Radical cyclization of highly functionalized precursors: Stereocontrol of ring closure of acyclic 1-substituted-2,4-dihydroxylated hex-5-enyl radicals

Article abstract of DOI:10.1039/a904206g

Polysubstituted cyclopentane rings can be synthesized with good to high stereocontrol by radical cyclization using tributyltin hydride and a radical initiator, triethylborane-O₂ in anhydrous xylene at room temperature. We have demonstrated that

Full text of DOI:10.1039/a904206g

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Radical cyclization of highly functionalized precursors:
stereocontrol of ring closure of acyclic 1-substituted-2,4-
dihydroxylated hex-5-enyl radicals
1
Arlène Roland, Thierry Durand,* David Egron, Jean-Pierre Vidal and Jean-Claude Rossi
Laboratoire de Chimie Biomoléculaire et des Interactions Biologiques Associé au C.N.R.S.
Université Montpellier I, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34060
Montpellier, France. Tel: 33-4-67-54-86-23, Fax: 33-4-67-54-86-25.
E-mail: Thierry.Durand@pharma.univ-montp1.fr
Received (in Cambridge, UK) 25th May 1999, Accepted 29th October 1999
Polysubstituted cyclopentane rings can be synthesized with good to high stereocontrol by radical cyclization using
tributyltin hydride and a radical initiator, triethylborane–O2 in anhydrous xylene at room temperature. We have
demonstrated that the nature (protected or unprotected) of the hydroxy functions in position 2 and 4 is responsible
for the stereochemical cyclization outcome of acyclic 1-substituted-2,4-dihydroxylated hex-5-enyl compounds.
The presence of a 2,4-diol leads to the all-syn precursor of isoprostanes while the diprotected diol affords the
diastereoisomer syn-anti-syn precursor.
Introduction
A new class of natural products called isoprostanes (isoPs) is
formed in humans and possesses powerful biological activity.1
Because of their non-enzymatic free-radical catalyzed bio-
synthesis from arachidonic acid, isoprostanes are all regiomers
of well-known prostaglandins. Indeed, isoPs are mainly charac-
terized by a polysubstituted cyclopentane ring bearing two
hydroxy groups in a cis position and two side chains also in a
cis position.
Carbocyclic annulations are extremely important reactions2
and the stereocontrolled intramolecular free-radical cyclization
has emerged as a powerful tool for carbon–carbon bond form-
ation in synthetic chemistry.3,4 Among all these reactions, the
hex-5-enyl radical cyclization is the most well-known for the
synthesis of cyclopentane rings. The conversion of carbo-
hydrates to highly O-functionalized carbocyclic compounds
through the intramolecular cyclization of hex-5-enyl radicals
possesses considerable synthetic utility because of its appli-
cation to the total synthesis of biologically active natural prod-
ucts.5 Over the last six years, we have focused our interest on the
synthesis of chiral cyclopentane rings6 from glucose leading to
new isoprostanes.7 We have studied herein which factors could
influence the stereochemical course of the radical key step in
the case of our previous intramolecular cyclization of acyclic
1-substituted polyhydroxylated hex-5-enyl radical.6b This study
allowed us to control the cyclization outcome to yield the all-
syn precursors (9 or 17) or the syn-anti-syn precursors (13 or
24). To confirm the relative configuration of such polysubsti-
tuted cyclopentane precursors, we have performed steady-state
difference NOE spectroscopy (DNOES) experiments.
Results and discussion
1) Synthesis of radical precursors 2, 3, 7 and 8
The synthesis of unprotected and protected radical generators
2/7 and 3/8, respectively, depicted in Scheme 1, was achieved
with the commercially available di-O-isopropylidene-α--gluco-
furanose as starting material. This aldofuranose, after radical
Barton deoxygenation8 and Wittig reaction, was converted to
highly functionalized radical generators. The precursor 2 (56%
overall yield after 6 steps6) is characterized by two free hydroxy
Scheme 1
J. Chem. Soc., Perkin Trans. 1, 2000, 245–251
245
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Table 1
groups at C-4 and C-6 as well as a benzoyl protecting group on
the primary hydroxy group at C-8. From the previous com-
pound 2, the two secondary hydroxy functions were protected
in the presence of Et3SiCl (8 equiv.) at 60 ЊC in pyridine leading
to 3 in 98% yield.
one that has found the most use in the construction of cyclic or
polycyclic natural products.3 The radical generators 2, 3, 7 and
8 were converted to highly functionalized hex-5-enyl radicals
then the intramolecular cyclization reaction was achieved6b at
room temperature in xylene with n-Bu3SnH (1.2 equiv.) and the
Et3B (0.2 equiv.)–O2 (dry air) system12 to yield quantitatively in
each experiment a mixture of four cyclopentane compounds
(9–12, 13–16, 17–20 and 21–24; Table 1). In all cases, the rad-
icals a or b cyclize to give predominantly the 1,5-cis products (9,
13, 17 and 24) as expected, with observed 1,5-cis:1,5-trans ratios
between 2.2 and 2.6 from compounds 2/7 and between 4.0 and
5.2 from compounds 3/8. But the main result (Table 1) was the
reversal of the stereochemistry in the 1,5-cis major products
between the unprotected and protected radical precursors 2/7
and 3/8 (64% and 55% of unprotected all-syn compounds 9 and
17; 70% and 75% of protected syn-anti-syn compounds 13 and
24).
For precursor analogues 7 and 8 bearing a TBDPS protecting
group instead of a benzoyl group on the primary hydroxy func-
tion, the synthetic route is the same as those previously
described.7,9 We started from the diol 1 which was protected on
its primary alcohol in the presence of TBDPSCl (1.1 equiv.)
and imidazole (2.3 equiv.) in DMF to provide the compound 4
in 95% yield. The substitution of the hydroxy group in position
5 (compound 5) by an iodine was achieved with Ph3P (1.02
equiv.), imidazole (2 equiv.) and I2 (1.1 equiv.) in xylene at 80 ЊC
in 96% yield.9 Deprotection of the 1,2-isopropylidene using
aqueous H2SO4 10% in a mixture of THF and dioxane yielded
86% of the hemiacetal 6. Finally a Wittig reaction in the pres-
ence of 2 equiv. of methoxycarbonylmethylene(triphenyl)phos-
phorane in dry THF permitted the introduction of the double
bond in 75% yield.10 The compound 7 represents a new cycliz-
ation precursor and the protection of its secondary hydroxy
functions with Et3SiCl provided the other precursor 8 with a
non-optimized 62% yield (30% overall yield after 7 steps).
3) Discussion
The stereoselectivity in the hex-5-enyl radical cyclization has
been widely studied and rational guidelines have been provided
to predict their stereochemical outcome.13 Moreover, an
advanced understanding of these details was provided by
Beckwith,13b Spellmeyer,14 and RajanBabu’s works.15 According
to Beckwith, in the case of simple 1,n-disubstituted hex-5-enyl
acyclic radicals (n = 2 to 5), the most favorable transition state
adopts a “chair-like” or a folded envelope conformation where
all the substituents are in a pseudo-equatorial orientation
because of the steric constraints. Consequently, the 1,5-ring
closure of 1- or 3-substituted hex-5-enyl radicals affords mainly
cis-disubstituted cyclic products, whereas 2- or 4-substituted
2) Radical cyclization reactions
Intramolecular ring closure of radical species is one of the most
powerful tools for the synthesis of a variety of cyclic com-
pounds.3 In particular, the 5-exo-trig closure reaction of the
hex-5-enyl radical kinetically controlled according to Baldwin’s
rules11 is well established and has been used to construct com-
plex five-membered rings. The critical 1,5-cis selectivity is the
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J. Chem. Soc., Perkin Trans. 1, 2000, 245–251

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species give trans compounds.13b It has also been shown that
the stereoelectronic effects caused by the substituent in position
1 favors the 1,5-cis cyclization in relation to the 1,5-trans
junction.16 Unfortunately, in the case of polysubstituted acyclic
hex-5-enyl compounds bearing a prostereogenic radical and a
double bond, only a few articles provide an interesting discus-
sion about the influence of the substituents on the stereo-
chemical outcome of the radical cyclization.5b,15 The previously
described results follow exactly Beckwith’s model since the
major cyclic compound obtained in each case has a 1,5-cis junc-
tion. However, the 4,5- and 1,2-cis or trans configurations can
only be explained by focusing our attention on the possible
transition states of the radical cyclization step.
Now, we propose an explanation of these results to provide
an in-depth understanding of the factors controlling the stereo-
selectivity of the radical cyclization in the case of polyhydroxy-
lated acyclic hex-5-enyl radicals. These new data allowed us to
understand how we were able to reverse the stereocontrol of the
radical cyclization described in Scheme 2 and get mostly 4,5-
Fig. 1
an intramolecular hydrogen bond. So in order to force the
radical transition state to assume the reverse “chair-like” con-
formation with two pseudo-equatorial hydroxy groups, leading
to the syn-anti-syn compounds 13 and 24, we have broken the
hydrogen bonds by adding bulky silyl ethers as protecting
groups which initiate very drastic steric interactions. When we
carried out the cyclization reaction on the 2,4-silyl ether radical
precursors 3 and 8, the soundness of our opinion was con-
firmed by newly observed results: the major products were now
the expected 13 (70%) and 24 (75%) compounds, i.e. those
which were minor compounds (12 8% and 20 14% respectively)
from the unprotected radical generators 2 and 7 (Table 1).
Another point must be emphasized now: the reason why two
different protecting groups have been used on the primary alco-
hol (R = Bz or TBDPS) comes from the fact that we had sus-
pected the benzoyl protecting group also to have an influence
on the stereochemical outcome of the radical cyclization.
Indeed, it was not excluded that a stabilizing intramolecular
H-bond between the carbonyl moiety of the benzoyl group and
the hydroxy group at C-2 (Fig. 1) could exist, favoring a 1,2-cis
junction.
The comparison of the 1,2-cis:1,2-trans ratios when R = Bz,
RЈ = H (1,2-cis:1,2-trans = 3.0) and R = TBDPS, RЈ = H (1,2-
cis:1,2-trans = 1.8) shows effectively that the protecting group
on the primary hydroxy has an influence on the stereochemical
outcome of the radical cyclization (Table 1). Moreover, since
the 1,2-cis:1,2-trans ratios are equal when R = Bz, RЈ = SiEt3
and R = TBDPS, RЈ = SiEt3 (1,2-cis:1,2-trans = 0.25), we can
confirm that the 1,2-cis orientation is due to an intramolecular
interaction between the benzoyl group and the alcohol at C-2
when this hydroxy group is free. All these new cyclization prod-
ucts were separated by chromatography on silica gel and a
structural analysis by one and two dimensional NMR, homo-
and heteronuclear, together with a differential NOE study,
allowed the determination of the configuration for each chiral
centre (vide infra).
Scheme 2
trans and 1,2-trans junctions instead of 4,5-cis and 1,2-cis ones,
without modifying our synthetic scheme profoundly. According
to the accepted rules, the major transition state should adopt a
“chair-like” conformation with all its substituents in a pseudo-
equatorial position. However, in accordance with our first
observed results from the radical precursor 2 (major compound
9 and minor compound 12), the most stable transition state
could only be 25 or 28 (Scheme 2).
If the cyclizations of conformationally rigid cyclic radicals
are critically influenced by the orientation of the side chains,15
in the conformationally less rigid systems, a conformational
equilibrium between several transition states can explain the
outcome more satisfactorily.
As shown previously by Houk et al.,14b the energetic barrier
between the “chair-like” and the “boat-like” conformations is
very weak (less than 1 kcal molϪ1). In a first approach, the
transition state 25 should be the most stable because the
weakest steric strain is observed when the two substituents have
a pseudo-equatorial orientation. But, among the different fac-
tors responsible for the stereochemical outcome of the radical
cyclization, the effect of the weakest allylic strain, like the one
observed in the transition state 28, should be predominant. So
between the transition states 25 and 28, only the “chair-like”
conformation 28 explains the major all-syn product formation 9
or 17 and this despite the presence of a drastic and destabilizing
steric diaxial interaction between the two hydroxy groups.
However, when we looked at the transition state 27, we noticed
a “chair-like” conformation bearing a weak allylic strain too
and the two hydroxy groups in an apparently more favored
pseudo-equatorial position. Consequently, according to us, the
only probable reason why the transition state 27 is not the most
favorable one for the radical cyclization of 2 and 7 comes from
the fact that in the transition states 28, such as occurs in
cyclohexane-1,3-diol,17 the 1,3-diaxial orientation is favored by
4) Determination of relative configuration of compounds 21, 22,
23 and 24 by 1H NMR NOE study
We have determined and confirmed the relative configurations
of compounds 21, 22, 23 and 24 by steady-state difference NOE
spectroscopy (DNOES) experiments, which have previously
been employed by our group.6b
Irradiation of 5a-H in products 21, 22, 23 and 24 induces a
significant NOE on the protons 4-H and 1-H, while irradiation
of 5b-H induces little or no NOE. The 1,3-triethylsilyl ethers
are therefore in a cis configuration with respect to each other, in
agreement with the synthesis, and a cis configuration as com-
pared to the 5b-H proton (Fig. 2, Tables 2 and 3, for NOE
spectra for compounds 21, 22, 23 and 24, see Fig. 3).
Concerning the relative configuration of chains situated in
C-3 and C-2 positions: for compound 24 the irradiation of 5b-
H (at 1.60–1.50 ppm) induces an NOE of 0.8% on 3-H (at 2.62–
2.53 ppm) and 0.3% on 2-H (at 2.17–2.10 ppm), the irradiation
of 7a-H (at 2.60–2.48 ppm) (7b-H being superposed on 7a-H)
induces an NOE of 0.3% on 1-H (at 4.09 ppm) and 1.3% on
J. Chem. Soc., Perkin Trans. 1, 2000, 245–251
247

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Table 2 1H NMR chemical shifts of compounds 21, 22, 23 and 24
(δ, 360 MHz, CDCl3)
Compound 1-H
2-H
3-H
4-H
5a-H
2.31
24
22
23
21
4.09
2.17–2.10 2.62–2.53 3.92
4.24–4.20 1.95–1.80 2.45–2.36 4.37–4.34 2.34–2.25
4.19
4.08
1.87–1.78 2.38–2.23 3.93–3.83 2.22–2.15
2.09–2.01 2.53–2.49 4.14
2.31
Compound 5b-H
6a-H 6b-H 7a-H
7b-H
24
22
23
21
1.60–1.50 3.64–3.55 3.64–3.55 2.60–2.48 2.60–2.48
1.75–1.65 3.88–3.84 3.72–3.67 2.64
2.19
2.45
2.55
1.68–1.58 3.93–3.83 3.68
1.50–1.45 3.88 3.88
2.45
2.71
Table 3 13C NMR chemical shifts of compounds 21, 22, 23 and 24
(δ, 90 MHz, CDCl3)
Compound
C-1
C-2
C-3
C-4
24
22
23
21
72.8
71.8
70.8
71.6
50.0
53.0
48.9
48.3
44.7
40.7
45.9
41.3
75.6
71.7
75.3
72.4
Compound
C-5
C-6
C-7
C-8
OCH3
24
22
23
21
45.0
44.6
44.5
44.7
62.8
61.9
63.7
61.3
32.9
32.2
35.5
30.4
173.8
173.7
173.2
174.6
51.3
50.9
51.1
51.1
Fig. 3 NOE Spectra for compounds 21 to 24.
The irradiation of 5a-H (at 2.22–2.15 ppm) in compound 23
induces an NOE of 0.4% on 2-H (at 1.87–1.78 ppm). Similarly,
irradiation of 5b-H (at 1.68–1.58 ppm) induces an NOE of
0.8% on 3-H (at 2.38–2.23 ppm) and irradiation of 7a-H (at
2.45 ppm) induces an NOE of 2.1% on 4-H (at 3.93–3.83 ppm)
and 1.4% on 2-H (at 1.87–1.78 ppm). The irradiation of 6a-H
(at 3.93–3.83 ppm) is without effect on 7a-H (at 2.45 ppm).
These results are in agreement with a relative trans configur-
ation between the protons 2-H (at 1.87–1.78 ppm) and 3-H (at
2.38–2.23 ppm), and a relative cis configuration between 7a-H
(at 2.45 ppm) and 5a-H (at 2.22–2.15 ppm), and between 6a-H
(at 3.93–3.83 ppm) and 5b-H (at 1.68–1.58 ppm).
For compound 21 the relative cis configuration of the
protons 2-H (at 2.09–2.01 ppm), 3-H (at 2.53–2.49 ppm) and
5a-H (at 2.31 ppm) is determined in the same manner. Indeed,
the irradiation of the proton 5b-H (at 1.50–1.45 ppm) induces
an NOE of 0.8% on 7a-H (at 2.71 ppm), the irradiation of 7b-H
(at 2.55 ppm) induces an NOE of 0.4% on 6a-H (at 3.88 ppm)
and the irradiation of 6a-H (at 3.88 ppm) induces an NOE of
1.0% on 5b-H (at 1.50–1.45 ppm), 0.8% on 7a-H (at 2.71 ppm)
and 1.5% on 7b-H (at 2.55 ppm).
Fig. 2
4-H (at 3.92 ppm), and the irradiation of 6a-H (at 3.64–3.55
ppm) induces an NOE of 2.8% on 1-H (at 4.09 ppm), 0.9% on
4-H (at 3.92 ppm) and 0.7% on 7a-H (at 2.60–2.48 ppm). These
observations allow one to check the relative cis configuration of
the protons 3-H (at 2.62–2.53 ppm), 2-H (at 2.17–2.10 ppm)
and 5b-H (at 1.60–1.50 ppm).
An identical reasoning is applied to compound 22. Assign-
ment of the relative cis configuration between the protons 7a-H
(at 2.64 ppm) and 2-H (at 1.95–1.80 ppm), and between the
protons 6a-H (at 3.88–3.84 ppm), 1-H (at 4.24–4.20 ppm) and
3-H (at 2.45–2.36 ppm) is made by successive irradiations of
7a-H (at 2.64 ppm) and 7b-H (at 2.19 ppm): NOE induced on
2-H (at 1.95–1.80 ppm; 0.6% and 0.5% respectively), and by
irradiation of 6a-H (at 3.88–3.84 ppm): NOE induced on 1-H
(at 4.24–4.20 ppm; 0.9%) and 3-H (at 2.45–2.36 ppm; 0.4%).
Conclusion
In conclusion, this study has highlighted the different param-
eters responsible for the stereochemical outcome of the radical
cyclization of acyclic 1-substituted polyhydroxylated hex-5-enyl
radicals and their relative importance. This can be helpful for
the prediction of radical cyclization outcomes from other con-
formationally flexible systems. Our results have demonstrated,
as Beckwith predicted before, that the most important
parameter is the presence of a substituent at C-1 which is
responsible for the 1,5-cis stereoselectivity. In addition to this
observation, our results have pointed out the parameter of
secondary importance which is the nature of the substituent at
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J. Chem. Soc., Perkin Trans. 1, 2000, 245–251

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C-2 and C-4. When they are hydroxy groups, as in our case, the
stereocontrol of the radical cyclization depends also on an equi-
librium between van der Waals’ and steric interactions: if the
hydroxy groups are protected, only the steric interactions con-
trol the transition states’ equilibrium, leading in our case to syn-
anti-syn cyclic compounds while, if the hydroxy groups are free,
the van der Waals’ forces overcome the steric interaction and
control the 1,2- and 4,5- cis/trans stereoselectivities to yield all-
syn compounds in our case. Moreover, as the last important
factor, we have found that the nature of the protecting group on
the primary alcohol at C-1 could also affect the 1,2-cis/trans
stereoselectivities due to the appearance of another intra-
molecular hydrogen bond when RЈ = Bz. Consequently, in
order to predict the stereoselectivity of intramolecular cycliz-
ations of acyclic 1-substituted polyhydroxylated hex-5-enyl
radicals, all these parameters should be considered and com-
parison of the stability of each possible transition state should
be made.
allowed to reach room temperature and was diluted with water
and extracted three times with CH2Cl2. The organic layers were
combined, washed with brine, dried over Na2SO4 and concen-
trated under reduced pressure. The crude product was purified
by chromatography on silica gel (heptane–ethyl acetate 90:10)
and a colorless oil was finally identified as the compound 3
(75 mg, 98% yield).
Rf 0.45 (heptane–ethyl acetate 80:20). IR: νmax/cmϪ1 1715
1
(C᎐O). H NMR (100 MHz, CDCl ): δ (ppm) = 0.4–1.0 (m,
᎐
3
30H, 2 Si(CH2CH3)3), 1.57–2.14 (m, 2H, H-5), 3.38 (t, 1H,
J = 6.3 Hz), 3.58 (s, 3H, OCH3), 4.30–4.75 (m, 4H, H-4, H-7,
H-8), 5.91 (d, 1H, H-2, J = 15.7 Hz), 6.87 (dd, 1H, H-3, J = 4.7,
15.7 Hz), 7.27–7.55 (m, 3H, Phenyl), 7.89–7.97 (m, 2H, Phenyl).
13C NMR (25 MHz, CDCl3): δ (ppm) = 4.5, 4.9, 5.6, 6.0, 6.3, 6.5
(2 Si(CH2CH3)3), 38.1 (C-5), 44.3 (C-7), 51.2 (OCH3), 66.3,
66.5, 68.8 (C-4, C-6, C-8), 119.9 (C-2), 128.1, 129.4, 132.8
(Phenyl), 149.8 (C-3), 165.3 (CO2 methyl ester), 166.2 (CO2
benzoyl group).
Finally these results allowed us to devise a very convergent
strategy for the total synthesis of isoP. We can reach, using the
cheaper -glucose, all the different IsoPs diastereoisomers by
choosing whether or not to protect the radical precursors. We
have demonstrated the efficacy of our synthetic route by the
achieved total synthesis of 8-epi- or 12-epi-PGF2α.6b,7b,18
Methyl (2E,4R,6S,7R)-8-tert-butyldiphenylsilyloxy-4,6-
bis(triethylsilyloxy)-7-iodooct-2-enoate 8
To a solution of compound 710 (1.25 g, 2.2 mmol) previously
dissolved in anhydrous pyridine (18 ml) at 60 ЊC was added
triethylsilyl chloride (1.7 ml, 10.09 mmol) under an inert
atmosphere. The solution was stirred for 4 hours at 60 ЊC. The
crude mixture was allowed to reach room temperature and
was diluted with water and extracted three times with CH2Cl2.
The organic layers were combined, washed with brine, dried
over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by chromatography on silica gel
(cyclohexane–ethyl acetate 90:10) and a colorless oil was finally
identified as the compound 8 (1.08 g, 62% yield).
Experimental
Materials
Xylene and methanol were distilled from sodium, tetrahydro-
furan from sodium–benzophenone and dichloromethane from
CaH2. Triethylborane, tributyltin hydride and Corey lactone
were purchased from Aldrich Chemical Company Inc. Reac-
tions were monitored by thin layer chromatography on E.
Merck aluminium sheet silica gel 60F254 (0.2 mm) and visual-
ized using UV light (254 nm) and/or heating with p-anis-
aldehyde solution or phosphomolybdic acid (20 wt% in ethyl
alcohol). All reactions were carried out under argon and crude
products were purified by chromatography using 70–200 mesh
Rf 0.53 (cyclohexane–ethyl acetate 90:10). IR: νmax/cmϪ1 1720
1
(C᎐O). H NMR (360 MHz, CDCl ): δ (ppm) = 0.54–0.69 (m,
᎐
3
12H, Si(CH2CH3)3), 0.94–1.04 (m, 27H, Si(CH3)3, Si(CH2-
CH3)3), 1.76–1.84 (m, 1H, H-5), 2.08–2.16 (m, 1H, H-5), 3.60
(m, 1H, H-6), 3.73 (s, 3H, OCH3), 3.93 (dd, 2H, H-8, J = 1.8,
6.3 Hz), 4.43–4.48 (m, 2H, H-4 and H-7), 6.08 (dd, 1H, H-2,
J = 1.4, 15.7 Hz), 7.02 (dd, 1H, H-3, J = 4.7, 15.7 Hz), 7.38–7.44
(m, 6H, Phenyl), 7.71–7.69 (m, 4H, Phenyl). 13C NMR (90
MHz, CDCl3): δ (ppm) = 4.9, 5.3, 6.4, 6.7, (2 Si(CH2CH3)3),
19.1 (C(CH3)3), 26.8 (C(CH3)3), 44.3 (C-5 and C-7), 51.3
(OCH3), 66.4 (C-8), 67.4 (C-4), 69 (C-6), 120.2 (C-2), 127.6,
129.7, 133.1, 133.5, 135.6 (Phenyl), 150.2 (C-3), 166.5 (CO).
Elemental analysis (Found C, 55.78; H, 7.67. Calc. for C37H61-
O5SiI3: C, 55.76; H, 7.71%).
1
silica gel (E. Merck). H NMR (360 MHz) and 13C NMR (90
MHz) spectra were recorded on a Bruker AMX-360 spec-
trometer at ambient temperature. IR Spectra were obtained
with a Beckmann Acculab-2 spectrophotometer. Elemental
analyses were performed by the “Centre National de la
Recherche Scientifique, Service Central d’Analyse, Vernaison,
France”.
1
For DNOES experiments, H NMR spectra were recorded
on a Bruker AMX 360 spectrometer operating in the pulse
mode. Compounds were dissolved in the indicated solvent
(Table 1). The probehead temperature was 32 ЊC. Solutions
were degassed by argon bubbling. The NOE procedure was as
follows: the standard Bruker library microprogram was used
to perform steady-state NOE difference spectroscopy. The
experiments were performed with interleaving. Thirty-two scans
(preceded by two dummy scans to establish equilibrium: l1 = 2)
were acquired for each irradiation frequency, and the entire
process was automatically repeated to afford the requisite
signal-to-noise ratio. The irradiation time was typically 3 s. A
90Њ read pulse was employed in all cases. The decoupler power
setting was chosen so as to minimize frequency spillover to
neighboring multiplets. NOE Values were calculated by
comparing summed peak heights in the vertically expanded
difference spectra with the control irradiation spectra.
General procedure for the radical cyclization step
The cyclization precursor (1 equiv.) was dissolved in anhydrous
xylene (4 ml for 0.3 mmol of starting material at room temper-
ature). The oxygen was removed from the solvent by smoothly
flushing nitrogen through the solution for 1 hour. Then, tri-
butyltin hydride (1.2 equiv.) and triethylborane (0.2 equiv. of a
1 M solution in hexane) were added successively under nitrogen
before smoothly flushing dry air through the solution for 10
minutes. The solvent was concentrated under reduced pressure
and the crude product was purified by chromatography on silica
gel. For compound 13, a cyclohexane–ethyl acetate mixture
(100:0 to 95:5) was used as eluent. Even after chromato-
graphing several times, it was still difficult to isolate the
compounds 14 to 16 since they have quite similar polarities.
Cyclohexane–ethyl acetate (100:0 to 50:50) and cyclohexane–
methylene dichloride (100:0 to 50:50) mixtures were used as
eluents to isolate compounds 17 to 20 and compounds 21 to 24,
respectively. The yields are shown in Table 1.
Methyl (2E,4R,6S,7R)-8-benzoyloxy-4,6-bis(triethylsilyloxy)-7-
iodooct-2-enoate 3
To a solution of compound 27b (50 mg, 0.115 mmol) previously
dissolved in anhydrous pyridine at 60 ЊC was added triethylsilyl
chloride (360 µl, 0.922 mmol) under an inert atmosphere. The
solution was stirred for 2 hours at 60 ЊC. The crude mixture was
(1S,2S,3R,4R)-2-Benzoyloxymethyl-1,4-bis(triethylsilyloxy)-
3-(methoxycarbonylmethyl)cyclopentane 13. This product was
also synthesized in another way from the compound 12.
J. Chem. Soc., Perkin Trans. 1, 2000, 245–251
249

View Article Online
Triethylsilyl chloride (1.59 ml, 4.080 mmol) was added to a
solution of 12 (157 mg, 0.510 mmol) previously dissolved in
anhydrous pyridine (8.2 ml) at 60 ЊC under an inert atmosphere.
The solution was stirred for 15 min at 60 ЊC before being cooled
to room temperature. The crude mixture was washed with water
and extracted three times with CH2Cl2. The organic layers were
combined, washed with brine, dried over Na2SO4 and concen-
trated under reduced pressure. The crude product was purified
by chromatography on silica gel (cyclohexane–ethyl acetate
90:10) which gave a pure colorless oil identified as the com-
pound 13 (243 mg, 89% yield).
tBu), 26.7 (CH3 tBu), 33.4 (C-7), 42.3 (C-3), 44.2 (C-5), 50.9
(C-2), 51.7 (OCH3), 62.8 (C-6), 74.3 (C-1), 76.8 (C-4), 127.6,
129.7, 132.7, 135.4 (Phenyl), 174.5 (CO). Elemental analysis
(Found C, 67.72; H, 7.94. Calc. for C25H34O5Si: C, 67.84; H,
8.04%).
(1S,2R,3S,4R)-1,4-Bis(triethylsilyloxy)-3-(methoxycarbonyl-
methyl)-2-tert-butyldiphenylsilyloxymethylcyclopentane 21. Rf
1
0.5 (cyclohexane–CH2Cl2 50:50). COSY homonuclear H–1H
(CDCl3): (H-4–H-3), (H-4–H-5a), (H-4–H-5b), (H-1–H-5a),
(H-1–H-5b), (H-1–H-2), (H-1–H-5a), (H-1–H-5b), (H-6–H-2),
(H-7a–H-7b), (H-7a–H-3), (H-7b–H-3), (H-5a–H-5b). COSY
heteronuclear 1H–13C (CDCl3): HMQC: (H-1–C-1), (H-4–C-4),
(H-6–C-6), (H-3–C-3), (H-2–C-2), (H-5a–C-5), (H-5b–C-5),
(H-7a–C-7), (H-7b–C-7). HMBC: (OCH –C᎐O), (H-7a–C᎐O),
Rf 0.65 (heptane–ethyl acetate 80:20). IR (NaCl): νmax/cmϪ1
1715, 1725 (C᎐O). 1H NMR (100 MHz, CDCl ): δ (ppm) = 0.3–
᎐
3
0.6 (m, 12H, 2 Si(CH2CH3)3), 0.8–1.2 (m, 18H, 2 Si(CH2CH3)3),
1.4–1.7 (m, 1H, H-5b), 2.2–2.7 (m, 4H, H-2, H-3, H-5a, H-7),
3.54 (s, 3H, OCH3), 3.6–3.9 (m, 1H, H-1), 3.9–4.1 (m, 1H, H-4),
4.2–4.4 (m, 2H, H-6), 7.2–7.6 (m, 3H, Phenyl), 8.4–8.0 (m, 2H,
Phenyl). 13C NMR (25 MHz, CDCl3): δ (ppm) = 4.6, 4.7, 5.7,
6.3, 6.4, 6.6 (2 Si(CH2CH3)3), 33.7 (C-7), 44.3 (C-3, C-5), 47.1
(C-2), 51.4 (OCH3), 63.8 (C-6), 72.5 (C-1), 75.2 (C-4), 128.3,
129.4, 129.8, 133.0 (Phenyl), 167.2 (CO2 benzoyl group), 173.2
(CO2 methyl ester).
᎐
᎐
3
(H-7b–C᎐O), (H-1–C-4), (H-7a–C-4), (H-7b–C-4), (H-2–C-4),
᎐
(H-5b–C-4), (H-6–C-1), (H-5b–C-1), (H-2–C-6), (H-4–C-3),
(H-1–C-3), (H-6–C-3), (H-7a–C-3), (H-7b–C-3), (H-5a–C-3),
(H-3–C-7), (H-2–C-7). Elemental analysis (Found C, 66.25;
H, 9.39; O, 11.91. Calc. for C25H34O5Si: C, 66.21; H, 9.31; O,
11.91%).
(1S,2S,3S,4R)-1,4-Bis(triethylsilyloxy)-3-(methoxycarbonyl-
methyl)-2-tert-butyldiphenylsilyloxymethylcyclopentane 22. Rf
(1R,5S,6S,7S)-7-Hydroxy-6-tert-butyldiphenylsilyloxy-
methyl-2-oxabicyclo[3.3.0]octan-3-one 17. Rf 0.60 (cyclo-
hexane–ethyl acetate 50:50). 1H NMR (100 MHz, CDCl3):
δ (ppm) = 1.05 (s, 9H, tBu), 1.8–2.3 (m, 3H, H-6, H-8), 2.6 (d,
1H, H-4b, J = 14.6 Hz), 2.65 (d, 1H, H-4a, J = 8.3), 2.9–3.3 (m,
1H, H-5), 3.7 (d, 1H, H-1Јb, J = 11.1 Hz), 3.95 (d, 1H, H-1Јa,
J = 7.7 Hz), 4.3–4.4 (m, 1H, H-7), 5.1 (t, 1H, H-1, J = 6.9 Hz),
7.2–7.4 (m, 3H, Phenyl), 7.5–7.8 (m, 2H, Phenyl). 13C NMR (25
MHz, CDCl3): δ (ppm) = 19.0 (quat. C tBu), 26.6 (CH3 tBu),
30.5 (C-4), 38.4 (C-5), 42.0 (C-8), 49.4 (C-6), 60.7 (C-1Ј), 73.0
(C-7), 84.6 (C-1), 127.6, 129.7, 135.3 (Phenyl), 177.5 (CO).
Elemental analysis (Found C, 70.13; H, 7.41. Calc. for C24H30-
O4Si: C, 70.21; H, 7.36%).
1
0.4 (cyclohexane–CH2Cl2 50:50). COSY homonuclear H–1H
(CDCl3): (H-4–H-3), (H-4–H-5a), (H-4–H-5b), (H-1–H-5a),
(H-1–H-5b), (H-1–H-2), (H-6a–H-6b), (H-6a–H-2), (H-6b–
H-2), (H-7a–H-3), (H-7a–H-7b), (H-3–H-7b), (H-5a–H-5b).
COSY heteronuclear 1H–13C (CDCl3): HMQC: (H-1–C-1),
(H-4–C-4), (H-6a–C-6), (H-6b–C-6), (H-3–C-3), (H-2–C-2),
(H-5a–C-5), (H-5b–C-5), (H-7a–C-7), (H-7b–C-7), (OCH3–
OCH ). HMBC: (OCH –C᎐O), (H-7a–C᎐O), (H-7b–C᎐O),
᎐
᎐
᎐
3
3
(H-1–C-6), (H-4–C-2), (H-5–C-2), (H-7a–C-3), (H-7b–C-3),
(H-5a–C-3), (H-5b–C-3). Elemental analysis (Found C, 66.24;
H, 9.24; O, 11.91. Calc. for C25H34O5Si: C, 66.21; H, 9.31; O,
11.91%).
(1S,2R,3R,4R)-1,4-Bis(triethylsilyloxy)-3-(methoxycarbonyl-
methyl)-2-tert-butyldiphenylsilyloxymethylcyclopentane 23. Rf
0.35 (cyclohexane–CH2Cl2 50:50). COSY homonuclear 1H–1H
(CDCl3): (H-1–H-8), (H-1–H-5a), (H-1–H-5b), (H-4–H-5a),
(H-4–H-5b), (H-4–H-3), (H-6a–H-2), (H-6b–H-2), (OCH3–
H-7), (H-7–H-3), (H-5a–H5b). COSY heteronuclear 1H–13C
(CDCl3): HMQC: (H-4–C-4), (H-2–C-2), (H-6a–C-6), (H-3–
C-3), (H-2–C-2), (H-5a–C-5), (H-5b–C-5), (H-7–C-7), (OCH3–
OCH3). HMBC: (H-1–C-4), (H-7–C-4), (H-3–C-4), (H-5a–C-4),
(H-5b–C-4), (H-4–C-1), (H-6–C-1), (H-7–C-1), (H-5a–C-1),
(H-5b–C-1), (H-2–C-6), (H-5a–C-2), (H-7–C-2), (H-6a–C-2),
(H-6b–C-2), (H-5a–C-3), (H-7–C-3), (H-6–C-3), (H-1–C-3),
(H-4–C-5), (H-7–C-5), (H-4–C-7). Elemental analysis (Found
C, 66.24; H, 9.24; O, 12.01. Calc. for C25H34O5Si: C, 66.21; H,
9.31; O, 11.91%).
(1R,5S,6R,7S)-7-Hydroxy-6-tert-butyldiphenylsilyloxymethyl-
2-oxabicyclo[3.3.0]octan-3-one 18. Rf 0.55 (cyclohexane–ethyl
acetate 50:50). 1H NMR (100 MHz, CDCl3): δ (ppm) = 1.05 (s,
9H, tBu), 1.6 (s, 1H, OH), 2.2–2.7 (m, 3H, H-4, H-5), 3.6–3.8
(m, 1H, H-1Ј), 4.15 (q, 1H, H-7, J = 6.2 Hz), 4.8–4.9 (m, 1H,
H-1), 7.2–7.4 (m, 3H, Phenyl), 7.6–7.7 (m, 2H, Phenyl). 13C
NMR (25 MHz, CDCl3): δ (ppm) = 19.0 (quat. C tBu), 26.7
(CH3 tBu), 35.0 (C-4), 39.2 (C-5), 40.5 (C-8), 55.0 (C-6), 64.1
(C-1Ј), 75.0 (C-7), 83.2 (C-1), 127.7, 129.8, 135.3 (Phenyl), 177.3
(CO). Elemental analysis (Found C, 70.11; H, 7.29. Calc. for
C24H30O4Si: C, 70.21; H, 7.36%).
(1S,2S,3R,4R)-3-(Methoxycarbonylmethyl)-2-tert-butyl-
diphenylsilyloxymethylcyclopentane-1,4-diol 19. Rf 0.35 (cyclo-
hexane–ethyl acetate 50:50). 1H NMR (100 MHz, CDCl3):
δ (ppm) = 1.03 (s, 9H, tBu), 1.8–2.2 (m, 4H, H-3, H-3, H-5),
2.4–2.6 (m, 2H, H-7), 3.63 (s, 3H, OCH3), 3.5–3.8 (m, 2H, H-6),
4.0–4.3 (m, 2H, H-1, H-4), 7.2–7.4 (m, 3H, Phenyl), 7.6–7.7
(m, 2H, Phenyl). 13C NMR (25 MHz, CDCl3): δ (ppm) = 19.2
(quat. C tBu), 26.7 (CH3 tBu), 33.6 (C-7), 42.2, 42.9 (C-3,
C-5), 51.5 (OCH3), 54.5 (C-2), 64.5 (C-6), 74.1 (C-1), 76.0 (C-4),
127.6, 129.6, 135.4 (Phenyl), 174.4 (CO). Elemental analysis
(Found C, 67.72; H, 8.11. Calc. for C25H34O5Si: C, 67.84; H,
8.04%).
(1S,2S,3R,4R)-1,4-Bis(triethylsilyloxy)-3-(methoxycarbonyl-
methyl)-2-tert-butyldiphenylsilyloxymethylcyclopentane 24. Rf
0.25 (cyclohexane–CH2Cl2 50:50). COSY homonuclear 1H–1H
(CDCl3): (H-1–H-2), (H-1–H-5a), (H-1–H-5b), (H-4–H-3),
(H-4–H-5a), (H-4–H-5b), (H-6–H-2), (H-7–H-3), (H-3–H-2),
1
(H-5a–H5b). COSY heteronuclear H–13C (CDCl3): HMQC:
(H-4–C-4), (H-1–C-1), (H-6–C-6), (H-2–C-2), (OCH3–OCH3),
(H-5a–C-5), (H-5b–C-5), (H-3–C-3), (H-2–C-2), (H-7–C-7).
Elemental analysis (Found C, 66.31; H, 9.39; O, 11.85. Calc. for
C25H34O5Si: C, 66.21; H, 9.31; O, 11.91%).
(1S,2R,3R,4R)-3-(Methoxycarbonylmethyl)-2-tert-butyl-
diphenylsilyloxymethylcyclopentane-1,4-diol 20. Rf 0.2 (cyclo-
hexane–ethyl acetate 50:50). 1H NMR (100 MHz, CDCl3):
δ (ppm) = 1.03 (s, 9H, tBu), 1.5–1.8 (m, 1H, H-5a), 1.81 (s, 1H,
OH), 2.2–2.6 (m, 5H, H-2, H-3, H-5a, H-7), 3.1 (d, 1H, OH,
J = 3.5 Hz), 3.63 (s, 3H, OCH3), 3.4–3.7 (m, 2H, H-6), 3.8–4.2
(m, 2H, H-1, H-4), 7.3–7.5 (m, 3H, Phenyl), 7.5–7.7 (m, 2H,
Phenyl). 13C NMR (25 MHz, CDCl3): δ (ppm) = 18.9 (quat. C
Acknowledgements
We wish to thank the Direction des Recherches, Etudes et
Techniques for financial support (grant no 94135/DRET) and
the Ministère de l’Education Nationale, de l’Enseignement
Supérieur et de la Recherche for financial support for one of us
250
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Roland, E. Cormenier and J.-C. Rossi, Tetrahedron Lett., 1998, 39,
(A. R.). We are indebted to Miss Nicole Marshall for correcting
the manuscript.
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