Pd(0) catalyzed intramolecular alkylation: stereoselective synthesis of furan and isoxazoline-2-oxide analogs

Article abstract of DOI:10.1016/j.tet.2006.11.066

New optically pure isoxazoline-2-oxide and furan analogs have been synthesized using Pd(0) catalyzed intramolecular cyclizations. Starting from a meso-diol, optically pure compounds were prepared without utilizing chiral ligands at any stage of the synthesis. The stereochemical outcome of the product (>99% ee) was influenced by desymmetrization catalyzed by Pseudomonas cepacia lipase and the stereoselective nature of the palladium catalyzed transformations.

Full text of DOI:10.1016/j.tet.2006.11.066

Tetrahedron 63 (2007) 1116–1126
Pd(0) catalyzed intramolecular alkylation: stereoselective
synthesis of furan and isoxazoline-2-oxide analogs
*
Pasha M. Khan, Ruizhi Wu and Kirpal S. Bisht
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA
Received 9 November 2006; accepted 22 November 2006
Available online 15 December 2006
Abstract—New optically pure isoxazoline-2-oxide and furan analogs have been synthesized using Pd(0) catalyzed intramolecular cycliza-
tions. Starting from a meso-diol, optically pure compounds were prepared without utilizing chiral ligands at any stage of the synthesis. The
stereochemical outcome of the product (>99% ee) was influenced by desymmetrization catalyzed by Pseudomonas cepacia lipase and the
stereoselective nature of the palladium catalyzed transformations.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
belong to important classes of pharmacophores found in
large number of natural products and are present in many
therapeutic agents.6 Furan derivatives have been used as
a building block for a large number of heterocyclic substruc-
tures and also as synthons in natural product synthesis.6k
Isoxazoline derivatives also have great biological impor-
tance, for example, many GPII/IIIa inhibitors and human
leukocyte elastase (HLE) inhibitors also have isoxazoline
skeleton.7 Isoxazoline derivatives have also been incorpo-
rated in fullerenes rendering special properties as nanoscale
connectors in molecular electronic devices.8 However, there
is a lack of convenient methods for the preparation of these
isoxazoline derivatives. The general strategy for synthesis of
these five-membered nitronates (isoxazoline-2-oxides) in-
volves cyclization of g-functionalized nitro compounds,9a,b
which themselves require tedious preparation. An alter-
native approach to their synthesis involves [3+2] cycloaddi-
tion of nitrile oxides with olefins,9c which however suffers
from another limitation of nitrile oxides undergoing rapid
dimerization to furoxan N-oxide.9d
The use of palladium catalysts in carbon–carbon and car-
bon–heteroatom bond forming reactions has been of great
synthetic utility.1,2 For example, Hayashi, et al.3 reported
that palladium(0) catalyzed reaction of dimethyl (Z)-2-but-
enylene dicarbonate with dimethyl malonate led to formation
of the (R)-dimethyl 2-vinylcyclopropane-1,1-dicarboxylate
(1); though in low enantiomeric excess (67%). Also reported
was the reaction of methyl acetyl acetate or acetylacetone
with 2-butenylene dicarbonate, which led to formation of
a trisubstituted furan derivative (2) (Scheme 1). The forma-
tion of compounds 1 and 2 has been rationalized through
a nucleophilic attack of the enolate carbon leading to the
C–C bond formation in 1 and the enolate oxygen leading
to the formation of the C–O bond in compound 2.3 In another
example of the carbon heteroatom bond formation, Mori4
and co-workers reported the formation of compounds 3
and 4 (Scheme 1) through the Pd(0) mediated alkylation.
Trost et al.5 have reported the formation of isoxazoline-2-
oxide 5 upon reaction of lithium[(phenylsulfonyl)methyl-
ene]nitronate with cis-1,4-diacetoxycyclopent-2-ene in
the presence of Pd(0) catalysts (Scheme 1). The authors
noted that ambivalent nature of the nitro-stabilized anions
permitted both C and O alkylations.
In this paper we explore the versatility of Pd catalyzed cycli-
zations and report stereoselective synthesis of several new
furan and isoxazoline derivatives under mild reaction condi-
tions. During preparation of this manuscript a report by
Tanimori et al.10 appeared that describes synthesis of the
substituted hydrofuran systems by Pd(0) catalyzed transfor-
mations.
The involvement of the heteroatom in the alkylation leading
to the substituted furan, lactams, isoxazoline, and other ring
systems provides opportunities for exploiting the palladium
catalyzed reaction in synthesis of these and other important
heterocyclic systems. Furan and isoxazoline derivatives
2. Results and discussion
The syntheses of furan and isoxazoline-2-oxide analogs
(Scheme 2) were achieved by an intramolecular Pd(0)
catalyzed cyclization and also involves enzymatic
Keywords: Isoxazoline-2-oxide; Furan; Palladium(0); Lipase.
* Corresponding author. Tel.: +1 813 974 0350; fax: +1 813 974 3203;
e-mail: kbisht@cas.usf.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.066

P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
1117
OCO2Me
MeO2C
O
MeO2C
COOMe
COOMe
CO2Me
O
H
-- Ref 3
(R)/(S)-BPPFA/Pd
(R)/(S)-BPPFA/Pd
COOMe
59% ee
2
THF(70%)
THF(70%)
1
67% ee
OCO2Me
CO2Me
COCH2CO2Me
Pd(OAc)2
CO2Me
COOMe
H
H
H
CONHBn
Pd(OAc)2
-- Ref 4
-- Ref 5
O
OBz
BzO
O
COOMe
35% ee
(S)-BINAPO
N
(S)-BINAPO
Bn
2% ee
H
3
4
SO2Ph
Pd2(dba)3.CHCl3
PPh3, THF, rt
ROCO
OCOR
NO2Li
N
O
PhO2S
+
O
5
Scheme 1. Synthesis of furans and isoxazoline-2-oxides via Pd catalyzed cyclization.
CO2C2H5
Y
HO
R3
Pd(0)
O
OCOCH3
7, 13-16
Pd(0)
O
R3
R3
N
O
CH3
O
O
Y
O2N
OC2H5
CH3
Scheme 2. Isoxazoline-2-oxides and furan analogs via Pd catalyzed cyclization.
desymmetrization of meso starting materials. The synthetic
approach described in this work brings the best of both
(chemical and enzymatic) approaches in organic synthesis.
potential in carrying out these desymmetrizations. Out of all
the hydrolases, lipases have been extensively used.13e meso-
2-Cycloalken-1,4-diols and diacetates have been subjected
to enzymatic desymmetrizations utilizing lipase B from
Candida antarctica (Novo SP-435) in organic and aqueous
media.13e Of a number of different available lipases, the
lipase from Pseudomonas cepacia (PS-30) was used to carry
out hydrolytic desymmetrization of the diacetate.13d PS-30
catalyzed reaction of meso-diacetate 6 produced monoace-
tate 7 in high enantiopurity (>97%) and 60% yield. Higher
conversion could not be achieved even with extended reac-
tion time. So, the recovered diacetate was again subjected
to hydrolysis with the recovered enzyme to obtain enantio-
pure monoacetate 7 ([a]2D0 +68.9 (CHCl3); lit.12 [a]D20
+69.6 (CHCl3)) in total yield of 90%. The absolute stereo-
chemistry of the monoacetate was established upon its
comparison with the literature data12,13e as (+)-(1S,4R)-4-
acetoxylcylcopent-2-en-1-ol. The enantiopurity of mono-
acetate 7 was confirmed by GC analyses upon injecting
racemic and enzymatically prepared monoacetate through
a cylcodexB (30 mꢁ0.25 mm, J&W scientific) chiral capil-
lary column.
Commercially available dicyclopentadiene was heated to
170 ꢀC to obtain the monomer cyclopentadiene, which was
oxidized using peracetic acid to its monoepoxide.11 The
monoepoxide was subsequently treated with acetic an-
hydride in the presence of Pd(PPh3)4 to obtain the meso-
3,5-diacetoxycyclopentene (6). The desymmetrization of
the meso-diacetate (6) with lipase to give the (+)-mono-
acetate (7) is the pivotal stereo-differentiation reaction
(Scheme 3). The desymmetrization of the meso-diacetate,
unlike resolution of a racemic substrate in which the yield
per enantiomer is limited to 50%, allowed conversion of
higher than 97% to the enantiomerically pure single enan-
tiomer.12 A simple protection/deprotection strategy would
enable access to the other enantiomer.
AcO
OAc
HO
Ref 13d
Lipase
OAc
Ref 11, 12
Dicyclopentadiene
meso- 6
7
[α]2D0 = +68.9
Monoacetate 7 was converted to ketone 8 using PCC (pyri-
dinium chlorochromate) in the presence of sodium acetate in
CH2Cl2 (Scheme 4).15 Ketone 8 was treated with alkyl lith-
ium to generate the cis-diols, 9–12 as the major products
(>98%). Spectral data for compounds 10–12 were in
complete agreement with the structures and for the known
Scheme 3. Formation of enantiopure (+)-monoacetate (7).
Enzymatic asymmetric induction is a powerful tool in
developing elegant synthetic methodologies for natural
products.13 We have recently reported chemoenzymatic
approach to enantioselective synthesis of both (R and S) en-
antiomers of imperanene, a platelet aggregation inhibitor.14
Desymmetrization of meso compounds is an extremely im-
portant reaction and involves elimination of one or more
symmetry elements in the substrate. A large number of com-
pounds including alcohols, esters, anhydrides, and nitriles
have been subjected to enzymatic desymmetrizations.13c
Hydrolases are the enzymes, which have shown immense
1
compound 9, H and 13C spectral data were identical to
that reported in the literature.16 Importantly, compound 11
produced colorless orthorhombic crystals and single crystal
X-ray diffraction experiment confirmed that the two hy-
droxyl groups are on the same side of the cyclopentene
ring thus confirming the cis relationship. The ORTEP
drawing is included in the Supplementary data. The absolute
stereochemistry of the molecule was also established as

1118
P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
HO
R3
HO
R3
OAc
HO
PCC
O
OH
OAc
OAc
excess R3Li
Ether, -78 °C
Ac2O, DMAP
THF
CH2Cl2
7
8
9-12
13-16
C-Ph ;
C-SiMe3
9, 13 : R3 = Me ; 10, 14 : R3 = Bu ; 11, 15 : R3 = C
12, 16 : R3 =C
Scheme 4. Syntheses of 13–16.
(1S,4R). Although diols 9, 10, and 12, did not crystallize but
all had the (+)-sign of optical rotation similar to that of 11.
Their absolute stereochemistry was therefore deduced as
1S,4R, identical to that of 11.
racemization (because of its proximity to the electron
withdrawing groups) and is involved in generation of a
carbanion in the following steps, no efforts were devoted
to its resolution and the mixture was taken for further steps
without separation.
The diols thus obtained were treated with 1 mol of acetic
anhydride and catalytic amount of DMAP to obtain the cor-
responding monoacetates (13–16) (Scheme 4). The mono-
acetates were then coupled to the soft nucleophiles generated
from the active methylene compounds (Table 1) via Pd
catalyzed alkylation to give compounds 17a–p (Scheme 5).
Acetates 18a–p were prepared by treating 17a–p with acetic
anhydride in the presence of excess triethylamine and cata-
lytic amount of DMAP. Most tertiary acetates but 18b and
18d were unstable and not amenable to purification on chro-
matographic columns and hence, were subjected to palla-
dium catalyzed alkylation without any further purification.
Table 1. Pd(0) catalyzed alkylation to obtain compounds 17a–p
Isoxazoline-2-oxides 19a–e were obtained in good to
excellent yield and in optically pure form upon treating the
acetates 18a–e, in presence of K2CO3 and palladium
tetrakistriphenylphosphine (Scheme 6, Table 2). Similar
reaction with the acetates 18f–m led to the formation of
the substituted dihydrofurans 19f–m in optically pure form
(Scheme 6, Table 2).
Compound R1
R2
R3
Diastereomeric Yield
ratio
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
17n
17o
17p
NO2
CO2Et
CO2Et Me
CO2Et Bu
CO2Et C^C–Ph
H
1.07:1
1.12:1
1.11:1
1.13:1
62
70
72
60
68
68
65
70
68
71
73
61
69
60
68
73
NO2
NO2
NO2
NO2
CO2Et C^C–SiMe3 1.15:1
COMe CO2Et
COMe CO2Et Me
COMe CO2Et Bu
H
1.04:1
1.28:1
1.19:1
1.07:1
1.15:1
1.13:1
1.06:1
CO2C2H5
CO2C2H5
H
AcO
R3
NO2
Pd(PPh3)4; THF
K2CO3
R3
COPh
COPh
COPh
COPh
COPh
CN
SO2Ph
SO2Ph Me
H
N
O
19a-e
O
18a-e
H
SO2Ph Bu
SO2Ph C^C–Ph
SO2Ph C^C–SiMe3 1.10:1
R2
H
R2
R3
AcO
R3
Pd(PPh3)4; THF
K2CO3
COR1
COOEt
PhSO2
CO2Me CO2Me
H
H
H
1.05:1
1.23:1
—
R1
19f-m
O
H
CN
18f-m
CO2CH3
CO2CH3
19p
CO2CH3
CO2CH3
Pd(PPh3)4; THF
K2CO3
AcO
H
18p
R1
R2
R1
R2
R1
6
R2
Bases used: NaH, K2CO3, KtOBu
5
OAc
HO
R3
AcO
R3
1
2
Ac2O, DMAP
THF
Base
4
3
HO
R3
Pd(0) catalysts used: Pd(PPh3)4, Pd2(dba)3
Pd(PPh3)4
PPh3
Scheme 6. Pd catalyzed intramolecular cyclization.
13-16
17a-p
18a-p
Scheme 5. Syntheses of compounds 17a–p via Pd(0) catalysis.
Table 2. Compounds 19a–m via Pd catalyzed cyclization
Compound R1
R2
R3
Yielda [a]D20 (CH2Cl2)
Pd catalyzed alkylation could result in the formation of a 1,2-
or 1,4-adduct,17 but under the conditions studied the reaction
proceeds with high regio- and stereo-selectivity to give the
1,4 adducts, 17a–p. The stereochemistry of the Pd catalyzed
allylation has been studied extensively and is known to pro-
ceed with retention of configuration via double inversion.17
19a
19b
19c
19d
19e
19f
19g
19h
19i
19j
19k
19l
19m
19n
19o
—
—
—
—
—
—
—
—
—
—
H
Me
85
64
70
63
67
85
57
55
>98
59
62
65
ꢂ95.2
ꢂ90.4
ꢂ88.3
ꢂ182.3
ꢂ177.2
ꢂ77.8
ꢂ146.1
ꢂ258.8
ꢂ20.0
ꢂ16.7
ꢂ10.0
ꢂ15.0
ꢂ20.1
—
Bu
C^C–Ph
C^C–SiMe3
H
Me
Bu
H
Me
Bu
C^C–Ph
C^C–SiMe3
H
H
Me CO2Et
Me CO2Et
Me CO2Et
Ph
Ph
Ph
Ph
Ph
As evident from the mechanism for these alkylations
(Scheme 5) compounds 17a–o would be a mixture of a pair
of diastereomers at the site of the carbon–carbon bond
formation (C–6). The diastereomeric ratio of 17a–o deter-
mined from integral value of the H-6, H-2, and H-3 reso-
nances in their 1H spectra was calculated to be w1:1
(Table 1). These pairs of diastereomers were inseparable on
a chromatographic column and appeared as a single spot on
a TLC plate. As the diastereotopic center (C-6) is prone to
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
64
b
CN COOEt
CN SO2Ph
—
—
b
—
a
Product isolated after column chromatography.
Starting material was recovered.
b

P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
1119
B-
H
H
R2
Z
R2
R2
Z
R2
Z
H
H
R3
R3
AcO
R3
R3
K2CO3
R1
R1
R1
Z
R1
Pd(PPh3)4
THF
O
O
LnPd
PdLn
H
O
O
Z= C, N
18a-m
19a-m
Scheme 7. Mechanism for the formation of isoxazoline-2-oxide and furan systems.
It is noteworthy to mention that starting from a meso-diol,
optically pure compounds were prepared without utilizing
chiral ligands at any stage of the reaction. The stereo-
chemical outcome of the product is solely influenced by
the P. cepacia lipase and the stereoselective nature of the
palladium catalyzed transformations. Literature reports on
the synthesis of the furan derivatives have been catalyzed
by palladium(0) in presence of chiral ligands leading to, at
best, modest enantioenrichments.3,4,10 The cyclization reac-
tions were also evaluated in presence of various bases, i.e.,
NaH, K2CO3, and KOtBu (Scheme 6) in THF using catalytic
amount of Pd(0) catalysts. The yield of the reaction was
independent of the base used. For all reactions recorded in
Table 2 K2CO3was used as the base. Pd(PPh3)4 and
Pd2(dba)3 were the two Pd(0) catalysts evaluated in this re-
action and identical results were obtained. Pd(II) catalysts
like PdCl2 did not catalyze the cyclization. The cyclizations
were also attempted in absence of base or catalyst and such
variations did not give the desired product indicating that
both base and the catalyst are vital for this cyclization.
nucleophile proceed in an anti fashion with respect to metal
resulting in a highly stereoselective reaction.18 One of the
isoxazoline-2-oxide 19d produced colorless orthorhombic
crystals. The single crystal X-ray diffraction experiment
confirmed its structure (Supplementary data). Unfortunately,
the X-ray data could not establish the absolute stereochem-
istry of 19d but it is deduced from the stereochemistry of the
monoacetate 7, as (1S,5S)-3-aza-4-(ethoxycarbonyl)-7-phe-
nylethynyl-2-oxabicyclo[3.3.0]oct-3,7-diene-3-oxide.
Compounds 18n and 18o, containing a –CN group, did not
give the desired bicyclic system; starting material was
1
always recovered and confirmed by H NMR. In order to
obtain the ee, compound 19a was treated with chiral
shift-reagent, europium tris[3-(hepta-fluoropropylhydroxy-
methylene)-(+)-camphorate] and H NMR indicated enan-
tiomeric excesses for compound 19a to be >97%.
1
Figure 1 shows 1H NMR comparison of racemic and enan-
tioenriched 19a in presence (+)-Eu(hfc)3. The H-3 signals
were used for calculation of % ee. The absence of doublet
at 5.9 ppm in enantioenriched 19a indicates a >97% ee.
Interestingly, compound 18p led to an unusual product
19p, which most probably results from an interconversion
between the two p-allyl complexes I and II (Scheme 8).19
Mechanism for formation of compounds 19a–m is shown in
Scheme 7, where the base deprotonates the methine proton
between the two electron-withdrawing groups. The carban-
ion thus generated results in the formation of 19a–m via
electron-flow through NO2 group (for isoxazoline-2-oxides)
or enolate oxygen (for furan) (Scheme 7). The stereochem-
ical outcome of the reaction is the result of two sequential
steps. First is the formation of the Pd p-allyl complex
formed on the opposite side of the OAc leaving group be-
cause of steric control. In the second step, the attack of the
In summary, we have studied Pd catalyzed cyclization to ob-
tain optically pure furan and isoxazoline-2-oxide analogs
that is practical, and utilizes mild reaction conditions. The
method involves tandem use of the enzymatic and chemical
catalysis. The key step is the desymmetrization of the meso-
H-3
(-)
(a)
COOEt
5
6
4
1
N
O
3
2
O
(-)
H-
1
H-2
COOEt
5
6
H-3
4
(b)
1
N
O
3
2
O
(-)
(+)
H-2
( )
H-1
6.6
6.5
6.4
6.3
6.2
6.1
6.0
5.9
PPM
Figure 1. 1H NMR of compound 19a: (a) enantioriched and (b) racemic in the presence of (+)-Eu(hfc)3.

1120
P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
CO2CH3
CO2CH3
3.2.1. (D)-(1S,4R)-4-Acetoxylcylcopent-2-en-1-ol
(7).11,12,13d meso-Diacetate 6,13d (10 g, 0.054 mol) was
taken in a mixture of phosphate buffer (pH 7.0; 75 ml) and
acetone (5 ml) in a round bottom flask. Lipase PS-30
(500 mg) was added while maintaining the pH of the reac-
tion mixture at 7.0 using 1 N NaOH solution. The reaction
was stopped when no change in the pH of the reaction me-
dium occurred. The conversion at this point was estimated
to be w60% by TLC. The reaction mixture was extracted
with ethyl acetate (3ꢁ200 mL). The organic layer was dried
over Na2SO4 and concentrated by rotoevaporation. The
crude product was subjected to column chromatography
over silica gel using ethyl acetate/hexane (1:3) to isolate
the monoacetate 7 as a white solid, mp 40–42 ꢀC; [a]D20
+68.9 (CHCl3); lit.12 [a]D20 +69.6 (CHCl3); 1H NMR (CDCl3,
400 MHz): d 1.60 (dt, 1H, J¼14.8, 4.0 Hz), 2.01 (s, 3H),
2.76 (p, 1H, J¼7.2 Hz), 4.6 (m, 1H), 5.4 (m, 1H), 5.94 (d,
1H, J¼4.0 Hz), 6.06 (m, 1H) ppm; 13C NMR (CDCl3,
100 MHz): d 20.5, 40.4, 74.6, 77.2, 132.3, 139.1, 171.3 ppm.
CO2CH3
CO2CH3
Pd(PPh3)4,THF
Base
AcO
H
19p
18p
CO2CH3
CO2CH3
CO2CH3
CO2CH3
H
H
H
B
H
B
L2Pd
I
CO2CH3
CO2CH3
H
L2Pd
II
Scheme 8. Plausible mechanism for the formation of compound 19p.
diacetate (6) using commercially available P. cepacia lipase
(PS-30), in high ee. We have also demonstrated the compat-
ibility of this Pd(0) catalyzed cyclization with wide spec-
trum of functional groups like NO2, COOR, COR, and
SO2R. This work provides a new pathway to obtain optically
pure furan and isoxazoline-2-oxide analogs, which are rather
difficult to obtain via previous strategies.
3.2.2. (R)-4-Acetoxy-2-cyclopenten-1-one (8).15 Viscous
liquid; H NMR (CDCl3, 250 MHz): d 2.03 (s, 3H), 2.22
1
(dt, 1H, J¼18.7, 2.2 Hz), 2.73 (dt, 1H, J¼19.0, 6.75 Hz),
5.78 (m, 1H), 6.26 (d, 1H, J¼5.7 Hz), 7.5 (m, 1H) ppm;
13C NMR (CDCl3, 62.5 MHz): d 20.8, 40.9, 71.9, 136.9,
158.9, 170.4, 204.8 ppm.
3. Experimental
3.1. General
3.3. General procedure for preparation of compounds
9–12
Lipase PS-30 was a generous gift from Amano Enzyme. 1H
NMR and 13C NMR spectra were recorded on a Bruker
250 MHz spectrometer and Varian 400, 500 MHz in CDCl3
and acetone-d6 with TMS as the standard. Chemical shifts
are reported in parts per million, multiplicities are indicated
by s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), h
(sextet), m (multiplet) and br s (broad singlet). Optical rota-
tions were measured with a Rudolph Research Analytical
AutoPol IV Automatic polarimeter. Thin-layer chromato-
graphy (TLC) was performed on glass plates coated with
0.25 mm thickness of silica gel. All solvents were dried
and distilled prior to use and organic solvent extracts dried
over Na2SO4. Mass calculations were carried out on an ESI
LC MS system (Agilent Technologies). GC studies were
carried out on Shimadzu gas chromatogram (Model 17A).
A cyclodextrin column (30 mꢁ0.25 mm) from J&W Scien-
tific was used for determining the ee of the monoacetate 7.
To a solution of (R)-4-acetoxy-2-cyclopenten-1-one 8
(200 mg, 1.428 mmol) in freshly distilled ether (15 ml) at
ꢂ78 ꢀC was added 1.6 M solution of methyl lithium in ether
(3.57 ml, 5.712 mmol) under a nitrogen atmosphere. The re-
action was allowed to stir for 1 h and was quenched using
NH4Cl solution. The product was purified by column chro-
matography using ethyl acetate/hexane (2:1) to afford 9
(150 mg, yield¼92%) as a viscous liquid.
3.3.1. (1S,4R)-1-Methylcyclopent-2-ene-1,4-diol (9). Vis-
cous liquid; [a]2D0 +55.2 (c 0.02, acetone); 1H NMR
(CDCl3, 250 MHz): d 1.27 (s, 3H, CH3), 1.71 (dd, 1H,
J¼14.5, 2.7 Hz), 2.29 (dd, 1H, J¼14.5, 7.2 Hz), 3.9 (br s,
2H), 4.58 (d, 1H, J¼6.2 Hz), 5.79 (m, 2H) ppm; 13C NMR
(CDCl3, 62.5 MHz): d 27.5, 49.5, 75.2, 81.2, 134.0,
141.0 ppm. HRESIMS calcd for C6H11O2 ([M+H]+):
115.0759; found: 115.0758.
3.2. X-ray crystallography
3.3.2. (1S,4R)-1-Butyl-cyclopent-2-ene-1,4-diol (10). Vis-
cous liquid; [a]D20 +50.2 (c 0.03, CH2Cl2); 1H NMR
(CDCl3, 250 MHz): d 0.81 (t, 3H, CH3, J¼6.7 Hz), 1.24
(m, 2H), 1.55 (m, 5H, H-4+OH), 1.60 (dd, 1H, J¼5.5,
3.2 Hz), 2.03 (s, 1H, OH), 2.31 (dd, 1H, J¼14.2, 7.0 Hz),
4.60 (d, 1H, J¼5.5 Hz), 5.83 (m, 2H) ppm; 13C NMR
(CDCl3, 62.5 MHz): d 14.0, 23.0, 26.5, 40.1, 48.2, 75.4,
84.1, 135.0, 140.0 ppm. HRESIMS calcd for C9H17O2
([M+H]+): 157.1229; found: 157.1221.
Single-crystal X-ray diffraction data for the compounds 11
and 19d were collected on a Bruker SMART-APEX CCD
Diffractometer with Kyroflex Low Temperature System us-
˚
ing Mo Ka radiation (l¼0.71073 A), operating in the U and
4 scan mode. Diffracted data were corrected for absorption
using the SADABS program. Crystallographic data (exclud-
ing structure factors) for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
622489 and 622490. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union road,
Cambridge CB2 1EZ, UK (fax: +44 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
3.3.3. (1S,4R)-1-Phenylethynyl-cyclopent-4-ene-1,4-diol
(11). White solid: mp¼114–116 ꢀC; [a]D20 +330.5 (c 0.11,
acetone); 1H NMR (CDCl3, 250 MHz): d 1.97 (s, 1H, OH),
2.00 (s, 1H, OH), 2.04 (dd, 1H, J¼14.0, 3.2 Hz), 2.82 (dd,
1H, J¼14.0, 6.7 Hz), 4.78 (dd, 1H, J¼6.7, 3.2 Hz), 6.01 (s,

P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
1121
2H), 7.26–7.32 (m, 5H) ppm; 13C NMR ((CD3)2CO,
62.5 MHz): d 52.4, 75.0, 76.2, 83.3, 93.3, 123.9, 129.1,
129.3, 132.2, 136.9, 137.7 ppm. HRESIMS calcd for
C13H13O2 ([M+H]+): 201.0916; found: 201.0921.
J¼5.5 Hz), 7.20–7.35 (m, 5H) ppm; 13C NMR (CDCl3,
62.5 MHz): d 21.2, 47.8, 76.0, 77.1, 84.5, 90.2, 122.2,
128.3, 128.6, 131.6, 132.0, 139.7, 170.9 ppm. HRESIMS
calcd for C15H15O3 ([M+H]+): 243.1021; found: 243.1018.
3.3.4. X-ray crystallographic data for (11). In the crystal
of (1S,4R)-1-phenylethynyl-cyclopent-4-ene-1,4-diol, four
molecules were found in each unit cell. The compound
crystallized in an orthorhombic space group P2 (1), with
3.4.4. (1R,4S)-4-Hydroxy-4-trimethylsilanylethynyl-
2-cyclopenten-1-yl acetate (16). 1H NMR (CDCl3,
250 MHz): d 0.20 (s, 9H), 1.99 (s, 3H), 2.02 (dd, 1H,
J¼14.5, 3.7 Hz), 2.50 (s, 1H, OH), 2.84 (dd, 1H, J¼14.5,
7.5 Hz), 5.54 (m, 1H), 5.93 (dd, 1H, J¼5.2, 2.0 Hz), 6.00
(d, 1H, J¼5.5 Hz) ppm; 13C NMR (CDCl3, 62.5 MHz):
d ꢂ0.3, 21.1, 47.5, 75.4, 76.8, 85.0, 105.9, 132.6, 139.9,
170.7 ppm. HRESIMS calcd for C12H19O3Si ([M+H]+):
239.1104; found: 239.1101.
˚
˚
cell dimensions a¼5.3082(10) A, b¼8.4869(16) A, c¼
˚
17.005(3) A. A total of 5642 unique reflection data were
obtained to give a final R index [l>2s(I)] of R1¼0.0337,
wR2¼0.0894 and
wR2¼0.0918.
R
indices (all data) R1¼0.0365,
3.3.5. (1S,4R)-1-Trimethylsilanylethynyl-cyclopent-4-
ene-1,4-diol (12). Viscous liquid; [a]2D0 +278.2 (c 0.03,
CH2Cl2); 1H NMR (CDCl3, 250 MHz): d 0.23 (s, 9H),
1.90 (br s, 1H, OH), 1.94 (dd, 1H, J¼14.2, 3.5 Hz), 2.47
(s, 1H, OH), 2.72 (dd, 1H, J¼14.2, 7.0 Hz), 4.72 (m, 1H),
5.91 (d, 1H, J¼5.5 Hz), 5.97 (dd, 1H, J¼5.5, 2.0 Hz) ppm;
13C NMR (CDCl3, 62.5 MHz): d ꢂ0.5, 50.6, 75.0, 75.6,
85.3, 105.8, 136.5, 137.4 ppm. HRESIMS calcd for
C10H17O2Si ([M+H]+): 197.0998; found: 197.0995.
3.5. General procedure for preparation of compounds
17a–p (Scheme 5)
To a solution of ethyl nitroacetate (100 mg, 0.752 mmol) in
dry THF (10 ml) at room temperature was added potassium
carbonate (110 mg, 0.800 mmol) under a nitrogen atmo-
sphere. The reaction was allowed to stir for 20 min and
Pd(PPh3)4 (43.4 mg, 0.037 mmol), PPh3 (197 mg,
0.752 mmol), and monoacetate 7 (106 mg, 0.752 mmol) dis-
solved in 5 ml THF was added to it. The reaction was
allowed to stir at 40 ꢀC for 12 h and then vacuum filtered
through Celite with subsequent concentration of the filtrate.
The product was purified by column chromatography using
ethyl acetate/hexane (1:2) to afford 17a (120 mg, yield¼
62%) as a yellow viscous liquid.
3.4. General procedure for preparation of compounds
13–16
To a solution of 9 (100 mg, 0.877 mmol) in dry THF (10 ml)
at room temperature was added acetic anhydride (89 mg,
0.877 mmol), and catalytic amount of DMAP. The reaction
was allowed to stir for 3 h and then concentrated. The resi-
due was taken in ethyl acetate (40 ml) and was treated twice
with saturated sodium bicarbonate solution (20 ml), fol-
lowed by brine (10 ml). The organic layer was dried over
sodium sulfate and the resulting product 13 was purified
by column chromatography using ethyl acetate/hexane
(1:2) (80.25 mg, yield¼58.77%).
3.5.1. Ethyl (2R/S,10R,40S)-2-(40-hydroxy-20-cyclopenten-
10-yl)-2-nitroacetate (17a). Viscous yellow liquid; 1H
NMR (CDCl3, 400 MHz): d 1.25 (t, 3H, J¼7.2 Hz), 1.57
(m, 1H), 1.92 (br s, 1H), 2.50 (m, 1H), 3.46 (t, 1H,
J¼2.4 Hz), 4.23 (q, 2H, J¼6.8 Hz), 4.79 (br s, 1H), 5.06
(t, 1H, J¼8.0 Hz), 5.74–5.83 (dd, 1H, J¼6.0, 4.8 Hz),
5.95–5.97 (m, 1H); 13C NMR (CDCl3, 100 MHz): d 14.0,
36.2, 36.8, 45.4, 45.1, 63.3, 76.0, 76.3, 91.0, 91.4, 131.6,
132.0, 137.7, 137.9, 163.8, 163.9 ppm. HRESIMS calcd
for C9H14NO5 ([M+H]+): 216.0872; found: 216.0875.
3.4.1. (1R,4S)-4-Hydroxy-4-methyl-2-cyclopenten-1-yl
acetate (13). H NMR (CDCl3, 250 MHz): d 1.32 (s, 3H),
1
1.80 (dd, 1H, J¼14.5, 3.5 Hz), 1.97 (s, 3H), 2.2 (br s, 1H),
2.36 (dd, 1H, J¼14.5, 7.5 Hz), 5.46 (m, 1H), 5.76 (d, 1H, J¼
5.5 Hz), 5.92 (d, 1H, J¼5.5 Hz) ppm; 13C NMR (CDCl3,
62.5 MHz): d 21.2, 27.3, 46.7, 77.6, 80.9, 130.2, 143.2,
170.8 ppm. HRESIMS calcd for C8H13O3 ([M+H]+):
157.0865; found: 157.0871.
3.5.2. Ethyl (2R/S,10R,40S)-2-(40-hydroxy-4-methyl-20-
cyclopenten-10-yl)-2-nitroacetate (17b). Viscous yellow
liquid; 1H NMR (CDCl3, 250 MHz): d 1.21 (t, 3H,
J¼7.5 Hz), 1.34 (s, 3H), 1.79 (dt, 1H, J¼14.2, 5.0 Hz),
1.95 (br s, 1H), 2.19 (dd, 1H, J¼14.2, 8.2 Hz), 3.50 (m,
1H), 4.19 (q, 2H, J¼7.5 Hz), 5.03 (t, 1H, J¼8.2 Hz), 5.59
(2dd, 1H, J¼5.5, 2.0 Hz), 5.82 (dt, 1H, J¼5.5, 2.0 Hz) ppm;
13C NMR (CDCl3, 62.5 MHz): d 13.9, 27.5, 27.6, 42.2, 42.8,
45.1, 45.5, 63.1, 82.1, 82.4, 90.6, 91.0, 129.1, 129.6, 141.8,
142.1, 163.7 ppm. HRESIMS calcd for C10H16NO5
([M+H]+): 230.1029; found: 230.1034.
3.4.2. (1R,4S)-4-Hydroxy-4-butyl-2-cyclopenten-1-yl
acetate (14). Viscous liquid; H NMR (CDCl3, 250 MHz):
1
d 0.84 (t, 3H, J¼6.7 Hz), 1.26 (m, 4H), 1.54 (m, 2H), 1.72
(m, 2H, 1H+OH), 1.97 (s, 3H), 2.40 (dd, 1H, J¼14.7,
7.5 Hz), 5.43 (m, 1H), 5.80 (dd, 1H, J¼5.5, 2.2 Hz), 5.91
(dd, 1H, J¼4.7, 0.7 Hz); 13C NMR (CDCl3, 62.5 MHz):
d 14.0, 21.2, 23.1, 26.4, 40.0, 45.0, 77.5, 83.8, 131.0,
142.0, 170.9 ppm. HRESIMS calcd for C11H19O3 ([M+H]+):
199.1334; found: 199.1333.
3.5.3. Ethyl (2R/S,10R,40S)-2-(40-hydroxy-4-butyl-20-
cyclopenten-10-yl)-2-nitroacetate (17c). Viscous yellow
liquid; 1H NMR (CDCl3, 250 MHz): d 0.90 (t, 3H, J¼
7.0 Hz), 1.2–1.4 (m, 7H, 2CH2+CH3), 1.61 (t, 2H, J¼
7.0 Hz), 1.75 (dt, 1H, J¼14.2, 4.5 Hz), 1.89 (s, OH), 2.30
(dd, 1H, J¼14.2, 8.2 Hz), 3.53 (m, 1H), 4.26 (q, 2H,
J¼7.2 Hz), 5.15 (dd, 1H, J¼8.2, 6.5 Hz), 5.70 (dd, 0.5H,
J¼5.7, 2.0 Hz), 5.77 (dd, 0.5H, J¼5.7, 2.2 Hz), 5.88 (dt,
1H, J¼5.5, 2.2 Hz) ppm; 13C NMR (CDCl3, 62.5 MHz):
3.4.3. (1R,4S)-4-Hydroxy-4-phenylethynyl-2-cyclo-
penten-1-yl acetate (15). Viscous liquid; 1H NMR
(CDCl3, 250 MHz): d 1.98 (s, 3H), 2.09 (dd, 1H, J¼14.5,
3.7 Hz), 2.82 (s, 1H), 2.91 (dd, 1H, J¼14.5, 7.2 Hz), 5.6
(m, 1H), 5.92 (dd, 1H, J¼5.5, 2.2 Hz), 6.07 (d, 1H,

1122
P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
d 13.9, 14.0, 23.0, 26.3, 40.4, 41.0, 45.2, 45.4, 63.1, 85.1,
91.1, 129.8, 130.2, 140.7, 140.9, 161.5 ppm. HRESIMS
calcd for C13H22NO5 ([M+H]+): 272.1498; found: 272.1493.
3.5.9. 2-Phenylsulfonyl (2R/S,10R,40S)-2-(40-hydroxy-20-
cyclopenten-10-yl)-1-phenyl-ethanone (17i). Viscous yel-
low liquid; H NMR (CDCl3, 250 MHz): d 1.26–2.2 (dt,
1
1H, J¼14.0, 4.5 Hz), 2.52 (m, 2H), 3.32 (m, 1H), 4.67–
4.80 (m, 1H), 5.05 (dd, 1H, J¼21.2, 9.5 Hz), 5.45–5.49
(ddd, 1H, J¼5.7, 2.5, 1.0 Hz), 5.8–5.9 (dt, 1H, J¼5.7,
2.5 Hz), 7.3–7.7 (m, 10H) ppm; 13C NMR (CDCl3,
62.5 MHz): d 38.2, 38.4, 43.5, 44.0, 74.0, 74.3, 75.7,
128.7, 128.8, 128.9, 129.7, 129.8, 133.7, 134.0, 134.2,
134.6, 136.2, 137.1, 137.17, 192.9, 193.3 ppm. HRESIMS
calcd for C19H19O4S ([M+H]+): 343.1094; found: 343.1097.
3.5.4. Ethyl (2R/S,10R,40S)-2-(40-hydroxy-4-phenyl-
ethynyl-20-cyclopenten-10-yl)-2-nitroacetate (17d). Vis-
cous yellow liquid; H NMR (CDCl3, 250 MHz): d 1.24
1
(dt, 3H, J¼6.7, 1.0 Hz), 2.1 (m, 1H), 2.53 (d, 1H,
J¼2.7 Hz, OH), 2.74 (m, 1H), 3.65 (m, 1H), 4.19 (q, 2H,
J¼6.7 Hz), 5.06 (dd, 1H, J¼9.0, 1.0 Hz), 5.79, 5.87 (2dd,
1H, J¼5.5, 2.0 Hz), 6.00 (dt, 1H, J¼5.5, 1.7 Hz), 7.22–
7.36 (m, 5H) ppm; 13C NMR (CDCl3, 62.5 MHz): d 13.9,
43.7, 44.4, 44.9, 45.2, 63.21, 63.26, 76.5, 77.5, 85.2, 89.8,
90.6, 90.8, 122.1, 128.3, 128.7, 131.5, 131.6, 132.0, 138.8,
138.9, 163.5 ppm. HRESIMS calcd for C17H18NO5
([M+H]+): 316.1185; found: 316.1180.
3.5.10. 2-Phenylsulfonyl (2R/S,10R,40S)-2-(40-hydroxy-4-
methyl-20-cyclopenten-10-yl)-1-phenyl-ethanone (17j).
Viscous yellow liquid; 1H NMR (CDCl3, 250 MHz):
d 1.36 (s, 3H), 1.49 (dd, 1H, J¼14.0, 5.0 Hz), 2.05 (m,
1H), 2.29 (s, 1H, OH), 3.16–3.39 (m, 1H), 5.14 (dd, 1H,
J¼9.7, 2.5 Hz), 5.53, 5.78 (from 2 diastereomers) (2dd,
1H, J¼5.5, 2.5 Hz), 6.14 (dd, 1H, J¼5.2, 1.7 Hz), 7.29–
7.86 (m, 10H); 13C NMR (CDCl3, 62.5 MHz): d 27.5,
29.6, 43.3, 43.5, 43.6, 44.2, 64.1, 64.2, 82.2, 82.3, 127.9,
128.4, 128.5, 128.74, 128.76, 130.1, 130.4, 131.8, 132.3,
132.6, 133.8, 180.9, 190.4 ppm. HRESIMS calcd for
C20H21O4S ([M+H]+): 357.1161; found: 357.1158.
3.5.5. Ethyl(2R/S,10R,40S)-2-(40-hydroxy-4-trimethylsila-
nylethynyl-20-cyclopenten-10-yl)-2-nitroacetate (17e).
Viscous yellow liquid, 1H NMR (CDCl3, 250 MHz):
d 0.19 (s, 9H), 1.21 (t, 3H, J¼7.0 Hz, CH3), 1.93 (m, 1H),
2.50 (s, 1H, OH), 2.74 (m, 1H), 3.62 (m, 1H), 4.20 (q, 2H,
J¼6.7 Hz, CH2), 5.03 (dd, 1H, J¼9.0, 1.0 Hz), 5.75–5.81
(2dd, 1H, J¼5.5, 2.0 Hz), 6.01 (dt, 1H, J¼5.5, 1.7 Hz) ppm;
13C NMR (CDCl3, 62.5 MHz): d ꢂ0.2, 14.0, 42.7, 44.2,
60.5, 72.3, 75.4, 85.2, 90.8, 132.6, 148.1, 167.3 ppm.
HRESIMS calcd for C14H22NO5Si ([M+H]+): 312.1267;
found: 312.1264.
3.5.11. 2-Phenylsulfonyl (2R/S,10R,40S)-2-(40-hydroxy-4-
butyl-20-cyclopenten-10-yl)-1-phenyl-ethanone (17k).
Viscous yellow liquid; 1H NMR (CDCl3, 250 MHz):
d 0.79 (t, 3H), 1.18 (m, 4H, 2CH2), 1.46 (m, 3H, CH2+
1H), 1.89 (s, 1H, OH), 2.01 (dd, 1H, J¼13.7, 8.0 Hz), 3.40
(m, 1H), 5.15 (d, 1H, J¼9.7 Hz), 5.35 (dd, 0.5H, J¼5.5,
1.7 Hz), 5.68 (dd, 0.5H, J¼5.5, 2.0 Hz), 5.78 (dd, 0.5H,
J¼5.5, 1.5 Hz), 6.23 (dd, 0.5H, J¼5.7, 2.0 Hz), 7.29–
7.86 (m, 10H, COPh+PhSO2) ppm; 13C NMR (CDCl3,
62.5 MHz): d 12.8, 22.0, 25.3, 25.4, 39.3, 39.5, 41.5, 41.6,
42.6, 43.2, 72.9, 73.0, 83.4, 84.4, 127.73, 127.79, 127.8,
128.6, 128.7, 131.1, 132.0, 132.9, 133.1, 136.0, 136.2,
138.2, 191.9 ppm. HRESIMS calcd for C23H27O4S
([M+H]+): 399.1630; found: 399.1634.
3.5.6. Ethyl (2R/S,10R,40S)-2-(40-hydroxy-20-cyclopenten-
10-yl)-3-oxobutanoate (17f). Viscous yellow liquid; 1H
NMR (CDCl3, 250 MHz): d 1.18 (t, 3H, J¼7.2 Hz), 1.28
(t, 1H, J¼7.0 Hz), 2.18 (s, 3H), 2.37 (p, 1H, J¼7.2 Hz),
3.19 (m, 1H), 3.45 (m, 1H), 4.14 (q, 2H, J¼7.2 Hz), 4.6
(m, 1H), 5.67–5.83 (m, 2H) ppm; 13C NMR (CDCl3,
62.5 MHz): d 14.2, 29.7, 29.9, 37.2, 37.8, 43.1, 43.2, 61.0,
64.7, 65.1, 76.22, 76.28, 134.2, 134.6, 135.2, 135.5, 168.7,
169.0, 202.61, 202.66 ppm. HRESIMS calcd for C11H17O4
([M+H]+): 213.1127; found: 213.1134.
3.5.7. Ethyl (2R/S,10R,40S)-2-(40-hydroxy-4-methyl-20-
cyclopenten-10-yl)-3-oxobutanoate (17g). Viscous yellow
liquid; 1H NMR (CDCl3, 250 MHz): d 1.20 (t, 3H,
J¼7.0 Hz), 1.29 (s, 3H), 1.50–1.71 (2dd, 1H, J¼14.0,
5.2 Hz), 2.16 (m, CH3+H-5), 2.55 (br s, 1H, OH), 3.24 (m,
1H), 3.47 (dd, 1H, J¼8.7, 3.0 Hz), 4.13 (q, 2H, J¼7.0 Hz),
5.52–5.62 (2dd, 1H, J¼5.2, 2.5 Hz), 5.7 (dd, 1H, J¼5.5,
2.0 Hz) ppm; 13C NMR (CDCl3, 62.5 MHz): d 14.0, 27.5,
29.6, 30.0, 43.3, 43.5, 43.6, 44.2, 61.4, 64.1, 64.2, 82.2,
82.3, 131.8, 132.3, 139.7, 140.0, 168.8, 169.1, 202.3 ppm.
HRESIMS calcd for C12H19O4 ([M+H]+): 227.1283; found:
227.1280.
3.5.12. 2-Phenylsulfonyl (2R/S,10R,40S)-2-(40-hydroxy-4-
phenylethynyl-20-cyclopenten-10-yl)-1-phenyl-ethanone
(17l). Viscous yellow liquid; H NMR (CDCl3, 250 MHz):
1
d 1.72 (dd, 0.5H, J¼14.2, 4.0 Hz), 2.47 (dd, 0.5H, J¼14.2,
7.2 Hz), 2.73 (m, 2H), 3.47 (m, 1H), 5.15 (dd, 0.5H,
J¼15.0, 10.0 Hz), 5.49 (dd, 0.5H, J¼5.2, 2.0 Hz), 5.84
(dd, 1H, J¼5.2, 1.5 Hz), 5.99 (dd, 0.5H, J¼5.2, 1.0 Hz),
6.47 (dd, 0.5H, J¼5.2, 2.2 Hz), 7.15–7.86 (m, 15H) ppm;
13C NMR (CDCl3, 62.5 MHz): d 43.5, 44.1, 45.4, 45.7,
73.5, 73.9, 76.5, 77.4, 84.9, 85.0, 90.2, 90.4, 122.2, 122.3,
128.3, 128.3, 128.5, 128.8, 128.92, 128.97, 129.7, 129.8,
131.6, 131.7, 133.9, 134.1, 134.2, 135.1, 136.9, 137.04,
137.08, 137.2, 137.6, 192.8, 193.2 ppm. HRESIMS calcd
for C27H23O4S ([M+H]+): 443.1317; found: 443.1321.
3.5.8. Ethyl (2R/S,10R,40S)-2-(40-hydroxy-4-butyl-20-
cyclopenten-10-yl)-3-oxobutanoate (17h). 1H NMR
(CDCl3, 250 MHz): d 0.83 (t, 3H, J¼7.0 Hz), 1.21 (m, 7H,
CH3+2CH2), 1.50 (m, 4H, 1H+CH2+OH), 2.17 (m, 4H,
CH3+1H), 3.21 (m, 1H), 3.45 (dd, 1H, J¼5.2, 3.0 Hz), 4.11
(q, 2H, J¼7.0 Hz), 5.67 (m, 2H) ppm; 13C NMR (CDCl3,
62.5 MHz): d 13.0, 13.1, 22.1, 25.4, 25.6, 28.6, 29.0, 39.45,
39.47, 41.2, 41.4, 42.3, 42.5, 60.5, 63.3, 63.4, 84.1, 84.4,
132.1, 133.4, 137.1, 137.4, 167.8, 201.4 ppm. HRESIMS
calcd for C15H25O4 ([M+H]+): 269.1753; found: 269.1756.
3.5.13. Ethyl (2R/S,10R,40S)-2-(40-hydroxy-4-trimethyl-
silanylethynyl-20-cyclopenten-10-yl)-1-phenyl-ethanone
(17m). Viscous yellow liquid; 1H NMR (CDCl3, 250 MHz):
d 0.19 (s, 9H), 1.85 (dd, 1H, J¼14.2, 4.0 Hz), 2.47 (s, 1H,
OH), 2.73 (m, 1H), 3.49 (m, 1H), 5.14 (d, 1H, J¼10.0 Hz),
5.45 (dd, 0.5H, J¼5.2, 2.0 Hz), 5.79 (dd, 0.5H, J¼5.2,
1.5 Hz), 5.97 (dd, 0.5H, J¼5.2, 1.0 Hz), 6.37 (dd, 0.5H,
J¼5.2, 2.2 Hz), 7.15–7.86 (m, 10H) ppm; 13C NMR (CDCl3,

P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
1123
62.5 MHz): d ꢂ0.3, 43.52, 43.56, 45.4, 45.5, 73.71, 73.74,
75.23, 75.29, 87.9, 89.0, 106.1, 106.2, 122.3, 123.0, 128.4,
128.5, 129.01, 129.08, 130.4, 133.9, 135.1, 136.1, 137.8,
140.5, 140.6, 197.5, 197.6 ppm. HRESIMS calcd for
C24H27O4SSi ([M+H]+): 439.1399; found: 439.1395.
1H NMR (CDCl3, 250 MHz): d 1.21 (t, 3H, J¼7.0 Hz), 1.5
(s, 3H), 1.91 (s, 3H), 2.02 (dt, 1H, J¼14.2, 4.5 Hz), 2.21
(m, 1H), 3.52 (m, 1H), 4.2 (q, 2H, J¼7.0 Hz), 4.99 (dd,
1H, J¼9.2, 2.0 Hz), 5.71 (dd, 0.5H, J¼5.5, 2.5 Hz), 5.76
(dd, 0.5H, J¼5.7, 2.5 Hz), 6.13 (dt, 1H, J¼5.5, 2.0 Hz) ppm;
13C NMR (CDCl3, 62.5 MHz): d 13.9, 22.0, 24.5, 24.6, 40.3,
41.0, 44.5, 45.0, 63.1, 90.1, 90.4, 90.8, 131.2, 131.6, 138.6,
138.8, 163.5, 170.4 ppm. HRESIMS calcd for C12H18NO6
([M+H]+): 272.1134; found: 272.1131.
3.5.14. Ethyl (2R/S,10R,40S)-2-(40-hydroxy-20-cyclo-
penten-10-yl)-2-cyanoacetate (17n). Viscous yellow liquid;
1H NMR (CDCl3, 250 MHz): d 1.27 (t, 3H, J¼7.7 Hz), 1.5
(tt, 1H, J¼14.2, 4.0 Hz), 2.47 (s, 1H, OH), 2.56 (m, 1H),
3.23 (m, 1H), 3.53 (d, 1H, J¼6.7 Hz), 4.2 (q, 2H,
J¼7.7 Hz), 4.76 (m, 1H), 5.73–5.83 (dt, 1H, J¼5.5,
1.2 Hz), 5.99 (m, 1H) ppm; 13C NMR (CDCl3, 62.5 MHz):
d 13.9, 36.8, 43.0, 44.5, 44.8, 62.9, 76.0, 76.1, 116.1, 116.2,
132.0, 132.4, 137.6, 137.7, 165.3, 165.4 ppm. HRESIMS
calcd for C10H14NO3 ([M+H]+): 196.0974; found: 196.0977.
3.6.3. Ethyl (2R/S,10R,40S)-2-(40-acetoxy-4-phenyl-
ethynyl-20-cyclopenten-10-yl)-2-nitroacetate (18d). Vis-
cous liquid; H NMR (CDCl3, 250 MHz): d 1.14 (dt, 3H,
1
J¼7.2, 2.0 Hz), 1.98 (s, 3H), 2.24 (m, 1H), 2.83 (m, 1H),
3.68 (m, 1H), 4.18 (dq, 2H, J¼7.0, 1.5 Hz), 4.97 (dd, 1H,
J¼9.2, 5.5 Hz), 5.9 (m, 1H), 6.27 (dt, 1H, J¼5.5, 2.0 Hz),
7.19–7.35 (m, 5H) ppm; 13C NMR (CDCl3, 62.5 MHz):
d 13.9, 21.6, 41.9, 42.4, 44.4, 44.8, 63.2, 63.3, 81.9, 82.1,
86.3, 86.7, 90.5, 122.0, 128.2, 128.7, 131.8, 133.2, 133.7,
135.9, 136.2, 163.3, 169.1 ppm. HRESIMS calcd for
C19H20NO6 ([M+H]+): 358.1291; found: 358.1294.
3.5.15. Phenylsulfonyl (2R/S,10R,40S)-2-(40-hydroxy-20-
cyclopenten-10-yl)-2-acetonitrile (17o). Viscous yellow
liquid; 1H NMR (CDCl3, 250 MHz): d 1.6 (dq, 1H,
J¼14.0, 4.5 Hz), 2.2 (br s, 1H, OH), 2.58 (m, 1H), 3.43
(m, 1H), 3.99 (dd, 1H, J¼27.2, 4.5 Hz), 4.76 (s, 1H), 5.76–
6.02 (m, 2H), 7.55–7.71 (m, 5H) ppm; 13C NMR (CDCl3,
62.5 MHz): d 37.1, 38.8, 41.6, 42.2, 61.9, 62.1, 75.8, 76.2,
113.5, 113.7, 129.4, 129.8, 131.71, 131.75, 135.43, 135.47,
136.2, 136.3, 138.32, 138.35 ppm. HRESIMS calcd for
C13H14NO3S ([M+H]+): 264.0694; found: 264.0688.
3.6.4. Ethyl (2R/S,10R,40S)-2-(40-acetoxy-20-cyclopenten-
10-yl)-3-oxobutanoate (18f). Viscous liquid; 1H NMR
(CDCl3, 250 MHz): d 1.12 (t, 3H, J¼7.2 Hz), 1.4 (t, 1H),
1.96 (s, 3H), 2.18 (s, 3H), 2.9 (p, 1H, J¼7.5 Hz), 3.33 (m,
2H), 4.03 (q, 2H, J¼7.2 Hz), 5.5 (m, 1H), 5.81–5.82 (m,
2H) ppm; 13C NMR (CDCl3, 62.5 MHz): d 14.1, 21.2,
29.4, 29.7, 34.6, 34.7, 42.9, 43.0, 61.5, 61.6, 65.2, 65.3,
78.8, 78.9, 131.2, 131.3, 137.5, 137.6, 168.3, 170.7, 201.0,
201.9 ppm. HRESIMS calcd for C13H19O5 ([M+H]+):
255.1233; found: 255.1231.
3.5.16. 2-(4-Hydroxy-cyclopent-2-enyl)-malonic acid di-
methyl ester (17p). Viscous liquid; 1H NMR (CDCl3,
400 MHz): d 1.33 (m, 1H, J¼14.0, 4.5 Hz), 2.35 (p, 1H,
J¼7.6 Hz), 3.05 (m, 2H), 3.30 (t, 1H, J¼7.6 Hz), 3.58 (s,
6H), 4.63 (s, 1H), 5.67 (d, 1H, J¼5.2 Hz), 5.74 (s,
1H) ppm; 13C NMR (CDCl3, 100 MHz): d 37.6, 43.8,
52.6, 56.4, 76.3, 134.1, 135.9, 169.0, 169.2 ppm. HRESIMS
calcd for C10H15O5 ([M+H]+): 215.0919; found: 215.0922.
3.6.5. 2-Phenylsulfonyl (2R/S,10R,40S)-2-(40-acetoxy-20-
cyclopenten-10-yl)-1-phenyl-ethanone (18i). Viscous liq-
uid; 1H NMR (CDCl3, 250 MHz): d 1.85–1.97 (s, 3H),
2.2–2.6 (m, 2H), 3.2–3.4 (m, 1H), 4.50 (dd, 1H, J¼27.2,
10.2 Hz), 5.4–5.6 (m, 1H), 5.7–5.9 (dt, 1H, J¼5.5, 2.2 Hz),
6.5 (m, 1H), 7.34–7.78 (m, 10H) ppm; 13C NMR (CDCl3,
62.5 MHz): d 21.1, 21.2, 34.8, 35.6, 43.1, 43.8, 60.4, 65.1,
74.0, 74.2, 76.6, 128.8, 128.83, 128.89, 128.97, 129.92,
132.5, 134.1, 134.3, 134.4, 135.9, 136.6, 136.9, 137.1,
137.6, 170.4, 170.6, 192.5, 192.9 ppm. HRESIMS calcd
for C21H21O5S ([M+H]+): 385.1100; found: 385.1103.
3.6. General procedure for preparation of compounds
18a–p
To a solution of 17a (100 mg, 0.465 mmol) in dry THF
(10 ml) at room temperature was added acetic anhydride
(51 mg, 0.5 mmol) and catalytic amount of DMAP. The
reaction was allowed to stir for 3 h and then concentrated.
The residue was taken up in ethyl acetate (40 ml) and ex-
tracted twice with saturated sodium bicarbonate solution
(20 ml), followed by brine (10 ml). The organic layer was
dried over sodium sulfate and the resulting product 18a
(110 mg, yield¼92%) was obtained as light yellow liquid.
3.6.1. Ethyl (2R/S,10R,40S)-2-(40-acetoxy-20-cyclopenten-
10-yl)-2-nitroacetate (18a). Viscous liquid; 1H NMR
(CDCl3, 400 MHz): d 1.25 (t, 3H, J¼7.2 Hz), 1.54–1.69
(m, 1H), 1.97 (s, 3H), 2.53–2.61 (m, 1H), 3.51 (br s, 1H),
4.25 (q, 2H, J¼7.2 Hz), 4.96 (t, 1H, J¼8.8 Hz), 5.58
(br s, 1H), 5.89–5.98 (m, 2H) ppm; 13C NMR (CDCl3,
100 MHz): d 14.0, 21.3, 33.2, 33.7, 44.7, 44.8, 63.3, 78.1,
78.4, 91.1, 91.3, 133.8, 134.0, 134.3, 134.7, 163.5,
170.8 ppm. HRESIMS calcd for C11H16NO6 ([M+H]+):
258.0977; found: 258.0978.
3.6.6. Ethyl (2R/S,10R,40S)-2-(40-acetoxy-20-cyclopenten-
10-yl)-2-cyanoacetate (18n). Viscous liquid; 1H NMR
(CDCl3, 250 MHz): d 1.26 (t, 3H, J¼7.0 Hz), 1.65 (m,
1H), 1.9 (s, 3H), 2.57 (p, 1H, J¼6.5 Hz), 3.25 (m, 1H),
3.4–3.58 (2doublets, (0.5ꢁ2H), J¼6.5 Hz), 4.23 (q, 2H,
J¼7.0 Hz), 5.59 (m, 1H), 5.89–5.99 (m, 2H) ppm; 13C
NMR (CDCl3, 62.5 MHz): d 14.0, 21.1, 33.8, 34.5, 42.7,
44.3, 62.9, 78.2, 78.3, 115.1, 133.5, 134.73, 165.1, 170.7,
170.8 ppm. HRESIMS calcd for C12H16NO4 ([M+H]+):
238.1079; found: 238.1080.
3.6.7. Phenylsulfonyl (2R/S,10R,40S)-2-(40-acetoxy-20-
cyclopenten-10-yl)-2-acetonitrile (18o). Viscous liquid;
1H NMR (CDCl3, 250 MHz): d 1.76–1.9 (m, 1H), 2.0 (s,
3H), 2.67 (m, 1H), 3.41 (m, 1H), 3.87–4.05 (2doublets,
1H, J¼6.25, 5.0 Hz), 5.55 (m, 1H), 5.91–6.05 (m, 2H),
7.56–7.98 (m, 5H) ppm; 13C NMR (CDCl3, 62.5 MHz):
d 20.1, 32.8, 34.5, 40.5, 40.6, 60.5, 60.8, 76.9, 77.0,
3.6.2. Ethyl (2R/S,10R,40S)-2-(40-acetoxy-4-methyl-20-
cyclopenten-10-yl)-2-nitroacetate (18b). Viscous liquid;

1124
P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
111.8, 128.4, 128.5, 132.8, 133.0, 133.2, 133.5, 134.4, 134.9,
135.1, 169.7, 169.6 ppm. HRESIMS calcd for C15H16NO4S
([M+H]+): 306.0800; found: 306.0814.
41.8, 45.0, 61.8, 83.7, 83.9, 95.5, 110.9, 122.1, 128.4,
129.0, 131.0, 131.4, 131.7, 159.0 ppm; MS(ESI) m/z¼
298.1 [M+H]+. HRESIMS calcd for C17H16NO4 ([M+H]+):
298.1079; found: 298.1072.
3.6.8. 2-(4-Acetoxy-cyclopent-2-enyl)-malonic acid di-
methyl ester (18p). Viscous liquid; 1H NMR (CDCl3,
250 MHz): d 1.56 (dt, 1H, J¼14.0, 4.5 Hz), 2.05 (s, 3H),
2.54 (dt, 1H, J¼14.0, 8.0 Hz), 3.33 (m, 2H), 3.77 (s, 6H),
5.6 (m, 1H), 5.88 (dt, 1H, J¼5.7, 2.0 Hz), 6.00 (dt, 1H,
J¼5.7, 2.0 Hz) ppm; 13C NMR (CDCl3, 100 MHz): d 21.0,
34.5, 43.4, 52.3, 52.4, 56.7, 78.7, 131.3, 137.2, 168.4 (splits
into 2), 170.6 ppm. HRESIMS calcd for C12H17O6
([M+H]+): 257.1025; found: 257.1029.
3.7.5. X-ray crystallographic data for 19d. For the crystal
of 19d, four molecules were found in each unit cell. The
compound crystallized in an orthorhombic space group
˚
P2(1)2(1)2(1), with cell dimensions a¼6.630(4) A, b¼
˚
˚
10.067(6) A, c¼21.631(11) A. A total of 3479 unique reflec-
tion data were obtained to give a final R indices [l>2s(I)]
of R1¼0.0626, wR2¼0.1308 and R indices (all data)
R1¼0.0824, wR2¼0.1444.
3.7. General procedure for preparation of compounds
19a–m and 19p
3.7.6. (1S,5S)-3-Aza-4-(ethoxycarbonyl)-7-trimethylsila-
nylethynyl-2-oxabicyclo[3.3.0]oct-3,7-diene-3-oxide
(19e). 1H NMR (CDCl3, 250 MHz): d 0.10 (s, 9H), 1.25 (t,
3H, J¼7.0 Hz), 2.85–3.09 (m, 2H), 4.20 (m, 3H), 5.70 (d,
1H, J¼8.7 Hz), 6.05 (d, 1H, J¼2.0 Hz) ppm; 13C NMR
(CDCl3, 62.5 MHz): d 0.5, 14.3, 40.9, 44.5, 62.0, 82.7,
99.4, 102.0, 111.2, 128.1, 136.2, 160.0 ppm; MS(ESI)
m/z¼294.1 [M+H]+. HRESIMS calcd for C14H20NO4Si
([M+H]+): 294.1162; found: 294.1165.
To a solution of 18a (70 mg, 0.272 mmol) in dry THF
(10 ml) at room temperature were added potassium car-
bonate (37.6 mg, 0.272 mmol) and Pd(PPh3)4 (15 mg,
0.013 mmol). The reaction was allowed to stir for 12 h at
60 ꢀC and then vacuum filtered over Celite with subsequent
concentration of the filtrate. The product was purified by wet
column chromatography using ethyl acetate/hexane (1:2) to
afford 19a using column chromatography as a yellow vis-
cous liquid (45 mg, yield¼85%).
3.7.7. (1S,5S)-4-(Ethoxycarbonyl)-3-methyl-2-oxabi-
cyclo[3.3.0]oct-3,7-diene (19f). Viscous liquid; H NMR
1
(CDCl3, 250 MHz): d 1.20 (t, 3H, J¼7.2 Hz), 2.09 (s, 3H),
2.3 (m, 1H), 2.6 (m, 1H), 3.7 (t, 1H, J¼8.4 Hz), 4.10 (q,
2H, J¼6.8 Hz), 5.53 (d, 1H, J¼9.2 Hz), 5.7 (br s, 1H), 5.9
(br s, 1H) ppm; 13C NMR (CDCl3, 62.5 MHz): d 14.5,
14.6, 40.1, 43.9, 59.5, 91.9, 106.6, 128.5, 137.0, 166.4,
167.1 ppm. HRESIMS calcd for C11H15O3 ([M+H]+):
195.1021; found: 195.1018.
3.7.1. (1S,5S)-3-Aza-4-(ethoxycarbonyl)-2-oxabi-
cyclo[3.3.0]oct-3,7-diene-3-oxide (19a). Viscous liquid;
1H NMR (CDCl3, 250 MHz): d 1.29 (t, 3H, J¼5.8 Hz),
2.63–2.78 (m, 2H), 4.17–4.28 (m, 3H, CH2+H-4), 5.56–
5.62 (m, 1H), 5.75–5.78 (m, 1H), 6.09–6.12 (m, 1H) ppm;
13C NMR (CDCl3, 62.5 MHz): d 14.0, 38.2, 44.6, 61.4,
84.2, 111.3, 127.7, 137.0, 158.9 ppm. HRESIMS calcd for
C9H12NO4 ([M+H]+): 198.0766; found: 198.0762.
3.7.8. (1S,5S)-4-(Ethoxycarbonyl)-3,7-dimethyl-2-oxabi-
cyclo[3.3.0]oct-3,7-diene (19g). Viscous liquid; H NMR
1
3.7.2. (1S,5S)-3-Aza-4-(ethoxycarbonyl)-7-methyl-2-oxa-
bicyclo[3.3.0]oct-3,7-diene-3-oxide (19b). Viscous liquid;
1H NMR (CDCl3, 400 MHz): d 1.31 (t, 3H, J¼6.8 Hz),
1.81 (s, 3H), 2.56 (d, 1H, J¼17.6 Hz), 2.73 (dd, 1H,
J¼17.2, 8.0 Hz), 4.27 (m, 3H), 5.45 (s, 1H), 5.56 (d, 1H,
J¼8.8 Hz) ppm; 13C NMR (CDCl3, 100 MHz): d 14.4,
16.6, 42.6, 45.6, 61.8, 85.1, 112.1, 122.6, 148.5,
160.0 ppm. HRESIMS calcd for C10H14NO4 ([M+H]+):
212.0923; found: 212.0918.
(CDCl3, 250 MHz): d 1.21 (t, 3H, J¼7.0 Hz), 1.71 (m,
3H), 2.09 (d, 3H, J¼1.2 Hz), 2.27–2.34 (m, 1H), 2.51–
2.55 (m, 1H), 3.70 (dt, 1H, J¼7.7, 1.0 Hz), 4.1 (m, 2H),
5.34 (m, 1H), 5.46 (d, 1H, J¼8.8 Hz) ppm; 13C NMR
(CDCl3, 62.5 MHz): d 14.42, 14.48, 16.5, 44.1, 44.6, 59.2,
92.3, 106.5, 123.0, 147.8, 166.3, 167.2 ppm. HRESIMS
calcd for C12H17O3 ([M+H]+): 209.1178; found: 209.1181.
3.7.9. (1S,5S)-7-Butyl-4-(ethoxycarbonyl)-3-methyl-2-
oxabicyclo[3.3.0]oct-3,7-diene (19h). Viscous liquid; H
1
3.7.3. (1S,5S)-3-Aza-7-butyl-4-(ethoxycarbonyl)-2-oxabi-
cyclo[3.3.0]oct-3,7-diene-3-oxide (19c). Viscous liquid; 1H
NMR (CDCl3, 250 MHz): d 0.79 (t, 3H, J¼7.0 Hz), 1.20 (m,
5H, CH2+CH3), 1.33 (m, 2H), 2.07 (t, 2H, J¼7.5 Hz), 2.53
(d, 1H, J¼17.5 Hz), 2.75 (dd, 1H, J¼16.0, 7.7 Hz), 4.24
(m, 3H), 5.43 (d, 1H, J¼1.0 Hz), 5.33 (d, 1H, J¼8.7 Hz);
13C NMR (CDCl3, 62.5 MHz): d 13.9, 13.9, 22.4, 29.6, 30.6,
42.5, 45.8, 61.5, 84.8, 112.3, 120.8, 150.3, 160.8 ppm.
HRESIMS calcd for C13H20NO4 ([M+H]+): 254.1392;
found: 254.1394.
NMR (CDCl3, 250 MHz): d 0.78 (t, 3H, J¼7.0 Hz), 1.21
(m, 5H), 1.34 (m, 2H), 2.04 (m, 5H, CH3+CH2), 2.33 (dd,
1H, J¼14.0, 1.0 Hz), 2.53 (dd, 1H, J¼14.0, 8.0 Hz), 3.72
(m, 1H), 4.07 (m, 2H), 5.34 (d, 1H, J¼1.25 Hz), 5.47 (d,
1H, J¼9.0 Hz) ppm; 13C NMR (CDCl3, 62.5 MHz):
d 13.8, 14.45, 14.49, 22.5, 29.6, 30.7, 42.5, 44.1, 59.2,
92.2, 106.5, 121.5, 152.2, 166.4, 167.2 ppm. HRESIMS
calcd for C15H23O3 ([M+H]+): 251.1647; found: 251.1645.
3.7.10. (1S,5S)-3-Phenyl-4-(phenylsulfonyl)-2-oxabi-
cyclo[3.3.0]oct-3,7-diene (19i). Viscous liquid; H NMR
1
3.7.4. (1S,5S)-3-Aza-4-(ethoxycarbonyl)-7-phenyl-
ethynyl-2-oxabicyclo[3.3.0]oct-3,7-diene-3-oxide (19d).
(CDCl3, 250 MHz): d 2.73 (dt, 1H, J¼7.2, 2.2 Hz), 2.85
(p, 1H, J¼2.2 Hz), 3.82 (dt, 1H, J¼7.7, 5.2 Hz), 5.64 (dou-
blet of p, 1H, J¼7.2, 1.2 Hz), 5.74 (dq, 1H, J¼5.7, 2.2 Hz),
6.06 (dt, 1H, J¼5.7, 1.2 Hz), 7.18–7.6 (m, 10H) ppm; 13C
NMR (CDCl3, 62.5 MHz): d 40.1, 46.4, 91.9, 114.4, 127.0,
127.4, 127.9, 128.7, 128.8, 129.4, 130.7, 132.6, 137.2,
1
White solid: mp¼72–74 ꢀC; H NMR (CDCl3, 250 MHz):
d 1.26 (t, 3H, J¼7.0 Hz), 2.81–3.04 (m, 2H), 4.27 (m, 3H),
5.66 (d, 1H, J¼9.0 Hz), 6.01 (d, 1H, J¼2.0 Hz), 7.25–7.40
(m, 5H, Ph) ppm; 13C NMR (CDCl3, 62.5 MHz): d 14.2,

P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
1125
142.2, 163.9, 192.3 ppm. HRESIMS calcd for C19H17O3S
([M+H]+): 325.0898; found: 325.0892.
Supplementary data
ORTEP diagrams with structure factors for compounds
11 and 19d are provided. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2006.11.066.
3.7.11. (1S,5S)-7-Methyl-3-phenyl-4-(phenylsulfonyl)-2-
oxabicyclo[3.3.0]oct-3,7-diene (19j). Viscous liquid; 1H
NMR (CDCl3, 250 MHz): d 1.76 (s, 3H), 2.58–2.90 (m,
2H), 3.84 (dt, 1H, J¼7.7, 2.2 Hz), 5.41 (t, 1H, J¼2.0 Hz),
5.62 (d, 1H, J¼9.0 Hz), 7.19–7.60 (m, 10H, PhSO2+
COPh) ppm; 13C NMR (CDCl3, 62.5 MHz): d 15.5, 43.2,
46.2, 91.6, 113.3, 121.5, 125.9, 126.6, 127.7, 128.0, 128.4,
129.6, 131.5, 141.3, 147.3, 163.1 ppm. HRESIMS calcd
for C20H19O3S ([M+H]+): 339.1055; found: 339.1050.
References and notes
1. (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett.
1965, 6, 4387; (b) Trost, B. M.; Fullerton, T. J. J. Am. Chem.
Soc. 1973, 95, 292; (c) Trost, B. M.; Crawley, M. L. Chem.
Rev. 2003, 103, 2921; (d) Hegedus, L. S. Transition Metals in
the Synthesis of Complex Organic Molecules; University
Science Books: Sausalito, CA, 1999.
2. (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry. A Guide for the Synthetic Chemist; Pergamon:
Amsterdam and New York, NY, 2000; Vol. 20; (b) Nicolaou,
K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4442; (c) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2285.
3.7.12. (1S,5S)-7-Butyl-3-phenyl-4-(phenylsulfonyl)-2-
oxabicyclo[3.3.0]oct-3,7-diene (19k). Viscous liquid; H
1
NMR (CDCl3, 250 MHz): d 0.80 (t, 3H, J¼7.2 Hz), 1.19
(m, 2H), 1.31 (m, 2H), 2.05 (t, 2H, J¼7.5 Hz), 2.58–2.90
(m, 2H), 3.80 (dt, 1H, J¼7.7, 2.2 Hz), 5.40 (d, 1H,
J¼2.0 Hz), 5.60 (d, 1H, J¼9.2 Hz), 7.19–7.60 (m, 10H,
PhSO2+COPh) ppm; 13C NMR (CDCl3, 62.5 MHz):
d 13.9, 22.4, 29.5, 30.6, 42.5, 46.7, 92.4, 114.3, 121.1,
126.9, 127.7, 128.7, 129.1, 129.4, 130.6, 132.5, 142.4, 152.7,
164.1 ppm. HRESIMS calcd for C23H25O3S ([M+H]+):
381.1524; found: 381.1522.
3. Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1988,
29, 669.
4. Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.; Shibasaki, M.;
Mori, M. J. Org. Chem. 1995, 60, 2016.
5. Trost, B. M.; Li, L.; Guile, S. D. J. Am. Chem. Soc. 1992, 114,
8745.
3.7.13. (1S,5S)-3-Phenyl-7-phenylethynyl-4-(phenylsul-
fonyl)-2-oxabicyclo[3.3.0]oct-3,7-diene (19l). Viscous liq-
uid; H NMR (CDCl3, 250 MHz): d 2.89–3.17 (m, 2H),
1
3.94 (dt, 1H, J¼8.2, 2.2 Hz), 5.70 (d, 1H, J¼9.0 Hz), 6.00
(d, 1H, J¼1.7 Hz), 7.26–7.61 (m, 15H); 13C NMR (CDCl3,
62.5 MHz): d 43.7, 46.6, 84.5, 91.4, 94.8, 114.3, 122.5,
127.0, 127.7, 128.4, 128.6, 128.8, 129.4, 130.8, 131.0,
131.7, 131.9, 132.0, 132.7, 142.1, 164.2 ppm. HRESIMS
calcd for C27H21O3S ([M+H]+): 425.1211; found: 425.1203.
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3.7.14. (1S,5S)-3-Phenyl-4-(phenylsulfonyl)-7-trimethyl-
silanyl-2-oxabicyclo[3.3.0]oct-3,7-diene (19m). Viscous
liquid; H NMR (CDCl3, 250 MHz): d 0.14 (s, 9H), 2.85–
1
3.05 (m, 2H), 3.99 (dt, 1H, J¼8.5, 2.0 Hz), 5.72 (d, 1H,
J¼9.0 Hz), 6.10 (d, 1H, J¼1.7 Hz), 7.26–7.65 (m, 10H,
PhSO2+COPh) ppm; 13C NMR (CDCl3, 62.5 MHz): d 0.5,
43.5, 46.7, 90.5, 98.0, 102.1, 114.2, 122.7, 127.5, 128.7,
129.0, 129.6, 131.4, 133.0, 134.4, 165.0 ppm. HRESIMS
calcd for C24H25O3SSi ([M+H]+): 421.1294; found:
421.1288.
3.7.15. 2-Cyclopent-2-enylidene-malonic acid dimethyl
ester (19p). Viscous liquid; H NMR (CDCl3, 250 MHz):
1
d 2.58 (m, 2H), 2.90 (m, 2H), 3.70 (s, 3H), 3.73 (s, 3H),
6.76 (s, 2H) ppm; 13C NMR (CDCl3, 62.5 MHz): d 31.0,
32.9, 51.8, 52.0, 115.3, 132.4, 152.4, 166.2, 166.6,
168.3 ppm. HRESIMS calcd for C10H13O4 ([M+H]+):
197.0814; found: 197.0812.
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Acknowledgements
Financial support for this work from the American Cancer
Society, the Herman Frasch Foundation, and the American
Lung Association is greatly appreciated. We also extend
our thanks to Professor Bill Baker for providing access to the
optical polarimeter and to Professor Mike Zaworotko and
Mr. Greg McManus for the X-ray structures of 11 and 19d.

1126
P. M. Khan et al. / Tetrahedron 63 (2007) 1116–1126
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