Enantioselective synthesis of cis-1,2-dialkyl substituted cyclopentanoid and isoprostane building blocks via 6-exo-trigonal radical cyclizations

Article abstract of DOI:10.1016/S0957-4166(01)00312-3

Two different 6-exo-trigonal cyclizations of enantiomerically enriched 6-heptenyl radicals readily afforded versatile synthetic precursors of cis-1,2-dialkyl substituted cyclopentane derivatives. Starting from one of these intermediates, we accomplished a

Full text of DOI:10.1016/S0957-4166(01)00312-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1785–1792
Enantioselective synthesis of cis-1,2-dialkyl substituted
cyclopentanoid and isoprostane building blocks via 6-exo-trigonal
radical cyclizations
Giuseppe Zanoni, Savino Re, Alessia Meriggi, Francesca Castronovo and Giovanni Vidari*
Dipartimento di Chimica Organica, Universita` di Pavia, Viale Taramelli 10, 27100 Pavia, Italy
Received 12 June 2001; accepted 5 July 2001
Abstract—Two different 6-exo-trigonal cyclizations of enantiomerically enriched 6-heptenyl radicals readily afforded versatile
synthetic precursors of cis-1,2-dialkyl substituted cyclopentane derivatives. Starting from one of these intermediates, we
accomplished an enantiospecific formal synthesis of two important isoprostanes, namely 15-F2c-IsoP and ent-15-F2c-IsoP. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
dienoic cascade.2 In the preceding paper of this series3
we have described the kinetic resolution of ( )-2a
through an irreversible enantioselective transacylation
promoted by Pseudomonas cepacia lipase, which led
to enantiomerically enriched (+)-2c along with slow
reacting (+)-2a. Herein we report two complementary
asymmetric approaches to lactones (+)-2a and (−)-2a
based on two different stereoselective 6-exo-trigonal
cyclizations of chiral heptenyl radicals. En route to
2a, both enantiomers of lactones 1 and 3 were also
obtained in enantiomerically pure form. The enan-
tiomers (+)-2a and (−)-2a were then separately con-
verted into diols (−)-4a and (+)-4a, respectively, thus
accomplishing a formal synthesis of isoprostanes 15-
F2c-IsoP and ent-15-F2c-IsoP, respectively.
Over the last few years our interest has focused on
the synthesis of lactones 11 and 2a,2,3 which are
attractive building blocks for the synthesis of cis-1,2-
dialkyl substituted cyclopentane derivatives. In fact,
the three oxygenated functional groups of 1 and 2a
are all different in character, thus allowing for
chemo- and regioselective transformations; in addi-
tion, the cis fusion between the two rings allows pre-
dictable stereocontrol in addition reactions to the
carbon atoms of the ring systems. The synthetic util-
ity of compounds 1 and 2a, and the O-benzyl ether
2b4–6 has been demonstrated in the syntheses of
iridoids1,3–5 and compounds of the 12-oxophyto-
* Corresponding author. Tel.: +39 0382507322; fax: +39 0382507323; e-mail: vidari@chifis.unipv.it
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00312-3

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G. Zanoni et al. / Tetrahedron: Asymmetry 12 (2001) 1785–1792
2. Results and discussion
depending on the configuration of dilithiated
norephedrine used as a base (Scheme 2).5,11
Heptenyl radicals can cyclize in a 6-exo or 7-endo
fashion.7 Although a fair number of 7-endo cyclizations
are known, 6-exo-trigonal cyclizations are more com-
mon, and most examples of stereoselective heptenyl
radical cyclizations fall into this class.7 In particular,
Stork8 and others9 have demonstrated that radical
cyclization of bromoacetals can lead, in a highly
stereoselective fashion, to six-membered acetal rings
cis-annulated to rings of different size. We sought to
employ this strategy with the aim of constructing the
d-lactone ring of compounds 1 and 3, respectively,
using the 6-exo-trigonal radical cyclizations of bromo-
acetals 6 and 7, respectively (Scheme 1, routes a and
b, respectively).
For convenience, Schemes 1, 3 and 4 and the experi-
mental section describe the reactions performed in one
enantiomeric series; actually, both antipodes of lactones
1, 2a and 3 were obtained according to an identical
sequence of reactions starting from either (−)-5 or from
(+)-5.
2.1. Asymmetric synthesis of lactones 1, 2a and 3
Selective oxidation of the allylic hydroxy group of diol
(+)-5, [h]D20 +43.4 (c 1.0, CH2Cl2) [lit.11 [h]2D0 +46.7 (c
1.55, CH2Cl2)], with PCC readily afforded the keto-
alcohol 9, which was converted under standard condi-
tions to bromoderivative 6 as a mixture of epimeric
acetals. Exposure of 6 to tributyltin hydride cleanly
afforded the desired annulated product 10, which was
converted to lactone (+)-1 in two additional simple
steps (Scheme 3). Comparison of the spectroscopic data
of (+)-1 with an authentic sample of the racemic
compound1 confirmed the cis stereochemistry at the
ring fusion, whereas the absolute configuration and the
enantiomeric excess, up to 95%, was verified by conver-
sion to (+)-2a2 and subsequent enantioselective GC
analysis.3
In essence, the two reactions differ in the tactics used
for accelerating the radical cyclization; in route a the
alkene acceptor is activated with an electron-withdraw-
ing group,8 while in route
b
the intermediate
cyclopentyl radical would be trapped by a rapid elimi-
nation of a thiophenyl radical.10 We envisaged diol 5 as
a suitable starting material for the synthesis of acetals 6
and 7 in either enantiomeric series. In fact, Hodgson
has recently reported an efficient enantioselective base-
induced rearrangement of the achiral epoxy-alcohol 8,
which can afford either diol (−)-5 or (+)-5, e.e. ]95%,
Scheme 1.
Scheme 2.
Scheme 3. Reagents and conditions: (a) DMAPCC, CH2Cl2, 20°C, 12 h, 70%; (b) NBS, ethyl vinyl ether, CH2Cl2, −40“20°C, 23
h, 76%; (c) nBu3SnH, cat. AIBN, toluene, reflux, 6 h, 95%; (d) THF, 0.25N HCl, 0“20°C, 4 h, 94%; (e) PCC, CH2Cl2, 20°C, 3
h, 85%.

G. Zanoni et al. / Tetrahedron: Asymmetry 12 (2001) 1785–1792
1787
Scheme 4. Reagents and conditions: (a) TBDSMCl, imidazole, DMAP, CH2Cl2, 20°C,
3
h, 40% of 12; (b) N-
(phenylthio)phthalimide, nBu3P, benzene, 20°C, 4 h, 97%; (c) Bu4NF, 20°C, 10 h, 98%; (d) NBS, ethyl vinyl ether, CH2Cl2,
−40“20°C, 24 h, 98%; (e) Me3SnSnMe3, Ph2CO, 320 nm, 4 h; (f) THF, 0.25N HCl, 0“20°C, 5 h; (g) chromatographic separation,
56% of compound 20 from acetal 17; (h) PCC, CH2Cl2, 20°C, 3 h, 85%.
In order to perform pathway b of Scheme 1, at first
we needed to mask the primary hydroxy group of
diol (+)-5. Using standard methods, the desired
monoprotected silyl ether 12 was obtained in 40%
yield along with the regioisomeric derivative 13 and
the diprotected ether 14; the latter compounds were
easily separated from 12 by flash column chromatog-
raphy on silica gel and recycled (Bu4NF) to starting
diol 5. The allyl phenyl sulphide 15 was then intro-
duced with a Mitsunobu-type reaction12 and a bromo-
acetal group was subsequently installed on the depro-
tected primary alcohol 16. This reaction sequence
readily afforded the key intermediate 17 on gram
scale in reproducible high yields (ca. 90% over three
steps).
by conversion† of (+)-3 into (+)-2a and (−)-2c and
enantioselective GC analysis of the latter com-
pounds.3
2.2. Stereoselective synthesis of isoprostane and
prostaglandin building blocks
As stated in the introduction, enantiomerically
enriched lactones 1 and 2a are valuable starting mate-
rials for the enantioselective synthesis of iridoids and
compounds of the 12-oxophytodienoic cascade.1–3 To
further exploit the synthetic potential of 2a, we
decided to explore its conversion into the endo Corey-
like lactone 4a, which would constitute a practical
entry to F-prostaglandins and F-isoprostanes. Iso-
prostanes are a new class of reactive compounds that
are formed in mammalian cells as products of free
radical-induced peroxidation of arachidononoyl lipids.
They exert unique biological actions relevant to the
pathobiology of oxidative stress.13–15 In contrast to
the cyclo-oxygenase mediated process leading to
prostaglandins, the non-enzymatic radical mechanism
results in the formation of prostanoids with a cis-
arrangement of the 8- and 12-sidechains (compare
compounds 21 and 22 with 23).
Tandem photoinduced radical 6-exo-trigonal cycliza-
tion and phenylthio radical expulsion allowed the
clean conversion of bromoacetal 17 into the bicyclic
olefin 18 as a mixture of acetal epimers. They were
accompanied by variable amounts of the hydrode-
brominated product 19. The mixture of compounds
18 and 19 could not be efficiently separated at this
stage and was therefore directly submitted to hydroly-
sis of the acetal group. At this stage hemiacetals 20
were easily separated from alcohol 16 by flash
column chromatography and were then readily oxi-
dized to the expected lactone (+)-3. NMR data con-
firmed the structure, while the absolute configuration
and the enantiomeric excess, up to 95%, were verified
† The conversion was executed according to the procedure described
for ( )-3 in Ref. 2.

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G. Zanoni et al. / Tetrahedron: Asymmetry 12 (2001) 1785–1792
Isoprostanes are generated in racemic form, which is
consistent with a non-enzymatic pathway; however,
both enantiomers of the compounds are necessary for
biological evaluation. 15-F2c-Isop 2116–18 and its enan-
tiomer 2219,20 are among the most synthetically targeted
isoprostanes.21 Moreover, compound 21 possesses bio-
logical activity similar to that of PGF2a and was shown
to activate the PGF2a human receptor in the eye.22
To our knowledge, this simple method for the 1,3-func-
tionalization of a homoallylic acetate has no precedent
in the literature. The stereochemistry of compounds 26
and 27 was assigned by inspection of the vicinal cou-
pling constants in the 1H NMR spectra and proton
correlations in NOESY experiments; moreover, both
monoacetates gave a single diacetate 28 upon acetyla-
tion under standard conditions. Hydrodeiodination (n-
Bu3SnH) of compound 28, followed by removal of both
acetyl groups of 4b using an anionic exchange resin,
readily afforded diol (−)-4a in 86% yield over two steps.
The synthesized 4a had mp 126–127°C and [h]2D0 −13.5
(c 0.5, CHCl3), identical with the literature.15,23 As
mentioned earlier in the article, all the reactions of
(−)-2c have been duplicated with (+)-2c. Consequently,
we also prepared diol (+)-4a ([h]2D0 +12 (c 0.6, CHCl3),
Following the pioneering work of the Rockach group,
diols (−)-4a15,23 and (+)-4a,19,24 and derivatives,20,25,26
have been widely used as starting materials in the
asymmetric syntheses of F2c- and ent-F2c isoprostanes,
respectively. Notably, so far all these cyclopentane
derivatives have been obtained by annulating an endo-
cyclic radical to a butenolide acceptor double bond (a
radical 12“8 5-exo-trigonal cyclization, according to
the proposed IsoP numbering27) and their chirality have
been derived from members of the sugar chiral pool.
identical with the literature.19,24
)
3. Conclusion
With both (+)-2a and (−)-2a readily available either by
enzymatic kinetic resolution3 or asymmetric synthesis
(this paper), we envisaged their straightforward conver-
sion into diols (−)-4a and (+)-4a, respectively, through
the intermediacy of iododerivatives of type 26. How-
ever, we met no success in attempts to install a iodohy-
drin across the double bond of the acetate of (+)-2a
using conventional methods.28 In contrast, we discov-
ered that exposure of (−)-2c to ICl in MeCN–H2O (8:1)
gave rise to a mixture (ratio 7:3) of acetoxy-iodohydrins
26 and 27 in 96% isolated yield. The reaction occurred
rapidly at room temperature and proceeded with a
complete stereocontrol of the installed stereocenters at
C(10) and C(11). Formation of the two regioisomeric
monoacetates 26 and 27 could be explained by assum-
ing that the iodonium ion 24, installed on the less
hindered convex side of the bicyclic structure 2c, was
rapidly intercepted by the proximate acetoxy group
giving rise to the resonance stabilized cation 25 which,
in the presence of H2O, finally collapsed to the two
acetates (Scheme 5).
In conclusion, we have described the first asymmetric
synthesis of both enantiomers of building block lac-
tones 1 and 3 using two different 6-exo-trigonal radical
cyclizations of 6-heptenyl radicals. Each enantiomer of
these compounds was then separately converted, in a
completely stereocontrolled fashion, into diols (−)-4a
and (+)-4a, respectively, thus accomplishing an enan-
tiospecific formal synthesis of 15-F2c-IsoP 21 and ent-
15-F2c-IsoP 22, respectively. Our synthesis of diols
(−)-4a and (+)-4a describes an innovative approach
with respect to existing methods and compares favor-
ably with the literature in terms of stereoselectivity and
yield.
4. Experimental
Melting points were determined on a Fisher–Johns hot
plate and are uncorrected. IR spectra were recorded as
Scheme 5.

G. Zanoni et al. / Tetrahedron: Asymmetry 12 (2001) 1785–1792
1789
thin films on a Perkin–Elmer FT-IR Paragon 100 PC
spectrometer 1H NMR (300 MHz) and 13C NMR
(75.47 MHz) spectra were recorded in CDCl3 solution
unless indicated otherwise with a Bruker CXP 300
spectrometer. Chemical shifts are reported in l units
relative to CHCl3 [lH 7.26, lC (central line of t) 77.0];
the abbreviations s=singlet, d=doublet, t=triplet, q=
quartet, qu=quintuplet, m=multiplet, and br=broad
are used throughout. Coupling constants (J) are given
in Hz. The multiplicity (in parentheses) of each carbon
atom was determined by DEPT experiments. Mass
spectra (direct inlet system) were recorded at 70 eV (0.5
mA) with a Finnigan MAT 8222 instrument. Syringes
and needles for the transfer of reagents were dried at
140°C and allowed to cool in a desiccator over P2O5
before use. Analytical TLC was carried out on glass-
backed plates, pre-coated with a 0.25 mm layer of silica
gel, and visualization was effected with short-wave-
length UV light (254 nm) or with 0.5% vanillin solution
in H2SO4–EtOH (4:1) followed by heating. Flash
column chromatography was accomplished with
Kieselgel 60 (40–63 mm). E.e. values were determined
by HRGC using a Hewlett–Packard mod. 5890II
instrument, equipped with a EASY-SEP capillary
column purchased from Analytical Technology (25m×
0.32 mm id and 0.25 mm film thickness); injector (split
splitless, split ratio 1:36) temperature 250°C, detector
(FID) temperature 280°C, carrier gas He, 1.27 mL
min−1. Retention times (tR) are given in min. Optical
activity was measured with a Perkin–Elmer 241 polar-
imeter. [h]D values are given in 10−1 deg cm2 g−1. All
commercial reagent grade solvents were dried and
degassed by standard techniques directly before use.
Yields are reported for chromatographically and spec-
troscopically pure isolated compounds.
mg, 0.89 mmol) in dry CH2Cl2 (4 mL) under an argon
atmosphere. The mixture, cooled to −40°C, was treated
with ethyl vinyl ether (120 mL, 1.26 mmol), stirred for 2
h, allowed to warm to 20°C, and stirred for an addi-
tional 21 h. The reaction mixture was diluted with
CH2Cl2 (10 mL), extracted with H2O, and the aqueous
phase re-extracted with CH2Cl2 (3×5 mL). The organic
layer was dried (MgSO4) and concentrated, and the
residue purified by flash chromatography on silica gel
(5 g). Elution with hexane–EtOAc (4:1) gave an insepa-
rable mixture of diastereomeric bromoacetals 6 as a
pale yellow oil (178 mg, 76%); IR (neat): 3050, 2980,
2925, 1713, 1588, 1425, 1348, 1187, 1127, 1058, 785
1
cm−1; H NMR: l 1.22 (3H, t, J=7.0), 2.15 (1H, dd,
J=18.8 and 2), 2.51 (1H, dd, J=18.8 and 7.5), 3.25
(1H, m), 3.38 (2H, d, J=7.0), 3.50–3.80 (4H, m), 4.68
(1H, t, J=7.0), 6.24 (1H, dd, J=5.5 and 2.0), 7.72 (1H,
m); 13C NMR: l 15.1 (3), 37.8 (2), 38.0 (2), 41.7 (1),
41.9 (1), 60.9 (2), 62.7 (2), 66.5 (2), 66.6 (2), 68.0 (2),
68.1 (2), 99.5 (1), 99.6 (1), 134.9 (1), 135.1 (1), 164.8 (1),
165.3 (1), 206.4 (0).
4.3. (4aS,7aR)-3-Ethoxy-hexahydro-cyclopenta[c]pyran-
6-one 10
A catalytic amount of AIBN and a solution of tri-
butyltin hydride (280 mL, 1.04 mmol) in dry benzene (20
mL) were added to a solution of bromoacetals 6 (200
mg, 0.76 mmol) in dry benzene (8 mL) under an argon
atmosphere. The mixture was heated under reflux for 6
h, allowed to warm to rt, concentrated, and the residue
purified by flash chromatography on silica gel (5 g).
Elution with hexane–EtOAc (2:1) gave an inseparable
mixture of diastereomeric acetals 10 as a colorless oil
(133 mg, 95%); IR (neat): 2960, 2920, 2888, 1740, 1440,
1405, 1380, 1335, 1205, 1146, 1123, 1060, 1010, 970,
4.1. (4R)-4-Hydroxymethyl-cyclopent-2-enone (+)-9
1
950, 860 cm−1; H NMR: l 1.2–2.8 (11H, m), 3.4–4.1
4-(Dimethylamino)pyridinium chlorochromate (5.6 g,
21.6 mmol) was added in one portion to a solution of
diol (+)-5, e.e. ]95%,5,11 [h]D20 +43.4 (c 1.0, CH2Cl2)
[lit.11 [h]D20 +46.7 (c 1.55, CH2Cl2)], (0.5 g, 4.38 mmol) in
CH2Cl2 (30 mL). The mixture was stirred for 12 h at
20°C, diluted with Et2O and filtered on a Celite pad.
Evaporation of the solvent gave a residue which was
purified by flash chromatography on silica gel (15 g).
Elution with Et2O gave ketone (+)-9 (320 mg, 65%), as
a pale yellow oil; [h]D20 +159 (c 0.5, CH2Cl2); IR (neat):
3400, 2930, 2880, 1710, 1590, 1195, 1070, 1030, 945, 790
cm−1; 1H NMR: l 1.89 (1H, s), 2.18 (1H, dd, J=18 and
2), 2.51 (1H, dd, J=18 and 7), 3.15–3.24 (1H, m),
3.65–3.85 (2H, m), 6.24 (1H, dd, J=5.5 and 2), 7.70
(1H, dd, J=5.5 and 2); 13C NMR: l 37.4 (2), 43.8 (1),
64.4 (2), 135.3 (1), 164.9 (1), 209.2 (0); EIMS m/z (rel.
intensity): 112 [M+] (34), 97 (19), 94 (15), 82 (85), 67
(22), 66 (21), 53 (100), 31 (41). Anal. calcd for C6H8O2:
C, 64.27; H, 7.19. Found: C, 64.35; H, 7.11%.
(4H, m), 4.65–4.8 (1H, m). CIMS (CH4): m/z 185
[M+H+].
4.4. (4aS,7aR)-3-Hydroxy-hexahydro-cyclopenta[c]-
pyran-6-one 11
To a solution of acetals 10 (100 mg, 0.54 mmol) in
THF (2 mL) at 0°C was added aqueous HCl (0.25N, 1
mL). The solution was stirred at 0°C for 1 h, then at rt
for 4 h, diluted with H2O (5 mL), and extracted with
CH2Cl2 (3×5 mL). The organic layer was dried
(MgSO4) and concentrated, and the residue purified by
flash chromatography on silica gel (8 g). Elution with
hexane–EtOAc (35:65) gave an inseparable mixture of
diastereomeric lactols 11 as a colorless oil (80 mg,
94%); IR (neat): 3404, 2950, 2855, 1735, 1403, 1162,
1087, 1059, 1017, 945, 875, 855 cm−1; 1H NMR: l 2–2.6
(8H, m), 2.9 (0.5H, brs, OH), 3.2 (0.5H, brs, OH), 3.55
(0.5H, dd, J=14.0 and 3.4), 3.80 (0.5H, dd, J=14.0
and 3.4), 3.96 (0.5H, dd, J=14.0 and 3.4), 4.30 (0.5H,
dd, J=14.0 and 3.4), 4.88 (0.5H, brd, J=10.5), 5.20
(0.5H, brs); EIMS m/z (rel. intensity): 156 [M+] (9), 128
(3), 110 (30), 95 (20), 82 (30), 69 (48), 67 (65), 54 (43),
41 (100).
4.2. (1%RS,4R)-4-(2-Bromo-1-ethoxy-ethoxymethyl)-
cyclopent-2-enone 6
Freshly recrystallized (H2O) NBS (184 mg, 1.03 mmol)
was added in one portion to a solution of (+)-9 (100

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G. Zanoni et al. / Tetrahedron: Asymmetry 12 (2001) 1785–1792
4.5. (+)-(4aR,7aR)-Tetrahydro-cyclopenta[c]pyran-3,6-
dione (+)-1
4.8. (1%R,4%R)-(+)-(4-Phenylsulfanyl-cyclopent-2-enyl)-
methanol (+)-16
Solid pyridinium chlorochromate (PCC) (276 mg, 1.28
mmol) and NaOAc (20 mg) were added to a solution of
lactols 11 (100 mg, 0.64 mmol) in CH2Cl2 (5 mL) at rt
After stirring for 3 h, Et2O (10 mL) was added and the
reaction mixture was filtered on a pad of Celite, and
concentrated. The residue was purified by flash chro-
matography on silica gel (8 g). Elution with hexane–
EtOAc (1:1) gave lactone (+)-1 (84 mg, 85%), [h]D20
+17.0 (c 0.3, CH2Cl2), identical (1H, 13C NMR, and MS
spectra) with an authentic sample of ( )-1.1
To a solution of sulphide 15 (100 mg, 0.31 mmol) in
THF (3 mL) at rt, was added tetrabutylammonium
fluoride (1.0 M in THF, 1 mL). The mixture was
stirred at rt for 10 h, then evaporated to dryness, and
the residue purified by flash chromatography on silica
gel (8 g). Elution with hexane–EtOAc (7:3) gave sul-
phide 16 as a colorless oil (63 mg, 98%), [h]2D0 +184.1
(c 1.1, CH2Cl2); IR (neat): 3374, 3056, 2927, 1584,
1479, 1439, 1379, 1027, 791, 691 cm−1; 1H NMR: l
2.10–2.20 (2H, m), 2.90–3.05 (1H, m), 3.50–3.70 (2H,
m), 4.30–4.40 (1H, m), 5.82 (1H, brd, J=6.5), 5.90
(1H, brd, J=6.5), 7.15–7.50 (5H, m); 13C NMR: l
34.5 (2), 47.5 (1), 52.3 (1), 65.5 (2), 126.5 (1), 128.6
(2×1), 131.2 (2×1), 133.2 (1), 134.3 (1), 135.5 (0);
EIMS m/z (rel. intensity): 206 [M+] (39), 142 (6), 110
(75), 97 (50), 96 (45), 79 (100), 67 (75), 41 (22).
4.6. (1S,4R)-(+)-4-(tert-Butyldimethylsilanyloxymethyl)-
cyclopent-2-enol (+)-12
To a solution of diol (+)-5, e.e. ]95%,5,11 [h]D20 +43.4 (c
1.0, CH2Cl2) [lit.11 [h]D20 +46.7 (c 1.55, CH2Cl2)], (300
mg, 2.63 mmol) in dry CH2Cl2 (5 mL) at 0°C under an
argon atmosphere, was added sequentially imidazole
(353 mg, 5.2 mmol), 4-dimethylaminopyridine (DMAP)
(10 mg), and a solution of tert-BuMe2SiCl (356 mg,
2.36 mmol) in dry CH2Cl2 (9 mL). The mixture was
stirred at 0°C for 3 h, then filtered and evaporated to
dryness under vacuum. The residue was separated by
flash chromatography on silica gel (35 g). Elution with
hexane–EtOAc (85:15) gave, in addition to 13 (90 mg,
15%), 14 (45 mg, 5%) and recovered 5 (75 mg, 20%),
monoprotected diol (+)-12 as a colorless oil (242 mg,
40%), [h]2D0 +58.6 (c 0.6, CH2Cl2); IR (neat): 3405, 3050,
2955, 2857, 1614, 1361, 1256, 1177, 1083,1041, 1007
4.9. (1%%RS,1%R,4%R)-[4-(2-Bromo-1-ethoxy-
ethoxymethyl)-cyclopent-2-enylsulfanyl]-benzene 17
Freshly recrystallized (H2O) NBS (96 mg, 0.54 mmol)
was added in one portion to a solution of compound
(+)-16 (100 mg, 0.48 mmol) in dry CH2Cl2 (4 mL)
under an argon atmosphere. The mixture, cooled to
−40°C, was treated with ethyl vinyl ether (86 mL, 0.90
mmol), stirred for 2 h, allowed to warm to rt and
stirred for an additional 22 h. The reaction mixture
was diluted with CH2Cl2 (10 mL), extracted with H2O
(8 mL), and the aqueous phase re-extracted with
CH2Cl2 (3×5 mL). The organic layer was dried
(MgSO4) and concentrated, and the residue purified
by flash chromatography on silica gel (8 g). Elution
with hexane–EtOAc (19:1) gave an inseparable mix-
ture of diastereomeric bromoacetals 17 as a pale yel-
low oil (170 mg, 98%); IR (neat): 3050, 2973, 2924,
1
cm−1; H NMR: l 0.05 (6H, s), 0.90 (9H, s), 1.55 (1H,
brd, J=14.0), 2.28 (1H, ddd, J=14.0, 8.5, and 7.0),
2.70–2.85 (2H, m), 3.56 (2H, m), 4.60 (1H, m), 5.75
(1H, dd, J=7.0 and 2.0), 5.95 (1H, brd, J=7.0); 13C
NMR: l −5.6 (2×3), 18.4 (0), 25.9 (3×3), 36.9 (2), 46.2
(1), 64.4 (2), 75.5 (1), 134.8 (1), 135.2 (1).
1
1584, 1479, 1438, 1376, 1265, 1130, 738, 691 cm−1; H
NMR: l 1.10–1.30 (3H, m), 2.05–2.25 (2H, m), 2.95–
3.10 (1H, m), 3.30–3.70 (6H, m), 4.25–4.35 (1H, m),
4.60–4.72 (1H, m), 5.85 (2H, brs), 7.15–7.50 (5H, m);
13C NMR: l 15.0 (3), 34.5 (2), 35.1 (2), 45.1 (1), 47.6
(1), 52.2 (1), 52.4 (1), 62.5 (2), 65.6 (2), 69.5 (2),
101.4 (1), 101.5 (1), 126.5 (1), 128.7 (2×1), 131.2 (2×
1), 132.5 (1), 133.3 (1), 134.3 (1), 134.8 (1), 135.6 (0);
EIMS m/z (rel. intensity): 358 [M+(81Br)] (2), 356 [M+
(79Br)] (2), 232 (10), 205 (25), 189 (11), 153 (34), 151
(35), 149 (18), 147 (15), 125 (22), 123 (27), 109 (23),
79 (100), 73 (91), 45 (54).
4.7. (1%R,4%R)-tert-Butyldimethyl-(4-phenylsulfanyl-
cyclopent-2-enylmethoxy)-silane 15
To a solution of N-(phenylthio)phthalimide (134.2
mg, 0.53 mmol) in dry benzene (3 mL) at rt under an
argon atmosphere, was added n-Bu3P (130 mL, 0.53
mmol) and, after stirring for 5 min, a solution of
compound 12 (100 mg, 0.44 mmol) in dry benzene (1
mL). The mixture was stirred for 4 h at rt and then
evaporated to dryness. The residue was taken up in
hexane and the organic layer was washed with H2O
and dried (MgSO4). Evaporation under vacuum gave
an oily residue which was purified by flash chro-
matography on silica gel (8 g). Elution with hexane–
EtOAc (49:1) gave sulphide 15 as a colorless oil (136
mg, 97%), IR (neat): 3059, 2955, 2856, 1584, 1465,
1379, 1255, 1097, 837, 777 cm−1; 1H NMR: l 0.05
(6H, s), 0.95 (9H, s), 2.0–2.1 (2H, m), 2.90–3.0 (1H,
m), 3.4–3.6 (2H, m), 4.25–4.35 (1H, m), 5.80 (2H,
brs), 7.15–7.40 (5H, m); EIMS m/z (rel. intensity):
320 [M+] (8), 263 (35), 204 (30), 197 (19), 188 (10),
167 (25), 153 (32), 145 (16), 115 (16), 89 (100), 79
(39), 75 (54), 73 (81).
4.10. (3RS,4aS,7aR)-1,3,4,4a,7,7a-Hexaydro-cyclo-
penta[c]pyran-3-ol 20
A solution of bromoacetals 17 (100 mg, 0.28 mmol),
Me3SnSnMe3 (105 mg, 0.32 mmol), and benzophe-
none (51 mg, 0.28 mmol) in degassed, dry benzene (6
mL) in a quartz tube was irradiated at 320 nm in a
Rayonet photoreactor. After 4 h, the reaction mixture
was concentrated and the oily residue purified by
flash chromatography on silica gel (8 g). Elution with
hexane–CH2Cl2 (2:3) gave an inseparable mixture of
acetals 18 and 19, which were immediately submitted

G. Zanoni et al. / Tetrahedron: Asymmetry 12 (2001) 1785–1792
1791
1
to hydrolysis of the acetal group. A solution of 18 and
19 in THF (2 mL) was treated with HCl (0.25N, 4 mL)
and stirred at rt for 5 h. The reaction mixture was then
quenched with aqueous NaHCO3 and extracted with
CH2Cl2 (3×10 mL). The organic layer was washed with
brine, dried (MgSO4), and concentrated to give a
residue which purified by flash chromatography on
silica gel (8 g). Elution with CH2Cl2–hexane (4:1), fol-
lowed by Et2O–hexane (1:1), gave recovered alcohol 16
(10 mg, 17%) and lactols 20 (22 mg, 56% from 17), as
an inseparable mixture of epimers in the ratio of 1.3:1;
IR (neat): 3380, 3050, 2925, 2843, 1600, 1505, 1352,
cm−1; H NMR: l 2.1 (3H, s), 2.59 (1H, dd, J=19.0
and 11.0), 2.72 (1H, dd, J=19.0 and 4.3), 3.0 (brs,
OH), 3.11 (1H, m), 3.24 (1H, m), 4.22 (1H, dd, J=11.5
and 6.8), 4.41 (1H, d, J=5.2), 4.41 (1H, s), 4.49 (1H,
dd, J=11.5 and 8.1), 5.37 (1H, d, J=8.0); 13C NMR: l
20.7 (3), 29.9 (2), 31.1 (1), 37.4 (1), 42.7 (1), 60.8 (2),
79.8 (1), 91.7 (1), 171.2 (0), 176.1 (0); EIMS m/z (rel.
intensity): 340 [M+] (1), 280 (31), 262 (28), 153 (75), 125
(21), 109 (9), 107 (25), 79 (28), 54 (52), 43 (100). To a
solution of the two acetates 26 and 27 (200 mg, 0.59
mmol) in CH2Cl2 (4 mL) at rt under an argon atmo-
sphere, were added, in the order, pyridine (48 mL, 0.59
mmol), cat. DMAP, and Ac2O (56 mL, 0.59 mmol). The
mixture was stirred at rt for 30 min and then quenched
with MeOH. After diluting with CH2Cl2 (10 mL), the
organic layer was washed with saturated aqueous
NaHSO4 to remove pyridine, dried (MgSO4) and taken
to dryness. The solid residue (200 mg, 89%) was consti-
tuted by iododiacetate 28, mp 123–125°C, [h]2D0 +30.6 (c
0.8, CH2Cl2), which did not need further purification;
IR (KBr): 2925, 2853, 1783, 1744, 1370, 1221, 1171
1
1265, 1060, 1050 cm−1; H NMR: l 1.70–2.10 (6.9H,
m), 2.15 (1.3, m), 2.30–2.50 (5.6H, m), 2.75 (1H, m),
3.05 (1.3H, m), 3.41 (1.3H, dd, J=11.6 and.7.5), 3.74
(1H, dd, J=12.0 and 5.0), 3.85 (1H, dd, J=12.0 and
6.5), 3.93 (1.3H, dd, J=11.6 and 5.5), 4.95 (1.3H, m),
5.05 (1H, m), 5.62 (1.3H, dq, J=5.5 and 2.0), 5.73
(1.3H, dq, J=5.5 and 2.0), 5.76 (2H, brs); CIMS (CH4):
m/z 141 [M+H+], 123, 111, 97, 79.
1
cm−1; H NMR: l 2.05 (3H, s), 2.10 (3H, s), 2.60–2.75
4.11.(4aS,7aR)-(+)-4,4a,7,7a-Tetrahydro-1H-cyclopenta-
[c]pyran-3-one (+)-3
(2H, m), 3.30–3.40 (2H, m), 4.20 (1H, dd, J=12.0 and
6.7), 4.31 (1H, dd, J=12.0 and 7.2), 4.47 (1H, s), 5.24
(1H, brs), 5.36 (1H, d, J=6.1); 13C NMR: l 20.6 (3),
20.7 (3), 26.5 (1), 29.5 (2), 37.3 (1), 41.1 (1), 59.9 (2),
81.1 (1), 91.0 (1), 169.5 (0), 170.5 (0), 175.2 (0); EIMS
m/z (rel. intensity): 382 [M+] (1), 322 (5), 262 (85), 213
(22), 195 (13), 171 (18), 153 (67), 135 (35), 125 (16), 111
(16), 107 (36), 79 (25), 43 (100).
Solid PCC (154 mg, 0.71 mmol) and NaOAc (10 mg)
were added to a solution of lactols 20 (50 mg, 0.35
mmol) in CH2Cl2 (2 mL) at rt. After stirring for 3 h,
Et2O (10 mL) was added and the reaction mixture was
filtered on a pad of Celite, and concentrated. The
residue was purified by flash chromatography on silica
gel (5 g). Elution with Et2O–hexane (4:1) gave lactone
(+)-3 (42 mg, 85%) as a low melting point solid, [h]D20
+42.0 (c 0.3, CH2Cl2); IR (KBr): 3058, 2917, 1747,
1480, 1427, 1380, 1260, 1135, 1083, 992 cm−1; 1H NMR:
l 2.27 (1H, ddt, J=17.0, 2.5, and 3.0), 2.35 (1H, dd,
J=15.0 and 6.5), 2.62–2.87 (2H, m), 2.73 (1H, dd,
J=15.0 and 7.0), 3.30–3.40 (1H, m), 4.05 (1H, dd,
J=11.5 and 7.0), 4.30 (1H, dd, J=11.5 and 4.5), 5.55
(1H, dq, J=6.0 and 2.0), 5.75 (1H, dq, J=6.0 and 2.0);
13C NMR: l 33.8 (2), 33.9 (1), 36.1 (2), 41.9 (1), 70.2
(2), 130.8 (1), 131.8 (1), 173.1 (0); EIMS m/z (rel.
intensity): 138 [M+] (3), 120 (3), 96 (57), 79 (89), 77 (31),
67 (43), 66 (100), 60 (99), 51 (10), 39 (35). Anal. calcd
for C8H10O2: C, 69.54; H, 7.30. Found: C, 69.65; H,
7.12.
4.13. (3aR,4R,5R,6aS)-(−)-Acetic acid 5-acetoxy-2-oxo-
hexahydro-cyclopenta[b]furan-4-ylmethyl ester (−)-4b
A catalytic amount of AIBN and tributyltin hydride
(295 mL, 1.1 mmol) were added to a solution of iododi-
acetate 28 (350 mg, 0.92 mmol) in dry THF (5 mL)
under an argon atmosphere. The mixture was heated
under reflux for 3 h, allowed to cool to rt, concentrated,
and the residue partitioned between MeCN and hexane
(3×10 mL). The MeCN layer was concentrated and
purified by flash chromatography on silica gel (18 g).
Elution with a gradient of EtOAc in hexane gave
diacetate 4b (213 mg, 91%), [h]2D0 −49.1 (c 1.2, CH2Cl2);
IR (neat): 2960, 2890, 1740, 1720, 1378, 1227, 1185,
1120, 1070 cm−1; H NMR: l 2.0–2.10 (1H, m), 2.03
1
(3H, s), 2.07 (3H, s), 2.38 (1H, d, J=15.9), 2.49 (1H,
ddd, J=12.0, 7.0, and 3.6), 2.60–2.72 (2H, m), 3.27
(1H, qu, J=7.5), 4.17 (1H, dd, J=11.6 and 7.7), 4.31
(1H, dd, J=11.6 and 7.7), 5.17 (1H, t, J=7.0), 5.24
(1H, t, J=3.6); 13C NMR: l 20.4 (3), 20.6 (3), 29.5 (2),
38.1 (1), 39.0 (2), 44.4 (1), 59.9 (2), 75.0 (1), 83.5 (1),
169.6 (0), 170.3 (0), 176.4 (0). Anal. calcd for C12H16O6:
C, 56.24; H, 6.29. Found: C, 56.35; H, 6.33.
4.12. (3aR,4R,5S,6S,6aR)-Acetic acid 4-acetoxymethyl-
6-iodo-2-oxo-hexahydro-cyclopenta[b]furan-5-yl ester 28
To a solution of acetate (−)-2c3 (290 mg, 1.48 mmol) in
MeCN–H2O (4:1, 5 mL) at rt in the dark, was added
solid ICl (264 mg, 1.63 mmol) in one portion. The
mixture was stirred at rt for 4 h, concentrated to
remove MeCN, quenched with aqueous NaHCO3 and
extracted with Et2O (4×10 mL). The organic layer was
dried (MgSO4) and concentrated, and the residue was
purified by flash chromatography on silica gel (20 g).
Elution with EtOAc–hexane (4:6) gave 478 mg of iodo-
lactones 26 and 27 in the ratio of 7:3 and in 95% overall
yield. A sample of the mixture was separated on silica
gel to afford pure acetate 26 as a pale yellow oil; IR
(neat): 3428, 2960, 2924, 1740, 1368, 1241, 1176, 1016
4.14. (3aR,4R,5R,6aS)-(−)-5-Hydroxy-4-hydroxy-
methyl-hexahydro-cyclopenta[b]furan-2-one (−)-4a
Dowex® 1X8-200 ion-exchange resin (Cl− form, 1 g)
was added to aqueous NaOH (0.1 M, 15 mL); the
mixture was stirred at rt for 2 h, filtered and the resin
washed with 0.1 M NaOH and H2O. The collected resin
was resuspended in NaOH (0.1 M, 15 mL), stirred for

1792
G. Zanoni et al. / Tetrahedron: Asymmetry 12 (2001) 1785–1792
1 h, filtered, washed with H2O and dried overnight
under vacuum (0.01 mmHg). A solution of diacetate 4b
(30 mg, 0.12 mmol) in MeOH (2 mL) was treated with
the ion-exchange resin (OH− form) (220 mg) at rt for 30
min. The reaction mixture was then filtered, concen-
trated and the residue crystallized from EtOH to give
white crystals of diol (−)-4a (19 mg, 95%), mp 126–
127°C (lit.15,23 126–127°C), [h]D20 −13.5 (c 0.5, CHCl3)
[lit.24 [h]D +12 (c 1.5 10−2, CDCl3) for (+)-4a]; IR (KBr):
3420, 3000, 1750, 1368, 1224, 1175, 1120, 1030 cm−1; 1H
NMR: l 1.96 (1H, ddd, J=15.5, 7.0, and 3.7), 2.08–
2.22 (1H, m), 2.26 (1H, d, J=15.5), 2.59 (1H, dd,
J=19.0 and 11.5), 2.77 (1 OH, brs), 2.88 (1H, dd,
J=19.0 and 4.0), 3.15 (1H, ddt, J=11.5, 4.0, and 7.0),
3.50 (1 OH, d, J=3.7), 3.90 (1H, dd, J=11.0 and 6.9),
4.00 (1H, dd, J=11.0 and 7.6), 4.45 (1H, t, J=3.7),
5.17 (1H, t, J=7.0); 13C NMR (MeOH-d4): l 31.9 (2),
40.1 (1), 43.0 (2), 51.1 (1), 60.2 (2), 74.0 (1), 87.7 (1),
181.5 (0); CIMS (NH3): m/z 190 [M+NH+4]. The spec-
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troscopic
data
were
consistent
with
the
literature.15,19,23,24
Acknowledgements
We thank the Italian CNR, MURST (funds COFIN
1999), and the University of Pavia (funds FAR) for
financial support, and Professor Mariella Mella and
Prof. Giorgio Mellerio for NMR and MS spectra,
respectively.
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