Stereoselective synthesis of CD-ring precursors of vitamin D derivatives

Article abstract of DOI:10.1016/j.tet.2009.06.052

Two expedious and useful approaches to the construction of Vitamin D trans-hydrindane building blocks are proposed. These involve the desymmetrization of the anti meso-acetylmethyldivinylcyclopentane 3 which proceeds through either the selective formation

Full text of DOI:10.1016/j.tet.2009.06.052

Tetrahedron 65 (2009) 7001–7015
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of CD-ring precursors of vitamin D derivatives
,
y
*
*
Raphae¨l Rodriguez, Anne-Sophie Chapelon, Cyril Ollivier , Maurice Santelli
Laboratoire de Synthe`se Organique (Equipe Chirosciences, associe´e au CNRS), Universite´ d’Aix-Marseille, Facult´e des Sciences de St-Je´roˆme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2009
Received in revised form 7 June 2009
Accepted 12 June 2009
Available online 18 June 2009
Two expedious and useful approaches to the construction of Vitamin D trans-hydrindane building blocks
are proposed. These involve the desymmetrization of the anti meso-acetylmethyldivinylcyclopentane 3
which proceeds through either the selective formation of epoxyketone 5 and intramolecular enolate
cyclisation or a xanthate groupe transfer mediated radical cyclization to furnish trans-hydrindanes 7 and
16 respectively. Epoxyketone 5 is prepared by means of a three-step reaction process including reduction
of the ketone moiety, bishomoallylic alcohol-directed epoxidation and Dess–Martin oxidation. Alterna-
tively, an asymmetric reduction using borane/tetrahydrofuran complex and (R)-2-methyl-CBS-ox-
azaborolidin made accessible the epoxyketone in good optical purity. The xanthate 16 can undergo
a Johnson sulfoximine ketone resolution that allows access to both enantiomers. Various derivatizations
of 16 to more elaborated synthetic intermediates are also reported.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
as antitumor agent was hampered by toxic hypercalcemia side
effects. Therefore, analogs that do not disrupt the phosphocalcic
Vitamin D3 1 and its metabolites, more particularly the natural
hormone 1 ,25-dihydroxyvitamin D3 or calcitriol 2 (Scheme 1),
homeostasis are required.2 For this reason, preparation of
highly-potent vitamin D3 analogs has attracted the interest of
numerous synthetic groups.3 More recently, new compounds
showed promise in the treatment of a variety of diseases as
diverse as psoriasis, renal osteodystrophy, osteoporosis, diabetes,
leukemia, cancer (breast, colon, prostate), AIDS and multiple
sclerosis.4
a
have attracted considerable attention because of their remarkable
biological activity in such areas as regulation of calcium and
phosphorus metabolism, cellular differentiation, inhibition of cell
proliferation implied in cancers or other hyperproliferation diseases,
and immunology.1 However, the use of 1
a
,25-dihydroxyvitamin D3
Early generation vitamin D analogs have traditionally been
prepared from steroid precursors or vitamin D2. A versatile method
pioneered by Lythgoe has been used intensively for the preparation
of vitamin D3 and highly functionalized analogs. This pioneer work
OH
17
17
11
11
13
8
13
14
8
14
initiated a range of efficient strategies for the preparation of 1
a,25-
H
H
dihydroxyvitamin D3 derivatives modified at specific positions
involving cross-coupling between
hydrindanes.3
A rings and CD bicyclic
19
19
10
10
Despite the large number of synthetic methods known for
constructing these trans-hydrindane CD-ring building blocks,5
innovative, efficient and straightforward approaches to poly-
functionalized units, with a C13–C14 trans-junction and a cis re-
lationship between the substituents at C13 and C17 carbon centers,6
still represents a synthetic challenge.7 In fact, steroidal trans-8-
methyl-4-hydrindanones, such as the Grundman–Windaus ketone
obtained from ozonolysis of vitamine D3, turned out to be less
stable than the cis form by approximatively 0.76–1.45 to 2.36 kcal/
mol depending on the literature source (Scheme 2),8–10 then the
trans-ring junction can be easily epimerized under acidic or basic
conditions.11
1
2
HO
HO
OH
3
1
3
1
Scheme 1. Representation of vitamin D3 1 and calcitriol 2.
* Corresponding authors. Tel.: þ33 491288825; fax: þ33 491289112 (M.S.); tel.:
þ33 144272547; fax: þ33 144277360 (C.O.).
E-mail addresses: cyril.ollivier@upmc.fr (C. Ollivier), m.santelli@univ-cezanne.fr
(M. Santelli).
y
Present address: UPMC Univ Paris 06, UMR CNRS 7201, Institut Parisien de
Chimie Moleculaire, 4 place Jussieu, C. 229, F-75005 Paris, France.
´
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.052

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R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
R
H
O
O
R
O
7
1
6
5
8
2
9
4
3
H
I
H
X
H
X
O
7
OH
OPG
5
R = X = H, ΔE= –0.31 to –1.17 kcal/mol
R = Me; X = H, ΔE= + 0.98–1.23 kcal/mol
R = Me; X = O, ΔE= + 0.76–1.45 to +2.36 kcal/mol
Scheme 2. Stability cis- versus trans-hydrindane.
6
PG = Protective group
OH
anti-meso-3
4
2. Access to polyfunctionalized trans-hydrindane units from
stereoselective epoxidation of the anti meso-
acetylmethyldivinylcyclopentane
Scheme 4. Retrosynthetic approach for the preparation of the trans-hydrindane unit 7
from the anti meso-3.
O
OH
Some years ago, we described the synthesis in 78% yield (47%
yield on 0.8 mol scale) of acetylcyclopentanes anti-meso-3 and
(ꢀ)-3 from easily available 1,8-bis(trimethylsilyl)-2,6-octadiene
(Bistro)12 and 2,2,3,3-tetramethoxybutane in the presence of TiCl4
(Scheme 3). To explain its formation, we suggested that a tita-
nium tetrachloride-mediated SE20 substitution followed by
a pinacol-type rearrangement of the divinyl intermediate should
operate.13
t-BuOOH
NaBH4
VO(acac)2 cat.
MeOH, rt
CH2Cl2
anti meso-3
4, 91% yield
O
OH
OH
O
Dess-Martin
CH2Cl2, rt
+
O
O
O
5, >98% yield
SiMe3
8a
8b
anti meso-3
88:12 dr at 15 °C
82:18 dr at 25 °C
43% yield,
MeO
MeO
OMe
OMe
TiCl4 (4 eq.)
55% yield
+
MeNO2
CH2Cl2
Scheme 5. Diastereoselective synthesis of epoxyketone (ꢀ)-5 from anti meso-3.
O
on the reaction temperature. Subsequent Dess–Martin oxidation18
of the mixture of 8 gave the targeted epoxyketone 5 as a single
diastereoisomer.
Bistro
SiMe3
( )-3
23% yield
The relative configuration of the major epoxyalcohol 8a was
elucidated by X-ray diffraction analysis of a derivative. In fact,
the mixture of epoxides 8a and 8b was converted into the
corresponding crystalline bis-(3,5-dinitrobenzoyloxy)iodohy-
drin derivative 9. After recrystallization of the mixture, the
major isomer 8a was isolated and gave pure cristals suitable for
X-ray cristallography. Figure 1 shows an ORTEP representation
of 9.
Scheme 3. Preparation of divinylacetylcyclopropanes anti meso-3 and (ꢀ)-3 from
2,2,3,3-tetramethoxybutane and Bistro.
In connection with our interest in steroids synthesis, and
particularly in vitamin D synthesis,14 we decided to explore
new strategies for the stereoselective preparation of highly
functionalized trans-hydrindane units starting from the versa-
tile building block anti-meso-acetylmethyldivinylcyclopentane
anti-meso-3.14b,c We first tried to build the 6-membered ring of
the CD bicyclic moiety in a trans fashion by cyclization of the
protected iodohydrin 6 through intramolecular enolate alkyl-
ation. This intermediate could be constructed from the corre-
sponding epoxyketone 5, which could be obtained by
stereoselective desymmetrization of anti-meso-3. The latter
could be realized through a three step sequence involving se-
quential ketone reduction, bishomoallylic alcohol-oriented
monoepoxidation15 and reoxidation of alcohol providing the
epoxyketone 5 as a single diastereoisomer. Interestingly, 7
should present a structure and relative stereochemistry similar
to the Inhoffen–Lythgoe diol functionalized at the C12 position
(Scheme 4). It was demonstrated that the 12-oxygenated
functionality or 12-methyl plays an important role in the an-
titumor activity.16
3,5-DNBzO
1. NaI, CeCl3.7H2O
/CH3CN, rt
Mixture of
8a and 8b
3,5-DNBzO
2. 3,5-DNBzCl
Pyridine / CH2Cl2, rt
3. Recrystallization
I
9
From anti-meso-3, the initial methyl ketone reduction in
secondary alcohol generates a new stereogenic center which
induces discrimination between both vinyl groups in the bis-
homoallylic alcohol-oriented epoxidation process, as illustrated
in Scheme 6. As we observed, the bishomoallylic alcohol/VO-
(acac)2/TBHP chelate complexe C1 was preferentially formed.
The total discrimination between both faces of each vinyl group
in favor of the A face can be explained by the fact that the ro-
tation of the vinyl group is limited by the steric hindrance of the
angular methyl and renders its B face inaccessible.
Our first task was the diastereoselective synthesis of epoxy-
ketone 5 from anti-meso-3 as shown in Scheme 5. Methyl ketone
reduction of anti-meso-3 with NaBH4/MeOH was followed by
a bishomoallylic alcohol-oriented epoxidation of 4 with VO(acac)2/
t-BuOOH to furnish an inseparable mixture of epoxides 8a and 8b in
43% yield (63% based upon recovered 4) with a 88:12 dr for re-
actions run at 15 ꢁC and a 82:18 dr at 25 ꢁC.17 These diastereomeric
ratios, measured by means of GC, showed to be slightly dependent
Scheme 7 depicts the final stages of the elaboration of the C ring.
The above epoxyketone intermediate 5 was converted to iodohy-
drin 10 in 91% yield via a cerium trichloride-assisted regioselective
ring opening of the epoxide by NaI.19 Subsequently, protection of

R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
7003
Potassium enolate, generated by treatment of 11 with t-BuOK/THF
at 50 ꢁC, underwent a rapid 6-exo-tet cyclization involving nucleo-
philic substitution of iodide and gave rise to the hydrindane 12 in
89% yield.20 Removal of the THP protective group liberated the
polyfunctionalized hydrindane bicyclic compound 7 (Scheme 7,
Fig. 2).
O5
C18
N2
O6
C17
C7
C4
O4
N1
C16
C6
C19
C15
O3
C14
O2
C8
O1
C13
C3
C5
C22
C13
O14
C14
C11
C23
C2
C24
C1
C12
O11
C15
C21
C9
O13
C10
O12
C20
C22
O7
N3
C21
C23
C20
I1
C16
C18
C26
C25
C17
C24
O8
C19
O10
N4
O9
Figure 2. ORTEP drawing of X-ray structure of 7 with labeled heteroatom.
Figure 1. ORTEP drawing of X-ray structure of 9 with labeled heteroatom. Thermal
ellipsoid are scaled to 50% probability level. Hydrogen atoms are drawn to an arbitrary
scale.
A formal enantioselective access to this hydrindane, showing
the absolute configuration of the natural vitamin D3 at C13, C14 and
C17, is proposed with the asymmetric synthesis of the epoxyketone
(þ)-5 (Scheme 8). An approach based on catalytic CBS-reduction21
OH
followed by
a similar bishomoallylic alcohol-oriented epox-
Discrimination
between both vinyl
groups
idationdDess–Martin oxidation sequence has been investigated.
The enantioselective reduction of the methyl ketone moiety with
borane/tetrahydrofuran (BH3$THF) and a chiral oxazaborolidine
(Me-(R)-CBS) as catalyst at rt furnished the secondary alcohol (S)-
(þ)-4 in a good 70% yield and high optical purity (>99:1 to 97:3 er,
determined by chiral GC). According to the intensive studies of
Corey and co-workers21 on catalytic CBS reduction of methyl ke-
tones, the (S) absolute configuration of (þ)-4 can be assigned on the
basis of the known facial selectivity of the reducing agent. Re-
gardless to the nature of the ketone, the level of asymmetric in-
duction is in accordance with the earlier examples reported in the
litterature. We then applied the previous VO(acac)2-mediated TBHP
epoxidation procedure to the enantiomerically enriched alcohol
A Face
B Face
Discrimination between
both faces
t-Bu
O
O
t-Bu
O
R
O
O
H
V
R
O
O
H
H
V
O
H
C1
−R =
C2
O
O
Scheme 6. Two diastereomeric transition states for the VO(acac)2/TBHP-catalyzed
bishomoallylic alcohol epoxidation.
O
OH
Ph
(R)-CBS,
O
H
N
Ph
O
BH3.THF
O
NaI, CeCl3.7H2O
CH3CN, rt
DHP, APTS
CH2Cl2, rt
Toluene, rt
70%
B
HO
Me-(R)-CBS
O
5
10
91%
> 98%
(S)-(+)-4
anti-meso-3
97:3 er
I
O
O
O
t-BuOOH
VO(acac)2 cat.
Dess-Martin
t-BuOK
8a : 8b
THPO
CH2Cl2, rt
>98%
CH2Cl2, 15 ºC
43%
THF, 50 °C
89%
O
H
RO
I
(+)-5
APTS
MeOH/H2O, rt
99%
82:18 dr at 25 °C
80:20 er
R = THP, 12
R = H, 7
31% from
11
anti meso-3
Scheme 7. Synthesis of a trans-hydrindane unit from 7.
t-Bu
O
O
O
H
V
O
R
(S)
the hydroxyl group as a THP ether was carried out. To construct the
6-membered ring of the hydrindane, intramolecular ketone enolate
H
Scheme 8. Asymmetric approach to epoxyketone (þ)-5.
alkylation of the
d-iodoketone adduct 10 was then performed.

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R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
(þ)-4, leading to a 82:18 mixture of epoxyalcohols 8a and 8b at
25 ꢁC.22 During the process, a chiral transfer involving the reported
transition state was operating as the er was conserved. This result
was proved by chiral GC analysis. Finally, oxidation using Dess–
Martin reagent liberated the corresponding product (þ)-5 in
80:20 er.23
TMSO
then
TMSOTf
- Hünig's base
NBS - NaHCO3
dl and/or anti-
meso-3
/ CH2Cl2
/ THF (−78 ºC)
68% yield
14
S
S
LDA
/ THF (−78 ºC)
3. Access to trans-hydrindane units from the anti meso-
acetylmethyldivinylcyclopentane involving a radical pathway
S
S
OEt
EtO
75% yield
S
O
O
According to the retrosynthesis shown in Scheme 9, elaborated
vitamin D trans-hydrindane building blocks can also be obtained in
a straightforward way from the radical cyclization of dithiocar-
bonate anti-meso-13 and starting from anti-meso-3.14c
EtO
S-K
EtO
S
Br
/ acetone
68−82% yield
S
dl and/or
15
anti-meso-13
O
SC
O
O
O
Scheme 11. Preparation of dithiocarbonate anti-meso-13 and (ꢀ)-13.
anti-
H
meso-3
H
EtO
S
O
S
O
S
When xanthate anti-meso-13 was heated in degassed 1,2-di-
chloroethane in the presence of lauroyl peroxide (DLP) (20 mol %
added portion wise), an intramolecular cyclization occurred leading
to the expected hydrindanone 16 in good yield and with total
stereoselectivity (Scheme 12). From the xanthate (ꢀ)-13, the cy-
clization reaction led to a more complex mixture in which the
major compound was diquinane 17, besides the trans-hydrinda-
none 18 and the cis-hydrindanone 19 (Scheme 13). Moreover, yields
were moderate (overall yield, 51%) and the reaction required a large
amount of lauroyl peroxide (50 mol %) for completion of the re-
action. Consequently, when the reaction was performed on multi-
gram scale (20 mmol) with the mixture of anti-meso-13 and (ꢀ)-13
(70:30 meso/dl), 16 as well as 17 were easily isolated in 59% and 14%
yields, respectively together with only traces of 18 and 19 (<5%).
EtO
S
S
N
S
anti-meso-13
16
Scheme 9. Retrosynthetic analysis for the synthesis of trans-hydrindanes as pre-
cursors of vitamin D analogs.
Then, the coupling between these building blocks and a suitable
aldehyde according to the Kocienski-modified24,25 Julia olefination
reaction26 should allow the construction of the trienic system vi-
tamin D and its analogs (Scheme 10) as already reported in the
literature.
O
SC
SC
O
O
12
O
O
( )10
DLP (cat.)
O
H
+
H
O
O
S
O
2
S
anti-meso-13
PGO
N
H
/ ClCH2-CH2Cl
EtO
S
PGO
SC: Side chain; PG: Protective group
16, 70% yield
S
Scheme 10. Construction of the trienic part of vitamin D analogs by using a Julia-
Kocienski olefination coupling.
Scheme 12. Cyclization reaction of anti-meso-13.
The main step of our strategy consists of a dithiocarbonyl group
transfer cyclization, based on the degenerative radical exchange of
O
S
O
S
O
( )-13
a
xanthate group, extensively developed by Zard and co-
workers.27,28 We intend to examine the applicability of this meth-
odology on xanthate anti-meso-13 featuring its desymmetrization
through a selectively functionalization of one vinyl group. The
suitable acetyl xanthate derivative anti-meso-13 can be obtained
by either nucleophilic substitution of the bromine atom of the
+
+
H
H
H
S
S
EtO
EtO
EtO
S
S
17, 31% yield
18, 16% yield
19, 4% yield
Scheme 13. Cyclization reaction of (ꢀ)-13.
a
-bromoketone anti-meso-15 with the commercially available po-
tassium O-ethyl xanthogenic salt or directly by reaction of diethyl
bisdithiocarbonate (SC(S)OEt)2 with lithium ketone enolate of anti-
meso-13. As the separation of anti-meso-13 and (ꢀ)-3 by flash col-
umn chromatography or by distillation is difficult on multigram
scale,29 experiments have been led from the mixture with then
separation of products or on small quantities of pure acetylcyclo-
pentane anti-meso-3. Treatment of a mixture of anti-meso-3 and
(ꢀ)-3 or the sole anti-meso-3 with TMSOTf/Hu¨nig’s base/CH2Cl2
followed by reaction with NBS/NaHCO3/THF at ꢂ78 ꢁC gave the
bromides 15 (68–76%) which were placed in the presence of an
excess of KSC(S)OEt in acetone affording the xanthates 13 (68–
82%).28a However, the latter can be readily prepared in 75% yield by
quenching the lithium enolate of 3 with (SC(S)OEt)2 (Scheme 11).30
The formation of trans-hydrindanone 16 can be explained by the
following mechanism outlined in Scheme 14 where the -carbonyl
a
radical A, obtained from anti-meso-13 during the initiation step by
action of a lauroyl radical, undergoes a selective 6-endo-trig cycli-
zation with one of both vinyl groups. Usually, 5-hexenyl radicals
cyclize with high regioselectivity to give five-membered ring rather
than six-membered ring.31 However, acyclic 2-oxo-5-hexenyl rad-
icals have been shown to evolve through a preferential 6-endo-trig
cyclization pathway via a chair-like transition state leading to the
corresponding cyclohexanones.32,33 Indeed, as reported in the lit-
erature, MM2 Calculations investigated by Houk match the exper-
imental results and confirm this unexpected regioselectivity of the

R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
7005
Table 1
O
O
Reactions enthalpies for the cyclizations computed at the UB3LYP/6-311G level
6-endo
anti-
16
Radical Total energy
(hartree)
Zero-point ZPE corr.
Total energy
with ZPE corr. difference
Energy
meso-13
trans ring
junction
energya
(hartree)
B
H
A
(hartree)
(hartree)
(kcal/mol)
B
A
B
C
D
E
F
ꢂ542.785301 0.257681
ꢂ542.800363 0.259685
ꢂ542.783651 0.257542
ꢂ542.802081 0.258340
ꢂ542.799215 0.259714
ꢂ542.807466 0.260512
0.254846 ꢂ542.530454
0.256828 ꢂ542.543535
0.254709 ꢂ542.528943
0.255500 ꢂ542.546583
0.256857 ꢂ542.542358
0.257646 ꢂ542.549820
A/B¼ꢂ8.21
O
5-exo
17
C/D¼ꢂ11.07
C/E¼ꢂ8.42
C/F¼ꢂ13.10
cis ring
junction
H
D
a
(ZPEs) are scaled by a factor of 0.989, as recommended for calculation at the
E
O
Becke3LYP/6.311G(3df,2p) level.40
6-endo
H
O
18
trans ring
junction
( )-13
After successful formation of the trans-hydrindane ring skeleton
16, we explored its various functionalization. First, preparation of
the advanced intermediate 23, as a potent precursor for the Julia–
Kocienski coupling reaction, was accomplished through de-
rivatization of the xanthate moiety in a benzothiazole sulfonyl
group (Scheme 15). The ketone was first protected as its ethylene
ketal and subjected to ethylene diamine in ethanol to liberate 21 as
a free thiol.41 Deprotonation of the thiol with sodium hydride in
THF and subsequent reaction with 2-chlorobenzothiazone gener-
ated the corresponding 2-thiobenzothiazole adduct 22.42 This latter
was oxidized24c with (NH4)6Mo7O24 (cat.)/H2O2/EtOH to give the
sulfonyl derivative 23 (80%) of which the structure has been se-
cured by X-ray crystallographic analysis (Fig. 3).
D
E
F
C
O
6-endo
19
cis ring
junction
F
H
Scheme 14. Radical intermediates involved in cyclizations of anti-meso-13 and (ꢀ)-13.
radical cyclization.34 Thus, the transient secondary radical B can
propagate the radical chain by xanthate group transfer. The stereo-
selectivity of the xanthate moiety at the C-4 position, confirmed by
1H NMR and NOESY experiments, is modulated by the 1,3-diaxial
interaction with the angular methyl at C-8 favoring an equatorial
attack of the radical B onto the xanthate group of another molecule
of 13 during the chain process.
O
O
HO
OH
H2N
NH2
16
- H(+) / PhMe
/ EtOH
H
EtO
S
Contrary to anti-meso-13, the
a-carbonyl radical C, generated
20, 85% yield
S
from (ꢀ)-13, evolved through three different cyclization pathways
depending on the cyclization mode and the vinyl implicated. A
significant quantity of cis-fused bicyclic cyclization product 17,
resulting from a 5-exo-trig cyclisation process, and the 6-endo-trig
compound 19 were formed in an 8:1 ratio. The diquinane 17 was
obtained as a unique diastereomer whose relative stereochemistry
was corroborated by NOESY experiments. Presence of the adduct
18, resulting from a 6-endo-trig closure with the other vinyl sub-
stituent in a trans relationship with the acetyl group and leading to
a trans-fused compound, was also detected without any trace of the
corresponding 5-exo-trig cyclization product. This inversion of se-
lectivity giving a 5-exo/6-endo ratio of 8:5 in favour of the five-
membered ring formation was rationalized by calculations as
follows.
We have determined the relative enthalpies of reactant radicals
A (from anti-meso-13) and C (from (ꢀ)-13) and radicals resulting
from the cyclization using DFT calculations at the UB3LYP/6-
311Gþþ(d,p) level of theory.35 Density functional theory calcula-
tions have been performed using Gaussian 03, revision D.02.36
From calculations, we note that the radical A is weakly more stable
O
O
O
O
H
NaH / THF
S
H
S
S
Cl
HS
N
N
21, 90% yield
22, 63% yield
O
O
(NH4)6Mo7O24
H2O2 / EtOH
H
O
S
O
S
N
23, 80% yield
Scheme 15. Preparation of an advanced intermediate for the Julia–Kocienski coupling.
that its isomer C (DE w1 kcal/mol). All the cycloadditions are
weakly exothermic. Curiously, the diquinane derivative primary
radical D is particularly stable. In fact, radical C mainly reacted with
the cis-vinyl group and the more proximal carbon atom (D/
F¼7.75:1) (near-attack conformation37 or ‘propinquity’ effect38).
The topochemically controlled structure of C is in accordance with
the Bu¨rgi–Dunitz trajector39 and in this way minimizes both the
entropic and enthapic contributions of the free energy of the
transition state leading to D. At the UB3LYP/6-311g(d,p) level, for
the more stable conformation of the radical C, the distance between
the acyl radical carbon atom and the methine carbon atom of the
cis-vinyl group (attack D) is equal to 3.52 Å, and the value of the
corresponding Bu¨rgi–Dunitz angle is 112.2ꢁ (with trans-vinyl group,
4.40 Å and 102.7ꢁ, respectively) (Table 1).
C18
C14
C5
C11
C10
C9
C8
C17
C19
C20
O3
C16
C7
C4
C13
N1
C6
C1
C21
C15
O4
S1
S2
O1
Figure 3. ORTEP drawing of X-ray structure of 23 with labeled heteroatoms.
C12
C3
C2
O2

7006
R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
Then, we used the 17-vinyl group of 24 or 28 for the side chain
O
attachment according two different strategies. First, the thiol
function of 21 or 27 was protected as thiobenzoyl esters 24 or 28.43
Ozonolysis44 of these latter gave aldehydes 25 or 29 which were
suitable substrate for a selective Wittig–Horner–Emmons re-
action.45 Only one diastereomer 26 or 30 was formed, confirming
that no epimerisation occurred at the 17-position (Scheme 16).
LDA / THF
O
S
meso-3 +( )-3
74:26
S
O
S
S
meso-33 + ( )-33
2
74:26
R
O
O
R
O3
PhCOCl
CH2Cl2
- MeOH
- pyridine
H
+
Ph
S
H
H
H
S
S
S
S
HS
O
O
O
O
21, R = O-CH2CH2O
27, R = O
24, R = O-CH2CH2O, 66% yield
28, R = O, 74% yield
( )10
O
2
(cat.)
/ ClCH2-CH2Cl
CO2Et
H
34, 40% yield, 1:1
O
R
O
P
R
EtO
EtO
CO2Et
O
O
NaH / THF
H
H
Ph
S
Ph
S
H
S
O
S
H
S
+
O
O
25, R = O-CH2CH2O, 58% yield
29, R = O, 63% yield
26, R = O-CH2CH2O, 39% yield
30, R = O, 48% yield
O
S
Scheme 16. Functionnalization of the vinyl group by a ozonolysis/Wittig–Horner–
35, 8% yield, 1:1
Emmons olefination sequence.
Scheme 18. Preparation of dithioxanthates 33 and their radical cyclizations.
The second strategy involved cross metathesis reaction of the
vinyl group of 16 or 28 and the allyltrimethylsilane.46 Reaction with
2 mol % of Grubbs second generation catalyst gave the cross-me-
tathesis products 31 or 32 with a trans C–C double bond in mod-
erate yields (Scheme 17).
performed by eluting with a mixture solvent hexane/CH2Cl2/AcOEt
(60:37:3) (Scheme 19). Adducts 36 (23%) and 37 (28%) were isolated
in excellent yield with traces (<5%) of another stereoisomer. The
absolute configuration of the diastereomer 36 has been determined
by crystallographic X-ray analysis which shown that the ‘natural’
configuration fitted to 37 (Fig. 4). Thermolysis of the separated
adducts 36 and 37 by heating in xylene led to optically pure
hydrindanones (ꢂ)-16 or (þ)-16. The enantiomeric excesses were
determined by HPLC (Chiralcel OD-H), and found equal to 99.6% for
(ꢂ)-16 and 98.3% for (þ)-16.
SiMe3
O
H
O
SiMe3
N
H
N
Cl
Cl
H
Mes
Mes
RS
H
RS
Ru
16 or 28
Ph
PCy3
31, R = EtO-C(=S)-, 24% yield
32, R = Ph-C(=O)-, 30% yield
Ph
S
Ph
S
Scheme 17. Functionnalization of the vinyl group by cross-metathesis.
O
NMe
OH
O
NMe
OH
MeN
n-BuLi
Me
/ THF
Access to the key building block 16 in an enantiomerically pure
form was also studied. First, bis[(ꢂ)-menthyl(thiocarbonyl)]-
disulfide was used instead of diethyl bis-xanthate to quench the
lithium enolate mixture of anti-meso-3 and (ꢀ)-3 (74:26) (Scheme
18).47 Unfortunately, the diastereomeric mixture of hydrindanes 34,
resulting from the group transfer radical cyclisation process and
isolated as the major product, proved to be inseparable by flash
column chromatography on silica gel. An attempt with the bis[(S)-
2-(N-tosylpyrrolidinemethyl)(thiocarbonyl)] disulfide, prepared
from (S)-(þ)-prolinol,48 led to the corresponding diastereomeric
mixture of hydrindanes in poor yield and which showed the same
problem of separation.
S
+
then 16
O
H
H
EtO
S
EtO
S
(S)-(+)
S
S
36, 23% yield
37, 28% yield
xylene
120 °C
xylene
120 °C
O
O
As enantioselective cyclizations of chiral substrates did not look
optimistic, we used the sulfoximine ketone resolution methodology
developed by Johnson and co-workers49,50 that should allow us to
access to both enantiomers of 16. Addition of the lithio derivative of
(S)-(þ)-N,S-dimethyl-S-phenylsulfoximine51 to rac-16 in THF at
ꢂ78 ꢁC gave rise to the two diastereoisomers 36 and 37, of which
the separation by flash column chromatography has been
H
H
EtO
S
EtO
S
S
S
( )-16, 72% yield
(+)-16, 71% yield
Scheme 19. Resolution of the hydrindanone 16.

R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
7007
for 13C (
d¼77.16 ppm). Carbon–proton couplings were determined
by DEPT sequence experiments. Mp: not corrected. Bu¨chi capillary
apparatus. Low resolution mass spectra were recorded on a Sciex
API III Plus triple quadrupole spectrometer equipped with an
electrospray interface, on a Jeol SX 102 spectrometer equipped with
a FAB ionisation source (Nitro-Benzyl-Alcohol matrix) and on
a Varian Saturn 2100T GC/MS equipped with a WCOT fused silica
CP-Sil 8 CB, m/z (%). High resolution mass spectrometry were
measured on a Jeol SX 102 spectrometer equipped with a FAB
ionisation source (NBA matrix) to provide accurate mass. Dia-
stereomeric ratios were determined on a Varian 3900 GC equipped
with a WCOT fused silica CP Sil 5CB. Enantiomeric ratios were de-
termined on a Shimadzu GC-14A equipped with WCOT fused silica
Lipodex-E and Cyclosilb. Optical rotations were measured on
a Perkin–Elmer 341 polarimeter.
C21
S3
C22
C20
C19
C23
C18
C11
C10
C7
C12
C1
O1
O3
C16
N1
C8
C17
C2
C9
C5
C4
C3
5.2. 1-Acetyl-1-methyl-2,5-divinylcyclopentane meso-
3 and ( )-3
S1
S2
Synthesized from 2,2,3,3-tetramethoxybutane and 1,8-bis-
(trimethylsilyl)-2,6-octadiene (Bistro) according to the published
procedure13 on 0.8 mol scale, after purification by flash chroma-
tography (hexane/Et2O, 100:0 to 98:2) the product was obtained as
a 74:26 mixture of diastereoisomers meso-3 and (ꢀ)-3 with 47%
C13
O2
C14
yield as a yellow oil. 1H NMR meso-3 (300 MHz, CDCl3)
d 0.96 (s,
3H), 1.58–1.71 (m, 2H), 1.88–1.99 (m, 2H), 2.12 (s, 3H), 2.92 (br q,
J¼7.2 Hz, 2H), 5.00 (br d, J¼17.0 Hz, 2H), 5.01 (br d, J¼10.7 Hz, 2H),
5.68 (ddd, J¼16.9, 10.7, 7.8 Hz, 2H); TLC Rf¼0.47 (hexane/Et2O
85:15) (CAS Number: 172337-30-3); 1H NMR (ꢀ)-3 (300 MHz,
C15
Figure 4. ORTEP diagram of compound 36.
CDCl3)
d 1.14 (s, 3H), 1.50–1.69 (m, 2H), 1.85–2.04 (m, 2H), 2.06 (s,
4. Conclusion
3H), 2.45 (br q, J¼7.4 Hz, 1H), 3.20 (br q, J¼8.3 Hz, 1H), 4.90–5.08
(m, 4H), 5.65 (ddd, J¼17.0, 10.0, 9.4 Hz, 1H), 5.72 (ddd, J¼17.3, 10.4,
7.0 Hz, 1H); TLC Rf¼0.62 (hexane/Et2O, 85:15) (CAS Number:
172217-30-0).
From the easy preparation of epoxyketone 5 and anti meso
xanthate 13 obtained by desymmetrization of anti-meso-acetyl-
methyldivinylcyclopentane 3, we have described two expeditious
and efficient approaches of versatile trans-hydrindanones 7 and 16
respectively, considered as valuable intermediates in the vitamin D
derivatives synthesis. A formal enantioselective approach of 7 has
also been proposed with the preparation of the enantiomerically
enriched compound (þ)-5 involving enantioselective CBS-re-
duction and diastereoselective bishomoallylic epoxidation as key
steps. The Johnson sulfoximine ketone resolution of 16 allowed
access to both enantiomers in moderate yield. Functionalizations of
the vinyl group revealed as particularly difficult but could be re-
alized by ozonolysis or metathesis favoring the construction of new
side chains. Convertion of the xanthate moiety to a benzothiazole-
2-sulfonyl (Bts) group allowed the elaboration of an advanced in-
termediate for Julia–Kociensky coupling. Formation of the trienic
part via coupling with elaborated A rings is still underway in our
laboratory.
5.3. (1S
*
,2R
*
,5S
*
)-1-[(1S )-Hydroxyethyl]-1-methyl-2,5-
*
divinylcyclopentane 4
Procedure A. To a stirred solution of meso-3 (1 g, 5.6 mmol) in
MeOH (30 mL) was added portionwise NaBH4 (424 mg, 11.2 mmol)
at 0 ꢁC. After 4 h stirring at rt, the mixture was hydrolysed with
brine (30 mL) and stirred 30 min at rt. The solution was diluted
with brine (30 mL) and then extracted with CH2Cl2 (4ꢃ100 mL).
The combined organic layers were washed with brine (50 mL),
dried over MgSO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by flash silica gel chroma-
tography (95:5 30–40 P.E./EtOAc) to provide the racemic compound
(ꢀ)-4 (920 mg, 91%) as a colourless oil.
Procedure B. To a stirred molar solution of (R)-2-methyl-CBS-
oxazaborolidin (0.62 mL, 0.62 mmol) in toluene was slowly added
a 1 M solution of BH3/THF complex (0.56 mL, 0.56 mmol) under
argon at rt. A solution of meso-3 (100 mg, 0.56 mmol) in dry toluene
(0.5 mL) was added dropwise over 1 min, stirred 10 min and then
treated with brine (2 mL) during 30 min. The mixture was diluted
with brine (10 mL) and extracted with Et2O (3ꢃ10 mL). The com-
bined organic layers were dried over MgSO4, filtered and concen-
trated under reduced pressure. The crude mixture was purified by
flash silica gel chromatography (98:2 30–40 P.E./EtOAc) to provide
(þ)-(1S,2R,5S)-1-[(1S)-hydroxyethyl]-1-methyl-2,5-divinylcyclo-
pentane (þ)-4 (71 mg, 70%; er >99:1 to 97:3; from chiral GC
analysis (Lipodex-E column), 100 ꢁC, retention times: 22.72 min for
5. Experimental section
5.1. General remarks
THF was freshly distilled from sodium/benzophenone; CH2Cl2,
triethylamine and pyridine from CaH2 under N2. Other reagents and
solvents were obtained from commercial sources and used as re-
ceived. Flash column chromatography: Merck 230–400 mesh silica
gel; EtOAc, Et2O and hexane as eluents. Thin-layer chromatography
(TLC): Macherey-Nagel silica gel UV254 analytical plates; detection
either with UV, or by dipping in a solution of KMnO4 (3 g), K2CO3
(20 g), KOH (0.3 g) in H2O (300 mL) and subsequent heating. IR
spectroscopy: Perkin–Elmer Paragon 1600 Fourier Transform. NMR
spectroscopy: Bruker AC 300 (1H¼300 MHz, 13C¼75 MHz); chem-
the (1S) enantiomer and 24.20 min for the (1R) enantiomer) as
25
a colourless oil. [
a]
þ0.1 (c 1, CHCl3 for er¼97:3); Rf¼0.3 (90:10
D
30–40 P.E./EtOAc); IR 3418, 3075, 2975, 2951, 2873, 1636, 1378,
1000, 911 cmꢂ1 1H NMR (300 MHz, CDCl3)
0.80 (s, 3H), 1.16 (d,
J¼6.5 Hz, 3H), 1.47–1.62 (m, 2H), 1.70–1.82 (m, 2H), 1.86 (br s, 1H),
;
d
ical shift
d
in ppm relative to CHCl3 for 1H (
d¼7.26 ppm) and CDCl3

7008
R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
2.48–2.58 (m, 2H), 3.60–3.68 (m, 1H), 4.95–5.07 (m, 4H), 5.73–5.90
leading to the chiral mixture of epoxyalcohols 8a/8b with a 82:18
dr, which was oxidized immediately. All attemps made to separate
both enantiomers of the resulting epoxyketones on chiral GC so as
to measure the enantiomeric ratio (er) were unfruitful. The enan-
tiomeric ratio (er) can be calculated from the er values of (þ)-8 and
the dr values obtained for 8a/8b, er¼((0.97ꢃ82)þ(0.03ꢃ18)):
((0.97ꢃ18)þ(0.03ꢃ82))¼80:20.
(m, 2H); 13C NMR (75 MHz, CDCl3)
d 11.5, 18.5, 28.9, 29.1, 49.7, 51.2,
51.9, 74.5, 115.3, 115.4, 140.4, 140.9; MS (FABꢂ) m/z 179 ([MꢂH]ꢂ).
5.4. (1R
*
,2R
*
,5R
*
)-1-[(1S
*
)-Hydroxyethyl]-1-methyl-2-[(1R
,2S ,5S )-1-[(1S )-
)-oxiranyl]-5-
*
)-
oxiranyl]-5-vinylcyclopentane 8a and (1S
hydroxyethyl]-1-methyl-2-[(1S
*
*
*
*
*
vinylcyclopentane 8b
5.6. (1R
*
,2R
*
,5R
*
*
)-1-[(1S )-(3,5-Dinitrobenzoyloxyethyl)]-1-
*
To a stirred solution of VO(acac)2 (95 mg, 0.36 mmol) in dry
CH2Cl2 (15 mL) was added dropwise a solution of 4 (640 mg,
3.56 mmol) in dry CH2Cl2 (15 mL) under argon at rt. After 15 min
stirring was slowly added a 5 M tert-butylhydroperoxide/nonane
solution (1.06 mL, 5.32 mmol) and the resulting solution was stir-
red 16 h at 15 ꢁC. The yellow mixture was quenched with a satu-
rated Na2S2O3 solution (30 mL) and was stirred 30 min at rt. The
aqueous layer was extracted with CH2Cl2 (3ꢃ30 mL). The combined
organic layers were washed with brine (50 mL), dried over MgSO4,
filtered and concentrated under vacuum. The yellow oil obtained
was purified by flash silica gel chromatography (90:10 30–40 P.E./
EtOAc) to provide a mixture [dr¼88:12 at 15 ꢁC from GC analysis,
80 ꢁC/1 min to 260 ꢁC (5 ꢁC/1 min), retention times: 15.62 min for
the minor isomer 8b and 15.82 min for the major isomer 8a, and
82:18 at T¼25 ꢁC from chiral GC analysis (Cyclosilb column), 150 ꢁC,
retention times: 21.42 min for 8b (both enantiomers) and 22.82 min
for the (1S) enantiomer of 8a and 23.41 for the (1R) enantiomer of
8a] of two diastereoisomers 8a and 8b as a colourless oil (301 mg,
43%, corrected yield 63%) with a recovered amount of starting
material (204 mg, 32%). Rf¼0.3 (80:20 30–40 P.E./EtOAc); IR (mix-
ture of isomers) 3459, 3074, 3048, 2973, 2873, 1735, 1637, 1473,
1449, 1415, 1402, 1379, 1259, 1063, 1001, 919, 872 cmꢂ1; for the
methyl-2-[(1R
vinylcyclopentane 9
)-(3,5-dinitrobenzoyloxy)-2-iodoethyl]-5-
To a stirred solution of 8a and 8b (50 mg, 0.25 mmol) in wet
MeCN (2.5 mL) was first added NaI (39 mg, 0.26 mmol) followed by
CeCl3$7H2O (95 mg, 0.25 mmol) at rt. The solution was stirred 16 h
in the dark and quenched with a saturated Na2S2O3 solution (5 mL).
The mixture was extracted with CH2Cl2 (4ꢃ10 mL). The combined
organic layers were washed with brine (2ꢃ10 mL), dried over
MgSO4, filtered and concentrated under reduced pressure to pro-
vide a colourless oil (84 mg, >99%). The residue obtained (60 mg)
was diluted with dry CH2Cl2 (1 mL) and then added to a stirred
solution of dry pyridine (1 mL, 12.3 mmol) containing 3,5-dini-
trobenzoyl chloride (215 mg, 0.94 mmol). The solution was stirred 3
days under argon at rt and diluted with EtOAc (10 mL). The organic
layer was successively washed with a saturated CuSO4 solution
(4ꢃ5 mL) and brine (10 mL). The organic layer was dried over
MgSO4, filtered and concentrated under reduced pressure. The
crude solid obtained was purified by flash silica gel chromatogra-
phy (95:5 30–40 P.E./EtOAc) to provide the white crystalline com-
pound as an inseparable mixture (in the same relative ratio of the
starting material) of two diastereoisomers (130 mg, 99% over two
steps). The mixture was crystallised from Et2O to afford the major
product (ꢀ)-13 as a single product. Mp¼99–100 ꢁC; Rf¼0.6 (95:5
30–40 P.E./EtOAc); IR 3100, 2980, 1733, 1652, 1547, 1345, 1265, 1169,
major isomer 8a: 1H NMR (300 MHz, CDCl3)
d 0.92 (s, 3H), 1.15 (d,
J¼6.5 Hz, 3H), 1.51–1.63 (m, 2H), 1.71–1.81 (m, 2H), 2.34–2.43 (m,
1H), 2.56 (dd, J¼4.5, 3.0 Hz, 1H), 2.84–2.90 (m, 2H), 2.94 (br s, 1H),
3.54 (q, J¼6.5 Hz, 1H), 4.95–5.01 (m, 2H), 5.77 (dt, J¼18.0, 9.0 Hz,
737 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 0.93 (s, 3H), 1.38–1.48 (m,
1H); 13C NMR (75 MHz, CDCl3)
d 10.4, 18.4, 25.8, 29.8, 48.7, 51.5,
1H), 1.62–1.75 (m, 1H), 1.65 (d, J¼6.5 Hz, 3H), 1.98 (m, 2H), 2.67 (dd,
J¼19.0, 10.0 Hz, 1H), 3.02 (dd, J¼19.0, 8.5 Hz, 1H), 3.40 (dd, J¼11.5,
2.5 Hz, 1H), 3.76 (dd, J¼11.5, 3.0 Hz, 1H), 4.68 (dt, J¼10.5, 2.5 Hz,
1H), 5.24 (br d, J¼17.0 Hz, 1H), 5.36 (br d, J¼10.0 Hz, 1H), 5.49 (q,
J¼6.5 Hz, 1H), 5.96 (dt, J¼17.0, 10.0 Hz, 1H), 9.03 (d, J¼2.0 Hz, 2H),
9.16 (t, J¼2.0 Hz, 1H), 9.24 (d, J¼2.0 Hz, 2H), 9.34 (t, J¼2.0 Hz, 1H);
51.9, 52.2, 52.7, 75.1, 115.5, 139.7; MS (FABþ) m/z 197 ([MþH]þ).
Representative signals for the minor isomer 8b: 1H NMR (300 MHz,
CDCl3)
CDCl3)
139.0.
d
0.99 (s, 3H), 1.14 (d, J¼6.5 Hz, 3H); 13C NMR (75 MHz,
d
13.1, 17.9, 24.7, 28.3, 46.5, 48.8, 50.7, 51.8, 52.6, 72.6, 115.8,
13C NMR (75 MHz, CDCl3)
d 10.0, 14.0, 14.1, 24.8, 27.9, 48.5, 48.6,
5.5. (1R
*
,2R
*
,5R
*
)-1-Acetyl-1-methyl-2-[(1R )-oxiranyl]-5-
*
50.1, 74.7, 78.4, 116.0, 122.4, 123.2, 129.7 (2C), 129.8 (2C), 132.9,
134.0, 138.9, 148.7 (2C), 148.9 (2C), 161.5, 162.2; MS (ESIþ) m/z 730.2
([MþNH4]þ).
vinylcyclopentane 5
To stirred solution of racemic isomers 8a and 8b (120 mg,
0.61 mmol) in CH2Cl2 (6 mL) was added Dess–Martin periodinane
(312 mg, 0.73 mmol) in one portion at rt. The reaction was moni-
tored by TLC analysis. After completion (1 h), the solution was
quenched with a saturated Na2S2O3 solution (6 mL) and a saturated
NaHCO3 solution (6 mL). The mixture was extracted with CH2Cl2
(3ꢃ15 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
product was purified by flash silica gel chromatography (90:10 30–
40 P.E./EtOAc) to provide the single product 5 as a colourless oil
(118 mg, >99%). Rf¼0.5 (80:20 30–40 P.E./EtOAc); IR 3077, 3050,
5.7. (1R
*
,2R
*
,5R
*
)-1-Acetyl-1-methyl-2-[(1R )-hydroxy-2-
*
iodoethyl]-5-vinylcyclopentane 10
To a stirred solution of 5 (300 mg, 1.54 mmol) in wet MeCN
(15 mL) was first added NaI (464 mg, 3.08 mmol) and then
CeCl3.7H2O (575 mg, 1.54 mmol) at rt. The solution was stirred 16 h
in the dark at RT and then quenched with a saturated Na2S2O3
solution (15 mL). The mixture was extracted with CH2Cl2
(4ꢃ20 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated under vacuum. The crude product was
purified by flash silica gel chromatography (90:10 30–40 P.E./
EtOAc) to provide the white crystalline compound 10 (453 mg,
91%). 10 could be used in the next step without purification.
Mp¼113–115 ꢁC; Rf¼0.4 (80:20 30–40 P.E./EtOAc); IR 3447, 3369,
2980, 2956, 2876, 1698, 1639, 1421, 1355, 1239, 917, 874 cmꢂ1
;
1H
NMR (300 MHz, CDCl3)
d 1.16 (s, 3H), 1.51–1.73 (m, 2H), 1.82–1.97
(m, 2H), 2.06–2.15 (m, 1H), 2.17 (s, 3H), 2.46 (dd, J¼5.0, 2.5 Hz, 1H),
2.73 (dd, J¼5.0, 4.0 Hz, 1H), 2.80 (ddd, J¼8.0, 4.0, 2.5 Hz, 1H), 2.84–
2.93 (m, 1H), 4.96–5.01 (m, 2H), 5.65 (ddd, J¼17.0, 10.5, 7.5 Hz, 1H);
13C NMR (75 MHz, CDCl3)
d
11.6, 24.9, 26.9, 27.9, 47.2, 51.2, 52.1,
2953, 2873, 1685, 1360, 1224, 1023, 924 cmꢂ1
;
1H NMR (300 MHz,
52.4, 60.6, 116.6, 137.1, 212.8; HRMS (FABþ) calculated for C12H19O2
CDCl3) d 1.10 (s, 3H), 1.58–1.71 (m, 1H), 1.77–1.99 (m, 3H), 2.16 (s,
([MþH]þ): 195.1385, found: 195.1397.
3H), 2.18–2.21 (m, 1H), 2.64 (dd, J¼19.0, 9.5 Hz, 1H), 2.75 (dd,
J¼19.0, 8.0 Hz, 1H), 3.15–3.26 (m, 2H), 3.44 (dd, J¼9.5, 8.0 Hz, 1H),
4.94–5.05 (m, 2H), 5.67 (ddd, J¼17.0, 10.5, 8.0 Hz, 1H); 13C NMR
25
For compound (þ)-5: [
a
]
þ14.5 (c 0.6, CHCl3). (þ)-5 was
D
obtained from the epoxidation of (þ)-4 (synthesized with a 97:3 er)

R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
7009
(75 MHz, CDCl3)
d
11.1, 17.1, 25.1, 27.3, 28.0, 53.4, 53.6, 60.1, 71.8,
5.10. (1R
*
,5S
*
,6R
*
,9R )-1-Methyl-5-hydroxy-9-
*
116.8, 136.9, 214.5; MS (FABþ) m/z 323 ([MþH]þ).
vinylbicyclo[4.3.0]nonan-2-one 7
To a stirred solution of 12 (91 mg, 0.33 mmol) in MeOH/H2O
(2 mL, 2:1) was added p-TSA (70 mg, 0.36 mmol) at rt and the so-
lution was stirred for 18 h. The solution was then diluted with EtOAc
(50 mL), washed with a saturated NaHCO3 solution (2ꢃ20 mL), dried
over MgSO4, filtered and concentrated under vacuum. The crude
product was purified by flash silica gel chromatography (80:20 30–
40 P.E./EtOAc) to afford the single product 7 as a white solid (63 mg,
>99%) which was crystallised from hexane. Mp¼67–68 ꢁC; Rf¼0.3
(70:30 30–40 P.E./EtOAc); IR 3447, 3055, 2961, 2879,1703,1265, 738,
5.8. (1R
*
,2R
*
,5R
*
)-1-Acetyl-1-methyl-2-[(1R )-tetrahydro-
*
pyranyloxy-2-iodoethyl]-5-vinylcyclopentane 11
To a stirred solution of 10 (500 mg, 1.55 mmol) in CH2Cl2
(15 mL) was added a catalytic amount of p-TSA (15 mg, 0.08 mmol)
and 3,4-dihydro-2H-pyran (0.70 mL, 7.75 mmol). After 30 min
stirring at rt, the solution was treated with a saturated NaHCO3
solution (15 mL) and extracted with CH2Cl2 (2ꢃ30 mL). The com-
bined organic layers were washed with brine (30 mL), dried over
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash silica gel chromatography (98:2
30–40 P.E./EtOAc) to provide an inseparable mixture [dr¼50:50
from 1H NMR determination] of two diastereoisomers 11 (631 mg,
>99%) as a white waxy solid. Rf¼0.7 (80:20 30–40 P.E./EtOAc); IR
704 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 1.17 (s, 3H),1.57–1.97 (m, 6H),
2.03 (br s, 1H), 2.09 (ddd, J¼14.0, 5.5, 2.5 Hz, 1H), 2.16 (ddt, J¼14.5,
6.5, 2.5 Hz, 1H), 2.67 (ddd, J¼14.5, 8.5, 6.0 Hz, 1H), 2.94 (td, J¼14.5,
6.5 Hz, 1H), 4.17 (br s, 1H), 5.04 (dt, J¼11.0, 2.0 Hz, 1H), 5.05 (dt,
J¼16.5, 2.0 Hz, 1H), 5.93 (ddd, J¼16.5, 11.0, 6.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3)
d 14.8, 21.9, 24.1, 34.4, 35.7, 46.6, 53.7, 56.0, 67.2,
2943, 2869, 1697, 1651, 1455, 1436, 1370, 1123, 1022, 967 cmꢂ1
;
1H
115.3, 138.8, 215.5; MS (FABþ) m/z 195 ([MþH]þ).
NMR (300 MHz, CDCl3) of the mixture
d: 0.87 (s, 3H, one ds), 1.02 (s,
3H, one ds), 1.15–1.32 (m, 2H, two ds), 1.48–1.57 (m, 8H, two ds),
1.60–1.70 (m, 5H, two ds), 1.80–2.07 (m, 5H, two ds), 2.20 (s, 3H,
one ds), 2.21 (s, 3H, one ds), 2.70–2.91 (m, 5H, two ds), 3.01 (ddd,
J¼10.0, 3.0, 1.5 Hz, 1H, one ds), 3.16 (dd, J¼11.5, 1.5 Hz, 1H, one ds),
3.25 (dd, J¼10.5, 1.5 Hz, 1H, one ds), 3.40–3.56 (m, 2H, two ds), 3.57
(dd, J¼11.5, 3.0 Hz, 1H, one ds), 3.73–3.81 (m, 1H, one ds), 3.78 (dd,
J¼10.5, 3.0 Hz, 1H, one ds), 3.99–4.06 (m, 1H, one ds), 4.60 (br s, 2H,
two ds), 4.92 (br d, J¼17.0 Hz, 2H, two ds), 4.99 (br d, J¼10.5 Hz, 2H,
two ds), 5.56 (ddd, J¼17.0, 10.5, 7.5 Hz, 1H, one ds), 5.58 (ddd,
J¼17.0, 10.0, 7.0 Hz, 1H, one ds); 13C NMR (75 MHz, CDCl3) of the
5.11. 1-Trimethylsilyloxyvinyl-1-methyl-2,5-
divinylcyclopentane meso-14 and/or ( )-14
General procedure 1. To a solution of divinylcyclopentane meso-3
(500 mg, 2.8 mmol) in anhydrous CH2Cl2 (51 mL) at 0 ꢁC under
argon was added diisopropylethylamine (2.94 mL, 16.9 mmol),
followed by TMSOTf (2.03 mL, 11.2 mmol). The resulting yellow
mixture was stirred at 0 ꢁC under argon for 2 h before it was
quenched with satd NaHCO3 solution and diluted with hexane. The
organic layer was separated and the aqueous layer extracted with
hexane. The combined organic extracts were dried over K2CO3,
filtered, and concentrated in vacuo to afford the crude TMS/silyl
enol ether meso-14 (700 mg, 100% yield) as a yellow oil. The crude
product was not purified nor submitted to NMR analysis but di-
rectly used in the next reaction without further purification. (ꢀ)-14.
Prepared from the divinylcyclopentane (ꢀ)-3 (500 mg, 2.8 mmol)
according to the previous general procedure. The crude TMS/silyl
enol ether (ꢀ)-14 was obtained with quantitative yield as a yellow
oil. Mixture of meso-14 and (ꢀ)-14. Prepared from a 74:26 mixture
of divinylcyclopentanes meso-3 and (ꢀ)-3 (10 g, 56 mmol) follow-
ing the general procedure. The mixture of TMS-silyl enol ethers 14
was obtained with quantitative yield (14 g) as a yellow oil.
mixture d: 10.4, 10.9, 11.4, 16.4, 19.1, 19.4, 24.3, 24.4, 24.9, 25.3, 25.4,
25.5, 27.3, 27.4, 29.9, 30.6, 51.6, 52.2, 52.6, 53.8, 59.4, 59.8, 63.2,
63.5, 70.3, 78.4, 94.0, 101.4, 116.3, 116.5, 136.5, 136.8, 211.2, 211.5;
HRMS (FABþ) calculated for C17H28IO3 ([MþH]þ): 407.1083, found:
407.1089.
5.9. (1R
*
,5S
*
,6R
*
,9R )-1-Methyl-5-tetrahydropyranyloxy-9-
*
vinylbicyclo[4.3.0]nonan-2-one 12
To a stirred solution of 11 (631 mg, 1.55 mmol) in dry THF
(20 mL) was added dropwise a 20 wt % THF solution of potassium
tert-butoxide (1.25 mL, 2.01 mmol) at 50 ꢁC and then stirred
30 min. After completion, the mixture was cooled to rt and
quenched with a saturated Na2S2O3 solution (20 mL). The mixture
was then diluted with brine (20 mL) and extracted with CH2Cl2
(4ꢃ50 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure. The yellow
crude was purified by flash silica gel chromatography (95:5 30–40
P.E./EtOAc) to afford an inseparable mixture [dr¼50:50 from 1H
NMR determination] of two diastereoisomers 12 (432 mg, 89%) as
a yellow oil. Rf¼0.6 (80:20 30–40 P.E./EtOAc); IR 2940, 2873, 1710,
5.12. 1-Bromoacetyl-1-methyl-2,5-divinylcyclopentane 15.
meso-15
General procedure 2. To a stirred solution of TMS-enol ether
meso-14 (700 mg, 2.8 mmol) in 60 mL of anhydrous THF at ꢂ78 ꢁC
was added NaHCO3 powder (282 mg, 3.4 mmol), followed by the
addition of NBS (598 mg, 3.4 mmol) in one portion. The resulting
reaction was stirred at ꢂ78 ꢁC for 3 h and quenched with a satd
NaHCO3 solution. The organic phase was separated and the aque-
ous phase was extracted with ether. The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography eluting with
hexane/Et2O (95:5) to afford the desired product meso-15 (484 mg,
1456, 1351, 1199, 1126, 1022, 988, 908, 870 cmꢂ1
;
1H NMR
: 1.16 (s, 3H, one ds), 1.17 (s, 3H,
(300 MHz, CDCl3) of the mixture
d
one ds), 1.52–1.93 (m, 23H, two ds), 1.96–2.16 (m, 3H, two ds), 2.24
(ddt, J¼16.5, 8.5, 2.0 Hz, 1H, one ds), 2.37 (ddt, J¼16.5, 9.0, 2.5 Hz,
1H, one ds), 2.65–2.75 (m, 2H, two ds), 2.82 (td, J¼14.0, 6.5 Hz, 1H,
one ds), 2.94 (td, J¼14.0, 6.5 Hz, 1H, one ds), 3.49–3.58 (m, 2H, two
ds), 3.85–3.95 (m, 2H, two ds), 3.96 (br s, 1H, one ds), 4.12 (dd,
J¼5.5, 2.5 Hz, 1H, one ds), 4.63 (br t, J¼3.0 Hz, 1H, one ds), 4.78 (br
t, J¼2.5 Hz, 1H, one ds), 5.04–5.12 (m, 4H, two ds), 5.95 (ddd,
J¼16.5, 11.0, 2.5 Hz, 1H, one ds), 5.97 (ddd, J¼17.0, 11.0, 3.0 Hz, 1H,
1.9 mmol, 67%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
d 1.06 (s,
3H), 1.73–1.62 (m, 2H), 2.02–1.90 (m, 2H), 2.97 (br q, J¼6.8 Hz, 2H),
4.11 (s, 2H), 5.04 (br d, J¼16.8 Hz, 2H), 5.05 (br d, J¼10.6 Hz, 2H),
5.69 (ddd, J¼16.8, 10.6, 8.0 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 11.2,
27.8 (2C), 34.7, 52.3 (2C), 62.0, 117.1 (2C), 137.3 (2C), 204.3; IR 2952,
1718, 1637, 1386, 999, 919 cmꢂ1; TLC Rf¼0.52 (hexane/Et2O, 95:5)
(CAS Number: 886840-75-1). (ꢀ)-15 prepared from TMS/enol ether
(ꢀ)-14 (700 mg, 2.8 mmol) according to the general procedure 2.
After purification by flash chromatography, the desired product
(ꢀ)-3 was isolated as a yellow oil (491 mg, 1.9 mmol, 68%). 1H NMR
one ds); 13C NMR (75 MHz, CDCl3) of the mixture
d: 14.8, 14.9, 19.2,
19.8, 22.1, 22.3, 24.2, 24.3, 25.6, 25.7, 31.1, 31.3 (2C), 34.5, 34.7, 35.1,
46.7, 46.9, 53.6, 53.8, 56.2, 56.3, 61.8, 62.8, 69.4, 75.0, 94.9, 101.3,
115.2, 115.3, 139.1, 139.2, 215.3, 215.5; MS (FABþ) m/z 279
([MþH]þ).

7010
R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
(300 MHz, CDCl3)
d
1.21 (s, 3H), 1.70–1.54 (m, 2H), 2.06–1.89 (m,
layer extracted twice with ether. The organic layers were dried over
MgSO4, filtered and concentrated in vacuo. After purification by
flash chromatography (hexane/Et2O, 98:2 to 80:20), the desired
products meso-13 and (ꢀ)-13 were obtained as an inseparable
mixture in a 70:30 ratio (15.6 g, 52 mmol, 75%). Physical and
spectral data were in accordance with the data described
previously.
2H), 2.48 (br q, J¼7.6 Hz, 1H), 3.25 (br q, J¼8.3 Hz, 1H), 3.99 (1⁄2 AB,
J¼13.9 Hz, 1H), 4.10 (1⁄2 AB, J¼13.9 Hz, 1H), 4.97–5.11 (m, 4H), 5.60
(dt, J¼16.9, 9.8 Hz, 1H), 5.71 (ddd, J¼17.4, 10.3, 7.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3)
d 19.8, 28.5, 30.1, 35.1, 47.6, 56.1, 61.7, 116.0, 116.2,
138.0, 139.0, 203.4; IR 2954, 1716, 1637, 1381, 1002, 917 cmꢂ1; TLC
Rf¼0.52 (hexane/Et2O, 95:5) (CAS Number: 886732-18-9). Mixture
of meso-15 and (ꢀ)-15. Prepared from the mixture of TMS-enol
ether 14 (14 g, 56 mmol) according to the general procedure 2. After
purification by flash chromatography, the desired products were
obtained as an inseparable mixture of meso-15 and (ꢀ)-15 in
a 74:26 ratio (9.77 g, 38 mmol, 68%). Physical and spectral data
were in accordance with the data described below.
5.15. O-Ethyl S-[(1R
oxo-1-vinyl-1H-inden-4-yl] carbonodithioate 16, O-ethyl S-
[((3S ,3aR ,6R ,6aR )-octahydro-6a-methyl-1-oxo-6-
vinylpentalen-3-yl)methyl] carbonodithioate 17 and O-ethyl
S-[(1S ,3aR ,4R ,7aR )-octahydro-7a-methyl-7-oxo-1-vinyl-1H-
*
,3aR
*
,4R
*
,7aR
*
)-octahydro-7a-methyl-7-
*
*
*
*
*
*
*
*
inden-4-yl]carbonodithioate 18
5.13. O-Ethyl S-[2-(1-methyl-2,5-divinylcyclopentyl)-2-
oxoethyl] carbonodithioate 13. meso-13
General procedure 5. Under argon, 41 mg (0.1 mmol) of lauroyl
peroxide (DLP) was added to a refluxing solution containing
392 mg (1.3 mmol) of xanthate meso-13 in 48 mL of anhydrous 1,2-
dichloroethane. The reaction was refluxed for 1 h 30 min, and then
0.08 equiv of DLP was further added. After another 1 h 30 min
refluxing under argon, the solvent was removed in vacuo. The
residue was purified by flash chromatography (hexane/Et2O, 95:5
to 80:20) to give 271 mg (0.9 mmol, 70%) of 16 as a yellow oil. 1H
General procedure 3. To a stirred solution of
a-bromo ketone
meso-15 (484 mg, 1.9 mmol) in 73 mL of acetone at rt under argon
was added portionwise 2.33 g (14.6 mmol) of KSC(S)OEt. The
resulting reaction was stirred for 2 h at rt until it was diluted with
ether and washed with a satd solution of NaHCO3. The organic layer
was dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash chromatography (hexane/Et2O, 95:5)
to give 392 mg (1.3 mmol, 68%) of a yellow oil. meso-13. 1H NMR
NMR (300 MHz, CDCl3)
d
1.06 (s, 3H), 1.44 (t, J¼7.1 Hz, 3H), 1.60–
1.81 (m, 4H), 1.87–1.97 (m, 2H), 2.27 (ddd, J¼14.6, 5.8, 1.8 Hz, 1H),
2.56–2.66 (m, 1H), 2.70–2.85 (m, 2H), 4.12 (td, J¼11.9, 4.4 Hz, 1H),
4.67 (q, J¼7.1 Hz, 1H), 5.08 (dt, J¼10.8, 1.6 Hz, 1H), 5.10 (dt, J¼16.9,
1.6 Hz, 1H), 5.96 (ddd, J¼16.9, 10.8, 5.8 Hz, 1H); 13C NMR (75 MHz,
(300 MHz, CDCl3)
d
1.09 (s, 3H), 1.41 (t, J¼7.1 Hz, 3H), 1.65–1.75 (m,
2H), 1.91–2.03 (m, 2H), 3.02 (q, J¼7.1 Hz, 2H), 4.24 (s, 2H), 4.63 (q,
J¼7.1 Hz, 2H), 5.04 (br d, J¼16.6 Hz, 2H), 5.05 (br d, J¼10.7 Hz, 2H),
5.73 (ddd, J¼16.6, 10.7, 7.9 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d
11.4,
CDCl3) d 13.0, 13.9, 23.9, 24.8, 34.1, 38.0, 46.5, 47.8, 53.3, 57.0, 70.2,
13.8, 27.7 (2C), 45.0, 52.0 (2C), 61.7, 70.4, 116.8 (2C), 137.4 (2C),
205.8, 213.8; IR 2978, 1700, 1639, 1472, 1382, 1228, 1112, 1051,
918 cmꢂ1; TLC Rf¼0.52 (hexane/Et2O, 95:5) (CAS Number: 886732-
115.7, 138.3, 212.5, 214.0; IR 2954, 1698, 1639, 1454, 1379, 1225,
1047, 914, 810 cmꢂ1; TLC Rf¼0.40 (hexane/Et2O, 90:10). Besides,
COSY and NOESY experiments confirmed the stereochemistry.
NOESY CH3-9/H-10. Mixture of 17 and 18. Prepared from the
xanthate (ꢀ)-13 (390 mg, 1.3 mmol) according to the general pro-
cedure 5. The reaction was stirred at reflux and further DLP
(0.08 equiv) was added after 30 min, 1 h 30 min (0.08 equiv) and
2 h 30 min (0.16 equiv). After 3 h refluxing, the solvent was re-
moved in vacuo. After purification by flash chromatography, 62 mg
(0.2 mmol, 16%) of product 18 and 120 mg (0.4 mmol, 31%) of
product 17 were isolated as yellow oils. 1H NMR 17 (500 MHz,
15-6). (ꢀ)-13. Prepared from the -bromo ketone (ꢀ)-15 (491 mg,
a
1.9 mmol) according to the general procedure 3. After purification
by flash chromatography, the desired product (ꢀ)-13 was isolated
as a yellow oil (390 mg, 1.3 mmol, 68%). 1H NMR (300 MHz, CDCl3)
d
1.27 (s, 3H), 1.41 (t, J¼7.1 Hz, 3H), 1.56–1.71 (m, 2H), 1.89–2.08 (m,
2H), 2.51 (br q, J¼7.5 Hz, 1H), 3.24 (br, q, J¼8.1 Hz, 1H), 4.03 (1⁄2 AB,
J¼17.3 Hz, 1H), 4.36 (1⁄2 AB, J¼17.3 Hz, 1H), 4.63 (q, J¼7.1 Hz, 2H),
4.94–5.10 (m, 4H), 5.63 (dt, J¼16.9, 9.8 Hz, 1H), 5.71 (ddd, J¼17.4,
10.3, 7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
13.9, 19.8, 28.5, 30.1,
CDCl3)
d
0.96 (s, 3H), 1.43 (t, J¼7.1 Hz, 3H), 1.68–1.79 (m, 2H), 1.90–
45.9, 47.5, 56.1, 61.4, 70.5, 115.9, 116.0, 138.3, 139.1, 205.2, 214.0; IR
2976, 1707, 1637, 1458, 1380, 1220, 1113, 1052, 918 cmꢂ1; TLC
Rf¼0.52 (hexane/Et2O, 95:5); (CAS Number 886840-76-2). Mixture
1.95 (m, 1H), 2.08–2.12 (m, 3H), 2.22–2.28 (m, 1H), 2.52 (q, J¼8.1 Hz,
1H), 2.72 (1⁄2 AB, d, J¼18.1, 7.6 Hz, 1H), 3.07 (1⁄2 AB, d, J¼13.6,
8.5 Hz, 1H), 3.44 (1⁄2 AB, d, J¼13.6 Hz, 5.2 Hz, 1H), 4.66 (q, J¼7.1 Hz,
2H), 4.99 (br d, J¼17.3 Hz, 1H), 5.06 (br d, J¼10.4 Hz, 1H), 5.75 (ddd,
of meso-13 and (ꢀ)-13. Prepared from the mixture of
a-bromo
ketone meso-15 and (ꢀ)-15 (9.77 g, 38 mmol) according to the
general procedure 3. After purification by flash chromatography,
the desired products were obtained as an inseparable mixture of
meso-13 and (ꢀ)-13 in a 74:26 ratio (9.1 g, 31 mmol, 82%). Physical
and spectral data were in accordance with the data described
previously.
J¼17.3, 10.4, 7.1 Hz, 1H); 13C NMR 17 (75 MHz, CDCl3)
d 13.9, 17.5,
29.4, 30.4, 39.8, 40.9, 43.6, 48.7, 56.0, 59.7, 70.4, 116.4, 136.6, 214.5,
218.9; IR 17 2952, 1732, 1639, 1455, 1372, 1213, 1046, 1003, 915,
863 cmꢂ1; NOESY CH3-9/H-10, H-6/H-3, H-6/H-7 (
a), H-3/
H-2 (
a
), H-12/H-8 (
b
); TLC 17 Rf¼0.29 (hexane/Et2O, 90:10); 1H
NMR 18 (300 MHz, CDCl3)
d
1.02 (s, 3H), 1.44 (t, J¼7.1 Hz, 3H), 1.60–
2.15 (m, 6H), 2.45–2.72 (m, 4H), 3.01 (q, J¼8.4 Hz, 1H), 3.82 (td,
J¼11.1, 3.3 Hz, 1H), 4.67 (q, J¼7.1 Hz, 2H), 4.99 (br d, J¼17.3 Hz, 1H),
5.04 (br d, J¼10.4 Hz, 1H), 5.67 (ddd, J¼17.3, 10.4, 7.4 Hz, 1H); 13C
5.14. Mixture of meso-13 and ( )-13
General procedure 4. To a stirred solution of diisopropylamine
(11.9 mL, 85 mmol) in 200 mL of anhydrous THF at ꢂ78 ꢁC under
argon, was added dropwise a solution of n-BuLi 1.6 M in hexane
(48.8 mL, 78 mmol) in 50 mL of anhydrous THF. The mixture was
stirred 30 min at ꢂ78 ꢁC under argon. Then, the 70:30 mixture of
divinylcyclopentanes meso-3 and (ꢀ)-3 (12.5 g, 70 mmol) in 50 mL
of anhydrous THF was added dropwise at ꢂ78 ꢁC and the resulting
mixture stirred 1 h at ꢂ78 ꢁC under argon. O,O-Diethyl bis-xanthate
in 50 mL of anhydrous THF (34.2 g, 141 mmol), prepared according
to the method of Shi and co-workers,30b was added dropwise at
ꢂ78 ꢁC. The reaction was stirred 1 h at ꢂ78 ꢁC, then poured in a satd
NH4Cl solution. The layers were then separated and the aqueous
NMR 18 (75 MHz, CDCl3) d 13.9, 18.3, 27.8, 29.4, 31.4, 37.5, 49.6, 51.9,
53.2, 58.8, 70.2, 116.5, 136.8, 212.4, 214.3; IR 18 2956, 1704, 1640,
1456, 1376, 1215, 1048, 1002, 915, 843 cmꢂ1; TLC 18 Rf¼0.40 (hex-
ane/Et2O, 90:10). Mixture of 16 and 17. Prepared from the 70:30
mixture of xanthates meso-13 and (ꢀ)-13 (9.1 g, 31 mmol) accord-
ing to the general procedure 5. The reaction was stirred at reflux
and further DLP was added after 2 h (0.08 equiv). After 4 h reflux-
ing, the solvent was removed in vacuo. After purification by flash
chromatography, 5.45 g (18 mmol, 59%) of 16, 1.3 g (4 mmol, 14%) of
17 were isolated as yellow oils and no 18 was observed. Physical and
spectral data were in accordance with the data described
previously.

R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
7011
10
(300 MHz, CDCl3)
d
1.00 (s, 3H), 1.48–1.91 (m, 7H), 2.01–2.08 (m,
10
O
O
9
1H), 2.32–2.40 (m, 1H), 2.75 (q, J¼8.4 Hz, 1H), 3.87–4.02 (m, 5H),
4.94 (br d, J¼16.7 Hz, 1H), 4.96 (br d, J¼10.9 Hz, 1H), 5.96 (ddd,
J¼16.7, 10.9, 7.3 Hz, 1H), 7.29 (td, J¼7.7, 1.2 Hz, 1H), 7.41 (td, J¼7.4,
1.2 Hz, 1H), 7.74 (dd, J¼7.9, 0.6 Hz, 1H), 7.88 (dd, J¼8.1, 0.4 Hz, 1H);
6
2
7
3
8
4
S
H
H
S
S
S
12
OEt
EtO
17
13C NMR (75 MHz, CDCl3)
d 11.5, 25.3, 26.2, 32.1, 32.2, 46.5, 47.1,
16
50.6, 52.0, 64.7, 65.5, 77.4, 112.0, 113.9, 121.0, 121.8, 124.3, 126.1,
135.5, 140.3, 153.5, 166.5; IR 3442, 1652, 1625, 1404, 1322, 975, 869,
785 cmꢂ1; TLC Rf¼0.27 (hexane/Et2O, 90:10); mp¼118–120 ꢁC.
5.16. O-Ethyl S-[(1R
*
,3aR
*
,4R
*
,7aR )-octahydro-7a-methyl-7-
oxo-1-vinyl-1H-inden-4-yl] carbonodithioate ethylene ketal 20
*
A solution was prepared by refluxing, with a Dean–Stark water
trap under argon, a mixture of toluene (295 mL), ethylene glycol
(12 mL, 216 mmol) and p-TSA (137 mg, 0.72 mmol). Precursor 16
(5.45 g, 18 mmol) was then added and the mixture was refluxed for
5 h. The cooled solution was washed with a satd NaHCO3 solution
and water. The organic layer was dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash chroma-
tography (hexane/Et2O, 90:10) to give 5.2 g (15 mmol, 85%) of
5.19. (3R
*
,3aR
*
,7R
*
,7aR )-7-(Benzo[d]thiazol-2-ylsulfonyl)-
*
octahydro-3a-methyl-3-vinylinden-4-one ethylene ketal 23
A stirred suspension of the thioether 22 (3.3 g, 8.5 mmol) in
110 mL of EtOH at 0 ꢁC under argon was treated with ammonium
heptamolybdate tetrahydrate (1.05 g, 0.85 mmol) in 35% H2O2
(3.64 mL, 42.5 mmol) and the resulting suspension allowed to warm
to rt over 1 h. After subsequent stirring at rt for 6 h, further ammo-
nium heptamolybdate tetrahydrate (1.05 g, 0.85 mmol) in 35% H2O2
(3.64 mL, 42.5 mmol) was added and the mixture stirred at rt for
a further day. Then, the mixture was diluted with ether and water
and the layers separated. The aqueous layer was then extracted four
times with ether and the combined organic extracts washed with
brine. The organic layer was dried over MgSO4, filtered and con-
centrated in vacuo. The white solid obtained (2.85 g, 6.8 mmol, 80%)
was not purified and can be used as well in a subsequent reaction.
This compound was recrystallized in a solution ether/CH2Cl2 (just
a few drops) in order to be characterized by X-ray crystallographic
a yellow oil. 1H NMR (300 MHz, CDCl3)
d 0.96 (s, 3H), 1.41 (t,
J¼7.1 Hz, 3H), 1.45–1.64 (m, 4H), 1.68–1.86 (m, 3H), 1.98 (td, J¼7.1,
5.1 Hz, 1H), 2.16–2.25 (m, 1H), 2.71 (q, J¼8.5 Hz, 1H), 3.76 (td,
J¼12.0, 4.3 Hz,1H), 3.85–4.01 (m, 4H), 4.63 (q, J¼7.1 Hz, 2H), 4.67 (q,
J¼7.1 Hz, 1H), 4.92 (br d, J¼16.7 Hz, 1H), 4.94 (br d, J¼10.8 Hz, 1H),
5.08 (dt, J¼10.8, 1.6 Hz, 1H), 5.10 (dt, J¼16.9, 1.6 Hz, 1H), 5.94 (ddd,
J¼16.7, 10.8, 7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 11.4, 13.9, 25.0,
26.1, 31.1, 32.1, 46.5, 48.7, 49.4, 51.9, 64.7, 65.5, 66.8, 111.9, 113.9,
140.3, 214.8; IR 2955, 1636, 1448, 1381, 1343, 1210, 1048, 1002, 906,
774 cmꢂ1; TLC Rf¼0.46 (hexane/Et2O 90:10); MS (ESIþ) m/z 343.1
([MþH]þ).
analysis. 1H NMR (300 MHz, CDCl3)
d 0.89 (s, 3H), 1.45–1.80 (m, 4H),
1.85–1.95 (m, 3H), 2.04 (br q, J¼9.0 Hz, 1H), 2.29 (td, J¼11.5, 7.9 Hz,
1H), 2.68 (q, J¼8.6 Hz,1H), 3.62–3.66 (m,1H), 3.82–3.98 (m, 4H), 4.92
(brd, J¼17.5 Hz,1H), 4.94 (brd, J¼10.7 Hz,1H), 5.89 (ddd, J¼17.5,10.7,
7.3 Hz, 1H), 7.61 (br q, J¼7.6 Hz, 2H), 8.0 (dd, J¼7.8, 1.1 Hz, 1H), 8.23
5.17. (3R
*
,3aR
*
,7R
*
,7aR )-Octahydro-7-mercapto-3a-methyl-3-
*
vinylinden-4-one ethylene ketal 21
Under argon, compound 20 (5.2 g, 15 mmol) was diluted in
13 mL of ethanol at rt. Then, ethylene diamine (4.1 mL, 61.5 mmol)
was added dropwise at rt, the mixture was stirred for 4 h at rt
under argon and poured on a 2 M H2SO4 aqueous solution. The
layers were separated and the aqueous layer extracted twice with
ether. The organic layers were washed with a 2 M H2SO4 aqueous
solution, followed by a satd NaHCO3 solution. The organic layer
was dried over MgSO4, filtered and concentrated in vacuo. The
yellow oil obtained (3.43 g, 13.5 mmol, 90%) was not purified and
(dd, J¼8.0, 1.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 11.6, 24.5, 25.0,
26.8, 30.5, 44.5, 45.3, 52.0, 62.8, 64.8, 65.5, 111.0, 114.3, 122.4, 125.6,
127.7,128.0,137.0,139.7,153.0,166.1; IR 3441, 3051,1652,1622,1403,
1320, 1145, 974, 821, 728 cmꢂ1; TLC Rf¼0.44 (hexane/Et2O, 50:50);
mp¼88–90 ꢁC; MS (ESIþ) m/z 420.4 ([MþH]þ).
5.20. S-(1R
*
,3aR
*
,4R
*
,7aR )-Octahydro-7a-methyl-7-oxo-1-
*
vinyl-1H-inden-4-yl benzothioate ethylene ketal 24
directly used in the next reaction. 1H NMR (300 MHz, CDCl3)
d
0.86
To a stirred solution of thiol 21 (1.77 g, 7 mmol) in dry pyridine
(10.1 mL) under argon was added dropwise at 0 ꢁC benzoyl chloride
(1.61 mL, 14 mmol). The mixture was stirred at rt and after 7 h it
was diluted with CH2Cl2. The organic phase was washed with wa-
ter, a satd solution of NaHCO3 and brine. The organic layers were
dried over MgSO4, filtered and concentrated in vacuo. The residue
obtained was purified by flash chromatography (hexane/Et2O,
90:10) to give 55 mg (0.2 mmol, 3%) of starting material 10, 0.247 g
(0.5 mmol, 7%) of disulfide and 1.745 g (4.9 mmol, 66%) of the
(s, 3H), 1.29–1.39 (m, 3H), 1.45–1.61 (m, 5H), 1.69–2.03 (m, 7H),
2.67–2.85 (m, 2H), 3.85–4.00 (m, 4H), 4.92 (br d, J¼16.3 Hz, 1H),
4.94 (br d, J¼11.2 Hz, 1H), 5.93 (ddd, J¼16.3, 11.2, 7.4 Hz, 1H); 13C
NMR (75 MHz, CDCl3)
d 11.3, 25.6, 25.9, 32.3, 36.1, 37.8, 46.6, 51.4,
54.2, 64.6, 65.4, 112.1, 113.7, 140.4; IR 2952, 2873, 1520, 1170, 1133,
1057, 951, 908 cmꢂ1; TLC Rf¼0.83 (hexane/Et2O, 90:10 eluting two
times).
5.18. (3R
*
,3aR
*
,7R
*
,7aR
*
)-7-(Benzo[d]thiazol-2-ylthio)-
protected thiol 24 as a white solid. 1H NMR (300 MHz, CDCl3)
d 1.00
octahydro-3a-methyl-3-vinylinden-4-one ethylene ketal 22
(s, 3H), 1.35–1.85 (m, 4H), 1.89 (1⁄2 AB, d, J¼14.9, 4.7 Hz, 1H), 2.01
(1⁄2 AB, d, J¼12.4, 7.2 Hz, 1H), 2.06–2.15 (m, 3H), 2.74 (q, J¼8.4 Hz,
1H), 3.78 (td, J¼12.2, 4.2 Hz, 1H), 3.87–4.04 (m, 4H), 4.94 (br d,
J¼16.7 Hz, 1H), 4.95 (br d, J¼10.9 Hz, 1H), 5.96 (ddd, J¼16.7, 10.9,
7.4 Hz, 1H), 7.43 (br t, J¼7.3 Hz, 2H), 7.54 (br d, J¼8.0 Hz, 1H), 7.94
(br d, J¼8.4 Hz, 2H); TLC Rf¼0.33 (hexane/Et2O, 90:10).
Thiol 21 (3.43 g, 13.5 mmol) in 61 mL of anhydrous THF was
added to a suspension of 1.62 g of sodium hydride (40.5 mmol) in
21 mL of anhydrous THF at rt under argon. The reaction mixture
was stirred at rt for 30 min. Then,
a solution of 2-chloro-
benzothiazole (5.73 g, 34 mmol), prepared according to the method
of Boga and co-workers,51 in 30 mL of anhydrous THF was added
dropwise. The reaction was refluxed overnight. Then, the THF was
distilled and the mixture washed with brine and extracted twice
with ether. The organic layer was dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash chroma-
tography (hexane/Et2O, 90:10 to 70:30) to give a brown oil crys-
tallizing when cooled to 5–10 ꢁC (3.3 g, 8.5 mmol, 63%). 1H NMR
5.21. S-(1S
*
,3aR
*
,4R
*
,7aR )-1-Formyl-octahydro-7a-methyl-7-
*
oxo-1H-inden-4-yl benzothioate ethylene ketal 25
To a stirred solution of compound 24 (1.6 g, 4.5 mmol), MeOH
(1 mL, 24 mmol) and a catalytic amount of dye sudan III (20 mg,
0.056 mmol) in dry CH2Cl2 (40 mL) was bubbled a stream of ozone
in oxygen at ꢂ60 ꢁC until the red color of sudan III became yellow

7012
R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
(25 min). Excess of ozone and oxygen were removed with argon
flushed and then ozonide was quenched with Me2S (5 mL) slowly
added at ꢂ78 ꢁC. The solution was warmed to rt over 12 h, washed
four times with water, dried over MgSO4, filtered and concentrated
in vacuo and the residue was purified by flash chromatography
(hexane/EtOAc, 75:25) to give 0.94 g (2.6 mmol, 58%) of compound
25 as a yellow oil and 0.130 g (0.3 mmol, 7%) of ozonide. 1H NMR
J¼7.8 Hz, 1H), 7.95 (d, J¼7.6 Hz, 2H); TLC Rf¼0.29 (hexane/Et2O,
90:10).
5.25. S-(1S
*
,3aR
*
,4R
*
,7aR )-1-Formyl-octahydro-7a-methyl-7-
*
oxo-1H-inden-4-yl benzothioate 29
To a stirred solution of compound 28 (0.314 g, 1 mmol), MeOH
(0.22 mL, 5.3 mmol) and a catalytic amount of dye sudan III (5 mg,
0.014 mmol) in dry CH2Cl2 (29 mL) according to the procedure
described for 19. The residue was purified by flash chromatography
(hexane/EtOAc, 85:15) to give 0.200 g (0.63 mmol, 63%) of com-
pound 29 as a yellow oil and 0.032 g (0.09 mmol, 9%) of ozonide. 1H
(300 MHz, CDCl3)
d 1.10 (s, 3H), 1.85–1.95 (m, 6H), 2.02–2.16 (m,
3H), 2.97 (td, J¼9.9, 2.3 Hz, 1H), 3.78 (td, J¼12.2, 4.3 Hz, 1H), 3.94–
4.16 (m, 4H), 7.44 (t, J¼7.8 Hz, 2H), 7.56 (t, J¼6.9 Hz, 1H), 7.94 (d,
J¼7.8 Hz, 2H), 9.76 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 12.0, 19.5,
25.2, 31.0, 31.3, 40.8, 50.4, 53.2, 54.9, 64.6, 65.4, 111.0, 127.1 (2C),
128.6 (2C), 133.3, 137.1, 191.6, 204.3; TLC Rf¼0.52 (hexane/EtOAc,
75:25).
NMR (300 MHz, CDCl3)
d 1.13 (s, 3H), 1.55–1.72 (m, 2H), 1.80–2.20
(m, 6H), 2.38–2.56 (m, 4H), 2.84 (td, J¼14.0, 7.0 Hz, 1H), 3.18 (t,
J¼9.1 Hz, 1H), 4.06–4.15 (m, 2H), 7.46 (t, J¼7.6 Hz, 2H), 7.59 (t,
J¼7.4 Hz, 1H), 7.94 (d, J¼7.6 Hz, 2H), 9.91 (s, 1H); 13C NMR
5.22. (E)-Ethyl 3-((3R
*
,3aR
*
,7R
*
,7aR )-octahydro-3a-methyl-7-
*
benzoylsulfanyl-4-oxo-1H-inden-3-yl)acrylateethyleneketal26
(300 MHz, CDCl3)
d 13.6, 18.2, 24.7, 34.1, 37.5, 39.9, 54.1, 55.6, 57.1,
127.2 (2C), 128.7 (2C), 133.6, 136.7, 190.9, 202.1, 211.3; TLC Rf¼0.33
To a stirred solution of sodium hydride (0.042 g, 1.05 mmol) in
dry THF (1.5 mL) under argon was added dropwise triethyl phos-
phonoacetate (0.29 mL, 1.5 mmol) at 0 ꢁC. The mixture was stirred
30 min at rt until the aldehyde 25 (0.360 g, 1 mmol) in 1.4 mL of dry
THF was added dropwise at 0 ꢁC and the mixture stirred at rt. After
2 h 30 min, the reaction mixture was quenched with a satd NH4Cl
solution and the aqueous layer extracted twice with ether. The
residue was purified by flash chromatography (hexane/EtOAc,
75:25) to give 0.168 g (0.39 mmol, 39%) of compound 26 as a col-
orless oil and 0.074 g (0.21 mmol, 21%) of starting material 25. 1H
(hexane/EtOAc, 85:15).
5.26. (E)-Ethyl 3-((3R
*
,3aR
*
,7R
*
,7aR )-octahydro-3a-methyl-7-
*
benzoylsulfanyl-4-oxo-1H-inden-3-yl)acrylate 30
To a stirred suspension of sodium hydride (0.042 g, 1.05 mmol)
in dry THF (1.5 mL) under argon was added dropwise triethyl
phosphonoacetate (0.21 mL, 1.05 mmol) at 0 ꢁC. The mixture was
stirred 30 min at rt until the aldehyde 29 (0.316 g, 1 mmol) in
1.4 mL of dry THF was added dropwise at 0 ꢁC and the mixture
stirred at rt. After 1 h, the reaction mixture was quenched with
a satd NH4Cl solution and the aqueous layer extracted twice with
ether. The combined organic extracts were dried over MgSO4, fil-
tered and concentrated in vacuo to give a yellow residue which was
purified by flash chromatography (hexane/EtOAc, 75:25) to give
0.185 g (0.48 mmol, 48%) of compound 30 as a yellow oil. 1H NMR
NMR (300 MHz, CDCl3)
d
1.05 (s, 3H), 1.28 (t, J¼7.1 Hz, 3H), 1.40–
1.90 (m, 5H), 2.02–2.14 (m, 4H), 2.89 (q, J¼8.5 Hz, 1H), 3.78 (td,
J¼12.2, 4.4 Hz, 1H), 3.84–4.04 (m, 4H), 4.18 (q, J¼7.1 Hz, 2H), 5.73
(dd, J¼15.6, 1.2 Hz, 1H), 7.09 (dd, J¼15.7, 7.8 Hz, 1H), 7.44 (t,
J¼7.5 Hz, 2H), 7.56 (t, J¼7.4 Hz, 1H), 7.94 (d, J¼8.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3)
d 11.5, 14.4, 25.2, 25.9, 31.7, 41.7, 45.3, 50.1, 52.6,
60.2, 64.6, 65.3, 111.6, 120.7,127.3 (2C),128.6 (2C),133.4,137.3, 151.0,
166.8, 191.9; TLC Rf¼0.61 (hexane/EtOAc, 75:25).
(300 MHz, CDCl3)
d
1.14 (s, 3H), 1.28 (t, J¼7.1 Hz, 3H), 1.62–2.02 (m,
6H), 2.31 (ddd, J¼14.4, 5.5, 1.6 Hz, 1H), 2.49 (br quint. J¼6.7 Hz, 1H),
2.83 (sext, J¼7.1 Hz, 1H), 2.99 (q, J¼8.1 Hz, 1H), 4.14 (td, J¼7.5, 3.2,
1H), 4.18 (q, J¼7.1 Hz, 2H), 5.91 (dd, J¼15.8, 1.3 Hz, 1H), 7.05 (dd,
J¼15.8, 6.5 Hz, 1H), 7.46 (t, J¼7.6 Hz, 2H), 7.59 (t, J¼7.3 Hz, 1H), 7.94
5.23. (3R
*
,3aR
*
,7R
*
,7aR )-Octahydro-7-mercapto-3a-methyl-
*
3-vinylinden-4-one 27
(d, J¼8.0 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 12.8, 14.2, 24.2, 24.9,
Prepared from precursor 16 (4.3 g, 14 mmol) in EtOH (15.5 mL)
and ethylene diamine (4.82 mL, 72 mmol) following the general
procedure described for thiol 21. The yellow oil obtained after
workup (3 g, 14 mmol, 100%) was not purified and directly used in
34.5, 37.7, 40.5, 45.5, 54.0, 57.5, 60.1, 122.5, 127.2 (2C), 128.6 (2C),
133.6, 136.8, 148.5, 166.5, 191.1, 211.7; TLC Rf¼0.60 (hexane/EtOAc,
75:25).
the next reaction. 1H NMR (300 MHz, CDCl3)
d 0.96 (s, 3H), 1.44–
1.88 (m, 5H), 1.96–2.06 (m, 1H), 2.22 (1⁄2 AB, dd, J¼14.6, 5.8,
1.8 Hz, 1H), 2.70 (ddd, J¼14.4, 13.8, 7.0 Hz, 1H), 2.38 (dddd, J¼13.3,
6.9, 4.3, 1.8 Hz, 1H), 2.82 (qm, J¼8.2, 1H), 3.17 (tdd, J¼11.4, 6.6,
4.4 Hz, 1H), 5.08 (dt, J¼10.7, 1.8 Hz, 1H), 5.09 (dt, J¼17.0, 1.8 Hz,
1H), 5.94 (ddd, J¼17.0, 10.7, 5.8 Hz, 1H); TLC Rf¼0.33 (hexane/Et2O,
90:10).
5.27. S-[(1R
*
,3aR
*
,4R
*
,7aR )-Octahydro-7a-methyl-1-((E)-3-
*
(trimethylsilyl)prop-1-enyl)-7-oxo-1H-inden-4-yl]
benzothioate 31
Precursor 16 (0.298 g, 1 mmol) in allyltrimethylsilane (0.48 mL,
3 mmol) was stirred at 40 ꢁC under argon in a round bottom flask
equipped with a reflux condenser. Second-generation Grubbs’
catalyst (0.017 g, 0.02 mmol) was added and the mixture stirred at
40 ꢁC. A second portion of catalyst was added after 6 h and a third
portion after 24 h (0.02 equiv each time). After 48 h the mixture
was concentrated in vacuo to afford a brown residue which was
purified by flash chromatography (hexane/Et2O, 90:10) to give
0.091 g (0.24 mmol, 24%) of cross-metathesis product 31 as a yel-
low oil and 0.131 g (0.44 mmol, 44%) of starting product 16. 1H NMR
5.24. S-(1R
*
,3aR
*
,4R
*
,7aR )-Octahydro-7a-methyl-7-oxo-1-
*
vinyl-1H-inden-4-yl benzothioate 28
Prepared from precursor 27 (3 g, 14 mmol) in dry pyridine
(20 mL) and dry benzoyl chloride (3.28 mL, 28 mmol) according
to the general procedure described for precursor 24. After 7 h
stirring at rt, the mixture was treated as described below and the
residue obtained was purified by flash chromatography (hexane/
Et2O, 90:10) to give 3.27 g (10.4 mmol, 74%) of the protected
(300 MHz, CDCl3)
d
ꢂ0.04 (s, 9H), 1.04 (s, 3H), 1.42 (t, J¼7.1 Hz, 3H),
1.61–1.90 (m, 8H), 2.23 (1⁄2 AB, dd, J¼14.5, 5.7,1.8 Hz,1H), 2.53–2.62
(m, 1H), 2.68–2.79 (m, 2H), 4.09 (td, J¼11.8, 4.3 Hz, 1H), 4.64 (q,
J¼7.1 Hz, 2H), 5.30 (1⁄2 AB, d, J¼15.4 Hz, 6.4 Hz, 1H), 5.48 (1⁄2 AB, td,
thiol 28 as a yellow solid. 1H NMR (300 MHz, CDCl3)
d 1.10 (s,
3H), 1.55–2.01 (m, 6H), 2.29 (1⁄2 AB, dd, J¼14.5, 5.7, 1.7 Hz, 1H),
2.45–2.54 (m, 1H), 2.77–2.89 (m, 2H), 4.12 (td, J¼12.0, 4.5 Hz,
1H), 5.09 (br d, J¼10.7, 1.6 Hz, 1H), 5.11 (br dt, J¼17.0, 1.6 Hz, 1H),
5.97 (ddd, J¼17.0, 10.7, 5.9 Hz, 1H), 7.46 (t, J¼7.8 Hz, 2H), 7.56 (t,
J¼15.4, 7.9, 0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
ꢂ1.8 (3C), 13.0,
13.9, 23.1, 24.9, 25.3, 34.1, 38.0, 46.0, 47.9, 53.2, 57.2, 70.0, 127.97,
128.04, 212.5, 214.0; TLC Rf¼0.60 (hexane/Et2O, 90:10).

R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
7013
5.28. O-Ethyl S-[(1R
*
,3aR
*
,4R
*
,7aR
*
)-octahydro-7a-methyl-1-
the mixture refluxed for 3 h before another 0.2 equiv were added.
After 6 h refluxing, the mixture was concentrated in vacuo. The
residue was purified by flash chromatography (hexane/Et2O, 95:5)
to give 0.395 g (0.97 mmol, 40%) of an inseparable mixture of
diastereomers 34 and 79 mg (0.19 mmol, 8%) of isomer 35 as
((E)-3-(trimethylsilyl)prop-1-enyl)-7-oxo-1H-inden-4-yl]
carbonodithioate 32
Prepared from compound 28 (0.062 g, 0.2 mmol), allyl-
trimethylsilane (0.28 mL, 1.8 mmol), second-generation Grubbs’
catalyst (3.4 mg, 0.004 mmol) and a few drops of 1,2-dichloro-
ethane according to the procedure described for compound 31.
Both allyltrimethylsilane (3 equiv) and Grubbs’catalyst (0.2 equivt)
were added every 12 h and after 4.5 days the mixture was con-
centrated in vacuo to give a brown residue which was purified by
flash chromatography (hexane/Et2O, 90:10) to give 0.025 g
(0.062 mmol, 30%) of cross-metathesis product 32 as a yellow solid
and 0.044 g (0.14 mmol, 70%) of starting product 28. 1H NMR
yellow oils. 1H NMR 34 (300 MHz, CDCl3)
d
0.81 (d, J¼6.9 Hz, 3H),
0.93 (t, J¼6.2 Hz, 6H), 1.06 and 1.05 (s, 3H), 1.59–1.95 (m, 14H),
2.20–2.24 (m,1H), 2.27 (1⁄2 AB, dd, J¼14.6, 5.7,1.8 Hz,1H), 2.59–2.66
(m, 1H), 2.70–2.86 (m, 2H), 4.12 (td, J¼11.7, 4.3 Hz, 1H), 5.09 (dt,
J¼10.8, 1.7 Hz, 1H), 5.10 (dt, J¼16.9, 1.6 Hz, 1H), 5.53 (tt, J¼10.8,
4.3 Hz,1H), 5.96 (ddd, J¼16.9,10.8, 5.8 Hz,1H); 13C NMR 34 (75 MHz,
CDCl3) d 12.9, 17.1, 11.2, 20.6, 22.0, 23.9, 24.7, 24.0, 24.8, 26.76, 26.84,
31.4, 34.0, 34.2, 34.3, 38.0, 39.7, 46.5, 47.4, 53.1, 53.5, 57.0, 84.6,115.6,
138.3, 212.5, 213.4, 213.5; TLC 34 Rf¼0.58 (hexane/Et2O, 95:5); 1H
(300 MHz, CDCl3)
d
ꢂ0.02 (s, 9H), 1.09 (s, 3H), 1.55–1.60 (m, 2H),
NMR 35 (300 MHz, CDCl3)
d
0.80 (d, J¼6.9 Hz, 3H), 0.92 (t, J¼6.7 Hz,
1.44 (d, J¼8.0 Hz, 2H), 1.66–2.0 (m, 6H), 2.25 (1⁄2 AB, d, J¼14.5, 5.7,
1.8 Hz, 1H), 2.44–2.52 (m, 1H), 2.75–2.87 (m, 2H), 4.11 (td, J¼12.0,
4.4 Hz, 1H), 5.32 (1⁄2 AB, d, J¼15.4, 6.4 Hz, 1H), 5.54 (1⁄2 AB, td,
J¼15.6 Hz, 8.0, 1.0, 1 Hz, 1H), 7.45 (t, J¼7.8 Hz, 2H), 7.57 (tt, J¼7.4,
6H), 0.97 (s, 3H), 1.55–2.3 (m, 6H), 2.08–2.30 (m, 4H), 2.53 (br q,
J¼8.0 Hz, 1H), 2.72 (1⁄2 AB, d, J¼17.5, 7.0 Hz, 1H), 3.06 (1⁄2 AB, d,
J¼13.5, 8.0 Hz,1H), 3.42 (1⁄2 AB, dd, J¼13.5, 5.0, 2.3 Hz,1H), 4.99 (brd,
J¼17.3 Hz, 1H), 5.06 (br d, J¼10.5 Hz, 1H), 5.52 (tdd, J¼10.8, 4.4, 2.3,
1H), 5.76 (ddd, J¼17.3,10.5, 7.1 Hz,1H); TLC 35 Rf¼0.38 (hexane/Et2O,
95:5).
1.2 Hz, 1H), 7.97 (d, J¼8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d
ꢂ1.8
(3C), 12.9, 23.1, 25.0, 25.2, 34.9, 38.2, 41.2, 46.1, 54.0, 57.3, 127.4
(2C),128.0, 128.2, 128.8 (2C), 133.6, 137.1, 191.7, 212.9; TLC Rf¼0.38
(hexane/Et2O, 90:10).
5.31. O-Ethyl S-[(1S,3aS,4S,7R,7aS)-octahydro-7-hydroxy-7a-
methyl-7-((S)-N-methyl-S-phenylsulfonimidoyl-S-methyl)-1-
vinyl-1H-inden-4-yl] carbonodithioate 36 and O-ethyl S-
[(1R,3aR,4R,7S,7aR)-octahydro-7-hydroxy-7a-methyl-7-((S)-N-
methyl-S-phenylsulfonimidoyl-S-methyl)-1-vinyl-1H-inden-
4-yl] carbonodithioate 37
5.29. O-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl] S-2-(1-
methyl-2,5-divinylcyclopentyl)-2-oxoethyl carbonodithioate
33. meso-33 and ( )-33
Prepared from a mixture of divinylcyclopentane meso-3 and
(ꢀ)-3 (2.0 g, 11 mmol) and bis[menthyl(thiocarbonyl)]disulfide
(10.18 g, 22 mmol, prepared according to the procedure of Mat-
sui),46c according to the general procedure 4. But 1 equiv of bis-
[menthyl(thiocarbonyl)disulfide was added first and the mixture
stirred for 30 min at ꢂ78 ꢁC before the second equivalent was
added. After 2 h 10 min at ꢂ78 ꢁC, the mixture was quenched with
a satd NH4Cl solution and the aqueous layer extracted twice with
ether. The organic layers were dried over MgSO4, filtered and con-
centrated in vacuo. After purification by flash chromatography
(hexane/Et2O, 100:0 to 80:20), the desired products meso-33 and
(ꢀ)-33 were obtained as an inseparable mixture in a 70:30 ratio
(2.56 g, 6.3 mmol, 57%) and 36% (0.7 g, 3.9 mmol) of divinylcyclo-
pentane meso-3 and (ꢀ)-3 was recovered. 1H NMR meso-33 and
To
a
solution of (S)-(þ)-N,S-dimethyl-S-phenylsulfoximine
(0.653 g, 3.90 mmol), prepared from methyl phenyl sulfoxide49
according to the procedure of Jonhson and co-workers48 in THF
(10 mL) at ꢂ10 ꢁC was added n-BuLi 1.6 M in hexane (2.3 mL,
3.70 mmol) dropwise and the mixture was stirred during 15 min.
At ꢂ90 ꢁC, a solution of racemic ketone 16 (1.0 g, 3.36 mmol) in
THF (3.5 mL) was added dropwise over 10 min. After 1 h 15 min,
the reaction was quenched with a satd NH4Cl solution and
extracted with Et2O (ꢃ3). The combined organic extracts were
washed with brine and dried over MgSO4. After filtration and
concentration in vacuo, the crude material was purified by flash
chromatography eluting with hexane/CH2Cl2/EtOAc, 60:37:3 to
afford the alcohol as a 1:1 mixture of diastereomers 36/37 as
white solids (0.357 gþ0.445 g, 23%þ28%) and 17% of starting
ketone 16 as a yellow oil (0.172 g). 1H NMR 36 (less polar dia-
stereomer, crystals after recrystallization in hot hexane). 1H NMR
(ꢀ)-33 (300 MHz, CDCl3)
d
0.78 (d, J¼6.9 Hz, 3H), 0.91 (t, J¼6.5 Hz,
6H), 1.07 (s, 3H, meso-33), 1.26 (s, 3H, (ꢀ)-13), 1.44–1.76 (m, 12H),
2.03–1.81 (m, 8H), 2.22 (br d, J¼12.0 Hz,1H), 2.51 (br q, J¼7.5 Hz,1H,
(ꢀ)-33), 2.96–3.07 (quint, J¼7.6 Hz, 2H, meso-33), 3.20–3.28 (m, 1H,
(ꢀ)-33), 4.04 (1⁄2 AB, d, J¼17.2, 4.9 Hz,1H, (ꢀ)-33), 4.24 (s, 2H, meso-
33), 4.35 (1⁄2 AB, d, J¼17.2, 2.2 Hz, 1H, (ꢀ)-33), 5.04 (br d, J¼17.5 Hz,
2H), 5.05 (br d, J¼10.0 Hz, 2H), 5.46 (td, J¼10.8, 4.4 Hz, 1H), 5.66–
5.79 (m, 4H); TLC meso-33 and (ꢀ)-33 Rf¼0.66 (hexane/Et2O, 95:5).
36 (300 MHz, CDCl3)
d
0.81 (s, 3H), 1.41 (t, J¼7.2 Hz, 3H), 1.70–2.16
(m, 8H), 2.35 (td, J¼12.5, 7.5 Hz, 1H), 2.54 (s, 3H), 2.83 (1⁄2 AB,
J¼13.8 Hz, 1H), 3.09 (q, J¼9.5 Hz, 1H), 3.75 (td, J¼12.3, 4.0 Hz, 1H),
3.98 (1⁄2 AB, J¼13.8 Hz, 1H), 4.63 (q, J¼7.2 Hz, 2H), 4.82 (br d,
J¼10.0 Hz, 1H), 5.13 (br d, J¼17.0 Hz, 1H), 5.64 (dt, J¼17.0, 10.0 Hz,
1H), 7.0 (br s, 1H), 7.77–7.81 (m, 2H), 7.54–7.62 (m, 3H); 13C NMR
5.30. S-[(1R,3aR,4R,7aR)-Octahydro-7a-methyl-7-oxo-1-vinyl-
1H-inden-4-yl] O-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]
carbonodithioate and S-[(1S,3aS,4S,7aS)-octahydro-7a-
methyl-7-oxo-1-vinyl-1H-inden-4-yl] O-[(1R,2S,5R)-2-
isopropyl-5-methylcyclohexyl] carbonodithioate 34 and S-
[((3S,3aR,6R,6aR)-octahydro-6a-methyl-1-oxo-6-
vinylpentalen-3-yl)methyl] O-[(1R,2S,5R)-2-isopropyl-5-
methylcyclohexyl] carbonodithioate and S-[((3R,3aS,6S,6aS)-
octahydro-6a-methyl-1-oxo-6-vinylpentalen-3-yl)methyl] O-
[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]
36 (75 MHz, CDCl3) d 10.7, 13.9, 24.7, 27.8, 29.0, 29.3, 33.9, 45.2,
47.2, 49.2, 52.0, 60.2, 69.7, 75.7, 116.2, 128.8 (2C), 129.6 (2C), 133.2,
139.1, 142.0, 215.0; TLC 36 Rf¼0.54 (hexane/CH2Cl2/EtOAc,
60:37:3); mp¼52–54 ꢁC. 1H NMR 37 (more polar diastereomer)
(300 MHz, CDCl3)
d
0.96 (s, 3H), 1.41 (t, J¼7.1 Hz, 3H), 1.48–1.63
(m, 5H), 1.71–1.81 (m, 1H), 1.97 (td, J¼14.4, 3.8 Hz, 1H), 2.19 (q,
J¼8.0 Hz, 1H), 2.26–2.35 (m, 1H), 2.57 (s, 3H), 2.81 (dt, J¼14.2,
3.3 Hz, 1H), 3.35 (1⁄2 AB, J¼13.5 Hz, 1H), 3.42 (br,
⁄
AB,
1
2
J¼13.7 Hz, 1H), 3.76 (td, J¼12.1, 4.2 Hz, 1H), 4.63 (q, J¼7.1 Hz, 2H),
4.87 (dt, J¼17.2, 1.4 Hz, 1H), 5.02 (dt, J¼10.5, 1.1 Hz, 1H), 6.14 (ddd,
J¼17.2, 10.5, 6.5 Hz, 1H), 6.80 (br s, 1H), 7.56–7.64 (m, 3H), 7.85–
carbonodithioate 35
7.88 (m, 2H); 13C NMR 37 (75 MHz, CDCl3)
d 8.9, 13.9, 24.7, 25.2,
Prepared from the mixture of xanthates meso-33 and (ꢀ)-33
(1.0 g, 2.45 mmol) in 1,2-dichloroethane (57 mL) using general
procedure. Lauroyl peroxide (0.195 g, 0.49 mmol) was added and
28.9, 31.8, 33.8, 48.3, 48.8, 49.0, 52.5, 58.3, 69.8, 76.5, 114.5, 129.1
(2C), 129.8 (2C), 133.4, 139.1, 139.2, 214.1; TLC 37 Rf¼0.43 (hexane/
CH2Cl2/EtOAc, 60:37:3); mp¼58–60 ꢁC.

7014
R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
Table 2
Crystal data and structure refinement for 7, 9, 23, and 36
Compound
7
9
23
36
Formula
Mw
C24H36O4
388.53
C28H31IN4O12.5
750.47
C23.5H28NO4.5S2
454.61
C23H33NO3S3
467.68
Crystal colour
Crystal size/mm3
Crystal system
Space group
a/Å
Colorless
0.5ꢃ0.4ꢃ0.25
Orthorhombic
P212121
6.477(1)
12.640(3)
26.067(5)
Colorless
0.25ꢃ0.25ꢃ0.15
Triclinic
Pꢂ1
Colorless
0.4ꢃ0.4ꢃ0.15
Triclinic
Pꢂ1
Colorless
0.6ꢃ0.3ꢃ0.3
Orthorhombic
P212121
7.2265(1)
12.2799(2)
27.8022(6)
12.3862(2)
12.7724(2)
13.4506(2)
92.2411(9)
117.136(1)
117.6769(7)
1589.71(4)
2
9.0679(5)
11.6008(7)
11.9303(7)
100.859(3)
106.303(3)
105.172(3)
1115.14(11)
2
b/Å
c/Å
ꢁ
ꢁ
a
/
b/
ꢁ
/
g
V/Å3
2134.09(7)
4
1.209
2467.19(7)
4
1.259
Z
Dc/g cmꢂ3
1.568
10.8
1.354
2.69
m
(Mo K
a
)/cmꢂ1
0.8
3.24
No. of unique data
No. param. refined
2941
252
7528
406
3910
277
3449
257
R[I>2
wR [unique]
Goodness of fit
Min; max Dr/e Åꢂ3
s
(I)]
0.058 [2623]
0.1787
1.046
ꢂ0.351; 0.347
0.055 [6048]
0.158
1.04
ꢂ0.842; 0.688
0.056 [3456]
0.155
1.04
ꢂ0.255; 0.633
0.049 [2507]
0.152
1.046
ꢂ0.299; 0.251
w¼1/[
s
2(Fo2)þ(AP)2þBP] where P¼(Fo2þ2Fc2)/3.
A¼0.0781a; 0.1143b; 0.0785c; 0.0831d.
B¼1.5544a; 0.5211b; 0.7545c; 0.6724d.
5.32. O-Ethyl S-[(1S,3aS,4S,7aS)-octahydro-7a-methyl-7-oxo-
1-vinyl-1H-inden-4-yl] carbonodithioate (L)-16 and O-ethyl
S-[(1R,3aR,4R,7aR)-octahydro-7a-methyl-7-oxo-1-vinyl-1H-
inden-4-yl] carbonodithioate (D)-16
Prof. M. Bertrand, Dr. S. Gastaldi (UMR 6517) and Dr. B. Vacher
(Pierre Fabre Medicaments) for helpful comments.
References and notes
A solution of 36 (0.357 g, 0.76 mmol) was heated at 120 ꢁC in
xylene (7.6 mL). After 30 h the mixture was concentrated in vacuo.
After purification by flash chromatography, (L)-16 was isolated as
a yellow oil with 72% yield (0.163 g, 0.55 mmol). Physical and
1. (a) Vitamin D; Feldman, D., Glorieux, F. H., Pike, J. W., Eds.; Academic: New
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12071–12150.
spectral data were in accordance with the data previously de-
20
scribed. ee¼99.6% determined by chiral HPLC. [
a
]
ꢂ62.98 (c 0.524,
D
CH2Cl2) for ee¼99.6%. (þ)-16 was prepared according to the same
procedure, starting with diastereomer 37 (0.445 g, 0.95 mmol).
After purification by flash chromatography, (þ)-16 was isolated as
a yellow oil with 71% yield (0.202 g, 0.68 mmol). Physical and
spectral data were in accordance wih the data previously described.
20
ee¼98.3% determined by chiral HPLC. [
a
]
þ61.81 (c 0.542, in
D
CH2Cl2) for ee¼98.3%.
6. Steroidal numbering is used.
´
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23), CCDC-724373 (for 36) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
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Acknowledgements
14. (a) Rodriguez, R.; Ollivier, C.; Santelli, M. Tetrahedron Lett. 2004, 44, 2289–2292;
trans-Hydrindanone precursors of CD-ring system of vitamin D have previously
been obtained from meso-3, for premilary communications see: (b) Rodriguez,
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We are grateful to the Centre National de la Recherche Scientifique
`
(CNRS) and the Ministere de l’Education Nationale for the financial
`
support. R.R. thanks the Ministere de l’Education Nationale for
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a MENRT fellowship. A.-S.C. is grateful to the ‘Region Provence-
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Giorgi for X-ray crystal structure determination and Dr. A. Archelas
and Dr. A.-L. Bottalla for the chiral GC analysis. We are indebted to
`
´
˜
showed that different substituents at the C
(b) Gonzales-Avion and Mourino
position increased to 4.4 times the affinity of the related calcitriol analogs for
12

R. Rodriguez et al. / Tetrahedron 65 (2009) 7001–7015
7015
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*
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