl2 (25 mL)
at ꢀ50 °C was added triethylamine (1.2 mL, 12.2 mmol)
followed by methanesulfonyl chloride (0.3 mL, 3.9 mmol).
The solution was stirred for 1 h at ꢀ50 °C and then the
reaction mixture was warmed to 23 °C and heated at reflux
for 12 h. The reaction mixture was then cooled to 23 °C,
solvents were evaporated, and purified by column chroma-
tography to afford phenyl dihydrofuran 2 (272 mg, 60%
yield over 2 steps) as clear oil Rf = 0.3 (pentane:
4.1.4. (2R,3R,5R)-1-Ethyoxy-2-methyl-1-oxo-3-styrylhept-
6-ene-2,4-diyl diacetate 6a. A mixture of tertiary alcohol
4 (350 mg, 1.15 mmol), Cu(OTf)2 (21 mg, 0.058 mmol),
and acetic anhydride (5.5 mL, 57.5 mmol) was heated to
110 °C in toluene (50 mL) with stirring. After 2 h, the reac-
tion mixture was cooled to room temperature and the reac-
tion mixture was washed with saturated aqueous NaHCO3
(2ꢂ). The organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure. The residue was
purified further by flash column chromatography on silica
gel to afford styrene 6a (355 mg, 80% yield) as a yellow oil,
23
CH2Cl2 = 3:1), ½aꢁ ¼ ꢀ66 ðc 1:05; CHCl3Þ; 1H NMR
(400 MHz, CDCl3)D: d 2.63 (qt, J = 2, 8 Hz, 1H), 3.06–
3.13 (m, 1H), 4.98 (dd, J = 2.5, 6.4 Hz, 1H), 5.53 (dd,
J = 8.5, 13.3 Hz, 1H), 6.47 (dd, J = 2.4, 4.7 Hz, 1H),
7.28–7.45 (m, 5 H); 13C NMR (100 MHz, CDCl3); 37.8,
82.3, 98.9, 125.5, 127.6, 128.5, 142.9, 145.2. IR (film, NaCl)
2928, 1619, 1135, 1051 cmꢀ1
.
4.1.2. (R)-Ethyl2-((2R,3R,5R)-2-allyl-5-phenyltetrahydrofu-
ran-3-yl)-2-hydroxypropanoate 4a. To a mixture of ethyl
pyruvate (232 mg, 2 mmol) and (R)-2,3-dihydro-2-phenyl-
furan 1 (350 mg, 2.4 mmol) in dry CH2Cl2 (20 mL) at
ꢀ78 °C was added a solution of TiCl4 (1.0 M in CH2Cl2,
2.2 mmol) and the resulting orange solution was stirred
at ꢀ78 °C for 1 h. Allyltrimethylsilane (686 mg, 6 mmol)
was added and the mixture was warmed from ꢀ78 °C to
23 °C over 1 h. Then the reaction mixture was quenched
carefully with 15 mL saturated sodium bicarbonate solu-
tion and the aqueous layer was extracted with dichloro-
methane (3ꢂ). The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified further by flash column
chromatography on silica gel to afford the tertiary alcohol
1
Rf = 0.48 (20% EtOAc in hexanes), H NMR (500 MHz,
CDCl3): d 1.23 (t, J = 7 Hz, 3H), 1.67 (s, 3H), 2.04 (s,
3H), 2.05 (s, 3H), 2.23–2.27 (m, 1H), 2.34–2.38 (m, 1H),
2.77 (d, J = 10 Hz, 1H), 4.07–4.20 (m, 2H), 5.07–5.11 (m,
2H), 5.38 (t, J = 5Hz, 1H), 5.76–5.88 (m, 1H), 6.24 (dd,
J = 16, 10 Hz, 1H), 6.46 (d, J = 16 Hz, 1H), 7.26–7.30
(m, 1H), 7.35 (t, J = 7 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H);
13C NMR (125 MHz, CDCl3) d 13.9, 20.8, 21.2, 21.3,
37.9, 52.7, 61.4, 70.3, 81.8, 118.5, 122.7, 126.4, 127.7,
128.6, 133.1, 135.7, 136.6, 169.7, 169.9, 170.6; FT-IR (film,
NaCl), 2981, 1742, 1642 cmꢀ1. HRMS (CI) [M+H]+ calcd
for C22H28O6 389.1964, found 389.1968.
4a (454 mg, 75% yield) as a yellow oil, Rf = 0.48 (25%
4.1.5. (3R,4S,5R)-3-(Ethoxycarbonyl)-1-methoxy-4-styryl-
oct-7-ene-3,5-diyl diacetate 6b. The procedure described
for 5a was used for 5b. Accordingly furan 4b (230 mg,
0.66 mmol), Cu(OTf)2 (12 mg, 0.03 mmol), and acetic
anhydride (3.1 mL, 33 mmol) were heated in toluene
(30 mL) to give styrene 6b (216 mg, 83% yield) as a 3:1 mix-
23
EtOAc in hexanes), ½aꢁD ¼ þ15:7 ðc 1:3; CHCl3Þ; 1H
NMR (500 MHz, CDCl3): d 1.27 (t, J = 7 Hz, 3H), 1.42
(s, 3H), 1.78–1.84 (m, 1H,), 2.03–2.07 (m, 1H), 2.42–2.48,
(m, 2H), 2.61–2.66 (m, 1H), 3.51 (s, 1H), 4.20–4.28 (m,
3H), 4.89 (dd, J = 10, 6.5 Hz, 1H), 5.15–5.21 (m, 2H),
5.98–6.07 (m, 1H), 7.23–7.37 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 14.2, 24.8, 38.2, 40.9, 49.8, 62.3,
74.4, 75.3, 78.9, 80.6, 117.4, 125.8, 127.3, 128.2, 134.7,
ture of inseparable diastereomers, Rf = 0.42 (hex/
23
EtOAc = 4:1), ½aꢁD ¼ þ44:9 ðc 1:0; CHCl3Þ; 1H NMR
(400 MHz, CDCl3): d 1.27 (t, J = 7 Hz, 3H, major), 1.99
(s, 3H, major), 2.01 (s, minor), 2.02 (s, minor), 2.08 (s,
3H, major), 2.23–2.32 (m, 1H), 2.33–2.41 (m, 3H), 2.52–
142.2, 176.8; FT-IR (film, NaCl) 3462, 2979, 1784 cmꢀ1
.
m/z (CI) 305.05 (M+H)+.

1024
A. K. Ghosh et al. / Tetrahedron: Asymmetry 19 (2008) 1020–1026
23
2.60 (m, 1H), 3.09 (d, J = 10 Hz, minor), 3.18 (d,
J = 10 Hz, 1H), 3.26 (s, 3H), 3.27 (s, minor), 3.41–3.49
(m, 3H), 4.05–4.29 (m, 3H), 5.04–5.11 (m, 3H), 5.33 (t,
J = 7.5 Hz, minor), 5.45 (t, J = 7 Hz, 1H), 5.65–5.79 (m,
1H), 6.17 (dd, J = 16, 10 Hz, 1H), 6.25 (dd, J = 16,
10 Hz, minor), 6.48 (d, J = 16 Hz, 1H), 7.13–7.19 (m,
2H), 7.34 (t, J = 7.5 Hz, 3H), 7.69 (d, J = 7.5 Hz, 2H);
13C NMR (100 MHz, CDCl3): d 13.9 (major), 21.0 (minor),
21.1 (major), 21.2 (major), 31.8 (minor), 32.1 (major), 37.9
(major), 38.0 (minor), 50.2 (major), 50.7 (minor), 58.4
(minor), 58.5 (major), 61.1 (minor), 61.3 (major), 67.7 (ma-
jor), 67.9 (minor), 70.4 (major), 70.7 (minor), 82.3 (major),
82.6 (minor), 118.0 (major), 118.1 (minor), 126.3 (minor),
126.4 (major), 127.5 (minor), 127.7 (major), 128.5 (major),
133.2 (minor), 133.4 (major), 135.7 (minor), 136.0 (major),
136.8 (major), 137.1 (minor), 169.6 (major), 169.7 (minor),
169.8 (major), 169.9 (major), 170.0 (minor); FT-IR (film,
NaCl) 2361, 1742 1370, 972 cmꢀ1. HRMS (CI) [M+Na]+
calcd for C24H32O7Na 455.2046, found 455.2050.
Compound 7c: ½aꢁD ¼ ꢀ5:5 ðc 1; CHCl3Þ; 1H NMR
(500 MHz, CDCl3): d 1.30 (t, J = 7 Hz, 3H), 2.04 (s, 3H),
2.09 (s, 3H), 2.31–2.37 (m, 2H), 2.43–2.47 (m, 1H), 2.65–
2.71 (m, 1H), 3.32 (s, 3H), 3.49–3.54 (m, 2H), 3.80 (br s,
1H), 4.14–4.28 (m, 2H), 5.56 (t, J = 7 Hz, 1H), 5.81–5.87
(m, 1H), 5.99–6.04 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 13.9, 21.1, 21.2, 33.2, 40.1, 53.7, 58.6, 61.4, 74.0, 81.8,
128.3, 130.4, 170.2, 170.4, 170.5; FT-IR (film, NaCl)
1738, 1371, 1233 cmꢀ1. HRMS (CI) [M+H]+ calcd for
C16H25O7 329.1600, found 329.1603.
4.1.8. (3S,3aS,6aR)-3-(2-Methoxyethyl)-2-oxo-3,3a,6,6a-
tetrahydro-2H-cyclopenta[b]furan-3-yl acetate 8b. To a
stirred solution of 6b (90 mg, 0.27 mmol) in a mixture
(3:1:1) of THF/EtOH/H2O (3 mL) at 0 °C was added solid
LiOH (35 mg, 0.82 mmol) and the mixture was stirred for
6 h at 23 °C. After this period, the solvent was evaporated
and aqueous layer was then acidified with 1 M HCl to pH 3
and extracted with EtOAc (3ꢂ). The combined organic
layer was dried over Na2SO4 and concentrated under re-
duced pressure and purified by flash column chromatogra-
phy on silica gel to provide the lactone (34 mg, 64% yield)
as colorless oil.
4.1.6. (R)-Ethyl 2-acetoxy-2-((1S,5R)-5-acetoxycyclopent-2-
enyl)propanoate 7a. To a stirring solution of 6a (230 mg,
0.59 mmol) in CH2Cl2 (120 mL) was added a second gener-
ation Grubbs catalyst (15 mg, 0.018 mmol) under argon.
The reaction was allowed to stir at 23 °C for 4 h. After this
period the reaction mixture was concentrated under re-
duced pressure and purified by flash column chromatogra-
phy on silica gel to afford cyclopentene 6a (147 mg, 88%
To the above lactone (34 mg, 0.17 mmol) in dry CH2Cl2
(3 mL) at 0 °C were added DMAP (103 mg, 0.84 mmol)
and acetic anhydride (160 lL, 1.7 mmol). The resulting
solution was stirred at 23 °C for 12 h. After this time the
reaction mixture was diluted with CH2Cl2 and washed with
1 N HCl, water, and brine. The organic layer was concen-
trated under reduced pressure and the residue purified by
column chromatography on silica gel to provide 8b
yield) as a colorless oil, Rf = 0.4 (20% EtOAc in hexanes),
23
½aꢁD ¼ ꢀ3:5 ðc 1; CHCl3Þ; 1H NMR (500 MHz, CDCl3): d
1.28 (t, J = 7 Hz, 3H), 1.69 (s, 3H), 2.03 (s, 3H), 2.07 (s,
3H), 2.23–2.37 (m, 1H), 2.69–2.74 (m, 1H), 3.40–3.42 (m,
1H), 4.14–4.22 (m, 2H), 5.51 (dt, J = 6.5, 3 Hz 1H), 5.38
(t, J = 5 Hz, 1H), 5.76–5.88 (m, 1H), 6.24 (dd, J = 16,
10 Hz, 1H), 6.46 (d, J = 16 Hz, 1H), 7.26–7.30 (m, 1H),
7.35 (t, J = 7 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d 13.9, 20.8, 21.2, 21.3, 37.9,
52.7, 61.4, 70.3, 81.8, 118.5, 122.7, 126.4, 127.7, 128.6,
133.1, 135.7, 136.6, 169.7, 169.9, 170.6; FT-IR (film, NaCl),
2981, 1742, 1642 cmꢀ1. HRMS (ESI) [M+Na]+ calcd for
C14H20O6Na 307.1158, found 307.1155.
1
(37 mg, 92% yield) as colorless oil. H NMR (500 MHz,
CDCl3): d 2.07–2.11 (m, 2H), 2.13 (s, 3H), 2.66 (d,
J = 18 Hz, 1H), 2.73–2.79 (m, 1H), 3.36 (s, 3H), 3.51–
3.54 (m, 1H), 3.67–3.75 (m, 2H), 5.35 (t, J = 6.7 Hz, 1H),
5.76–5.79 (m, 1H), 5.84–5.88 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 20.7, 34.3, 38.7, 56.5, 58.8, 67.3,
79.6, 81.4, 127.1, 131.8, 174.2.
4.1.9. (3S,3aS,6aR)-3-(2-Methoxyethyl)-2-oxo-3,3a,6,6a-
tetrahydro-2H-cyclopenta[b]furan-3-yl acetate 8c. The
procedure described for 8b was used for 8c. Accordingly,
cyclopentene 7c (25 mg, 0.08 mmol), and LiOH (10 mg,
0.23 mmol) afforded lactone (13 mg, 85% yield) as colorless
oil. The above lactone (12 mg, 0.06 mmol), DMAP (37 mg,
0.30 mmol), and acetic anhydride (57 lL, 0.6 mmol) in
CH2Cl2 (2 mL) afforded 8c (11 mg, 70% yield) as a color-
less oil. 1H NMR (500 MHz, CDCl3): d 2.16 (s, 3H),
2.23–2.28 (m, 1H), 2.58–2.64 (m, 1H), 2.78–2.79 (m, 2H),
3.34 (s, 3H), 3.52–3.57 (m, 1H), 3.62–3.66 (m, 1H), 3.95–
3.97 (m, 1H), 5.06–5.09 (m, 1H), 5.40–5.42 (m, 1H),
5.86–5.88 (m, 1H); 13C NMR (125 MHz, CDCl3) d 21.2,
35.2, 40.0, 56.1, 58.7, 67.3, 80.3, 81.8, 126.7, 131.8, 169.8,
173.3.
4.1.7. (R)-Ethyl-2-acetoxy-2-((1S,5R)-5-cetoxycyclopent-2-
enyl)-4-methoxybutanoate 7b. The procedure described
for 7a was used for 7b. Accordingly, styrene 6b (210 mg,
0.16 mmol), second generation Grubbs catalyst (12 mg,
0.015 mmol) in CH2Cl2 (30 mL) afforded cyclopentenes
7b (92 mg, 58%) and 7c (25 mg, 16%).
23
Compound 7b: ½aꢁD ¼ ꢀ3:2 ðc 1; CHCl3Þ; 1H NMR
(500 MHz, CDCl3): d 1.30 (t, J = 7 Hz, 3H), 2.02 (s, 3H),
2.10 (s, 3H), 2.52 (dt, J = 14.8, 6.5 Hz, 1H), 2.60 (dt,
J = 14.8, 6.5 Hz, 1H), 2.65–2.71 (m, 1H), 3.30 (s, 3H),
3.47–3.54 (m, 2H), 3.78–3.80 (m, 1H), 4.16–4.26 (m, 2H),
5.56 (dt, J = 6.5, 1.7 Hz, 1H), 5.82–5.85 (m, 1H), 5.87–
5.93 (m, 1H); 13C NMR (125 MHz, CDCl3) d 14.0, 21.0,
21.5, 34.2, 39.9, 54.5, 61.4, 68.1, 73.0, 82.7, 128.8, 129.5,
169.9, 170.1, 170.4; FT-IR (film, NaCl) 1739, 1370,
1236 cmꢀ1. HRMS (CI) [M+H]+ calcd for C16H25O7
329.1600, found 329.1607.
4.1.10. (R)-Ethyl2-((2R,3R,5R)-2-allyl-tetrahydro-5-phenyl-
furan-3-yl)-2-(tosylamino)acetate (10). To a mixture of
freshly distilled a-N-tosyl imino ester 9 (255 mg, 1 mmol)
and (R)-2,3-dihydro-2-phenylfuran 1 (175 mg, 1.2 mmol)
in dry CH2Cl2 (10 mL) at ꢀ78 °C was added a solution
of TiCl4 (1.0 M in CH2Cl2, 1.1 mmol) and the resulting

A. K. Ghosh et al. / Tetrahedron: Asymmetry 19 (2008) 1020–1026
1025
orange solution was stirred at ꢀ78 °C for 50 min. Dry ace-
tonitrile (205 mg, 5 mmol) was added at ꢀ78 °C and the
mixture was stirred at ꢀ78 °C for 10 min. Allyltrimethylsi-
lane (342 mg, 3 mmol) was added and the mixture was stir-
red at ꢀ78 °C for 1 h. Then the mixture was warmed to
ꢀ20 °C and stirred at ꢀ20 °C for 2 h. Then the mixture
was cooled to ꢀ30 °C and the reaction was quenched care-
fully with 15 mL ice-cooled saturated sodium bicarbonate
solution. After the mixture was warmed to room tempera-
ture, the aqueous layer was extracted with dichlorometh-
ane (3ꢂ). The combined organic extracts were dried over
anhydrous Na2SO4 and concentrated under reduced pres-
sure. The residue was further purified by flash column
chromatography on silica gel to afford the a-N-tosylamino
column chromatography on silica gel to afford oxazolidi-
none 11 (115 mg, 81% yield) as a yellow oil, Rf = 0.5
23
(25% EtOAc in hexanes), ½aꢁD ¼ ꢀ32:5 ðc 1:6; CHCl3Þ;
1H NMR (500 MHz, CDCl3): d 2.03–2.08 (m, 1H), 2.24–
2.29 (m, 1H), 2.37–2.44 (m, 2H), 2.45 (s, 3H), 2.58–2.62
(m, 1H) 4.06 (q, J = 6.5 Hz, 1H), 4.24 (dd, J = 2, 9 Hz,
1H), 4.38 (t, J = 8.5 Hz, 1H), 4.65–4.68 (m, 1H), 4.96 (t,
J = 7.5 Hz, 1H), 5.13–5.19 (m, 2H), 5.85–5.97 (m, 1H),
7.27–7.38 (m, 7H), 7.96 (d, J = 8.5 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 21.8, 36.5, 39.6, 47.4, 57.8, 67.3,
79.7, 79.8, 118.2, 125.6, 127.6, 128.5, 129.9, 134.0, 134.9,
142.3, 146.0, 152.6; FT-IR (film, NaCl), 2924, 1783 cmꢀ1
.
4.1.12. (3R,4R)-3-(2-Oxo-3-tosyloxazolidin-4-yl)-1-phenyl-
hepta-1,6-diene-4-yl acetate (12). A mixture of oxazolidi-
none 11 (80 mg, 0.19 mmol), Zn(OTf)2 (14.0 mg,
0.04 mmol) and acetic anhydride (890 lL, 9.4 mmol) was
heated to 110 °C in toluene (15 mL) with stirring. After
2 h the reaction mixture was cooled to room temperature
and the reaction mixture was washed with saturated aque-
ous NaHCO3 (2 ꢂ 5 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pres-
sure. The residue was further purified by flash column
chromatography on silica gel to afford acetate 12 (71 mg,
ester 10 (320 mg, 72% yield) as a yellow oil, Rf = 0.38 (hex/
23
EtOAc 3:2), ½aꢁD ¼ ꢀ11:8 ðc 0:9; CHCl3Þ; 1H NMR
(500 MHz, CDCl3): d 1.05 (t, J = 7.1 Hz, 3H), 1.7–1.80
(m, 1H), 2.21–2.29 (m, 1H), 2.31–2.33 (m, 1H), 2.38–2.22
(m, 5H), 3.87–3.91 (m, 3H), 4.04–4.06 (m, 1H), 4.89 (t,
J = 7.7 Hz, 1H), 5.11–5.17 (m, 2H), 5.39 (d, J = 9.9 Hz,
1H), 5.87–5.93 (m, 1H), 7.33–7.23 (m, 7H), 7.73 (d,
J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 13.8,
21.5, 36.1, 38.6, 45.9, 55.9, 62.0, 79.5, 79.7, 117.7, 125.7,
127.4, 128.3, 129.7, 134.1, 136.3, 142.1, 144.0, 171.0; FT-
IR (film, NaCl), 2980, 1746, 1349.2, 1163 cmꢀ1; m/z (ESI)
444.1 (M+H)+, 466.3 (M+Na)+.
81% yield) as a yellow oil, Rf = 0.4 (25% EtOAc in
23
hexanes), ½aꢁD ¼ þ41:4 ðc 1:05; CHCl3Þ; 1H NMR (500
MHz, CDCl3): d 2.1 (s, 3H), 2.22–2.25 (m, 1H), 2.32–2.38
(m, 1H), 2.40 (s, 3H), 2.92–2.95 (m, 1H) 4.31 (t,
J = 7 Hz, 1H), 4.47 (dd, J = 2, 9 Hz, 1H), 4.60 (dt, J = 2,
8.5 Hz, 1H), 5.03–5.08 (m, 3H), 5.50–5.59 (m, 1H), 6.20
(dd, J = 9.5, 16 Hz, 1H), 6.57 (d, J = 16, 1H), 7.22–7.40
(m, 7H), 7.96 (d, J = 8.5 Hz, 2H); 13C NMR (125MHz,
CDCl3) d 21.1, 21.7, 37.6, 48.5, 59.1, 66.3, 70.4, 118.8,
122.06, 126.6, 128.2, 128.5, 128.7, 129.7, 132.7, 135.1,
136.2, 137.4, 145.6, 152.4, 170.3; FT-IR (film, NaCl),
2921, 1786, 1596 cmꢀ1; HRMS (EI) [M+H]+ calcd for
C25H28NO6S 470.1637, found 470.1648.
4.1.11. (S)-4-((2R,3R,5R)-2-Allyl-5-phenyltetrahydrofuran-
3-yl)-3-tosyloxazolidin-2-one (11). To a stirring mixture
of furan 10 (220 mg, 0.5 mmol) in THF/ethanol
(2 mL:3 mL) at 0 °C was added CaCl2 (116 mg, 1.05 mmol)
followed by the addition of NaBH4 (80 mg, 2.1 mmol), and
the resulting solution was allowed to warm to room tem-
perature over 3 h. After this time the reaction mixture
was cooled to 0 °C and quenched carefully with 5% citric
acid solution. This mixture was then concentrated under
vacuum and the aqueous layer was extracted with ethyl
acetate (3ꢂ). The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was further purified by flash column
chromatography on silica gel to afford the primary alcohol
(153 mg, 76% yield) as a colorless solid, Rf = 0.2 (25%
4.1.13. (1R,2R)-2-((R)-2-Oxo-3-tosyloxazolidin-4-yl)cyclo-
pent-3-enyl acetate 13. The procedure described for 7a
was used for 13. Accordingly, styrene 12 (71 mg,
0.15 mmol), second generation Grubb’s catalyst (6 mg,
0.008 mmol) in CH2Cl2 (45 mL) afforded cyclopentene 13
(48 mg, 86% yield) as a white solid, Rf = 0.3 (20% EtOAc
23
1
EtOAc in hexanes), ½aꢁD ¼ þ4:7 ðc 1; CHCl3Þ; H NMR
(500 MHz, CDCl3): d 1.78–1.82 (m, 1H), 2.08–2.18 (m,
2H), 2.31 (t, J = 7 Hz, 2H), 2.43 (s, 1H), 3.31–3.35 (m,
1H), 3.53 (d, J = 4 Hz, 2H), 3.76 (q, J = 6 Hz, 1H), 4.68
(dd, J = 8.5, 6.5 Hz, 2H), 5.07–5.11 (m, 2H) 5.24 (d,
J = 9.5 Hz, 1H), 5.78–5.83 (m, 1H), 7.19–7.34 (m, 7H),
7.79 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) d
21.5, 29.6, 36.5, 39.4, 44.7, 63.4, 79.6, 80.5, 117.6, 125.5,
127.1, 127.2, 128.2, 129.9, 134.4, 137.3, 142.2, 143.9; FT-
23
1
in hexanes), ½aꢁD ¼ ꢀ87:4 ðc 0:85; CHCl3Þ; H NMR(500
MHz, CDCl3): d 1.60 (s, 3H), 2.04–2.09 (m, 1H), 2.26 (s,
3H), 2.66–2.74 (m, 1H), 3.58 (s, 1H), 4.00 (dd, J = 4,
9 Hz, 1H), 4.15 (t, J = 9 Hz, 1H), 4.57 (quintet, J = 4 Hz,
1H), 5.00 (dt, J = 7.7, 4 Hz, 1H), 5.34–5.36 (m, 1H),
5.73–5.77 (m, 1H), 7.17 (d, J = 8 Hz, 2H), 7.76 (d,
J = 8 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 20.5, 21.7,
40.9, 48.6, 56.1, 64.9, 73.6, 127.5, 128.1, 129.8, 132.6,
134.9, 146.7, 152.6, 169.9; FT-IR (film, NaCl) 1783, 1728,
1370, 1172 cmꢀ1; HRMS (ESI) [M+Na]+ calcd for
C17H19NO6SNa 388.0831, found 388.0833.
IR (film, NaCl), 3546, 3263, 2844 cmꢀ1
.
To a stirring mixture of above amino alcohol (133 mg,
0.33 mmol) in dry CH2Cl2 (3 mL) were added pyridine
(158 mg, 2 mmol) and triphosgene (49 mg, 17 mmol) at
0 °C, and the reaction mixture was allowed to warm to
room temperature over 3 h. The reaction mixture was di-
luted with CH2Cl2 and was washed with water (3ꢂ) and
saturated aqueous CuSO4 (5ꢂ) followed by brine. The or-
ganic layer was dried over MgSO4 and concentrated under
reduced pressure. The residue was further purified by flash
Acknowledgment
Financial support by the National Institute of Health (GM
53386) is gratefully acknowledged.

1026
A. K. Ghosh et al. / Tetrahedron: Asymmetry 19 (2008) 1020–1026
9. Ispriyan, R. M.; Belen’kii, L. I.; Gol’dfarb, Y. L. Bull. Acad.
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