Synthesis of tetracyclic analogues of calcitriol (1α,25-dihydroxyvitamin D3) with side-chain-locked spatial orientations at C(20)

Article abstract of DOI:10.1002/1522-2675(200210)85:10<3251::AID-HLCA3251>3.0.CO;2-Z

We present our first results on the synthesis of a new class of conformationally restricted vitamin D analogues bearing an extra five-membered ring formed by linking C(18) and C(21). Two analogues of calcitriol (1) with unsaturations at the extra ring and

Full text of DOI:10.1002/1522-2675(200210)85:10<3251::AID-HLCA3251>3.0.CO;2-Z

Helvetica Chimica Acta Vol. 85 (2002)
3251
Synthesis of Tetracyclic Analogues of Calcitriol (1a,25-Dihydroxyvitamin D3)
with Side-Chain-Locked Spatial Orientations at C(20)
by Carmen Varela1), Kristina Nilsson2), Mercedes Torneiro*, and Antonio Mourinƒo*
¬
Departamento de QuÌmica Organica y Unidad Asociada al CSIC, Universidad de Santiago de Compostela,
E-15782 Santiago de Compostela
(e-mail: qomourin@usc.es)
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
We present our first results on the synthesis of a new class of conformationally restricted vitamin D
analogues bearing an extra five-membered ring formed by linking C(18) and C(21). Two analogues of calcitriol
(1) with unsaturations at the extra ring and the lateral chain were prepared. The triene system was introduced by
the convergent WittigÀHorner approach developed by Lythgoe [8] and F. Hoffmann-La Roche [9]. The key
steps in the preparation of the requisite fragments were: i) the long-distance functionalization of ketal 11 at
C(18), ii) the ring closure on 15 through an intramolecular aldol condensation to give the a,b-unsaturated
ketone 10, and iii) the Pd-catalyzed installation of the side chains.
Introduction.
The current interest in the therapeutic properties of calcitriol
(1; vitamin D3 steroid hormone) and some of its analogues results from the ability of
these compounds to control abnormal cellular processes by modulating cell differ-
entiation, inhibiting cell proliferation, and regulating apoptosis [1]. Several analogues
of 1 (2 6) are currently either marketed or in clinical trials for the treatment of skin
diseases and cancer [1n p][2].
OH
R
25
O
H
OH
OH
R=
C
D
16
Calcitriol (1)
22-Oxacalcitriol
EB1089 (3; Leo)
(5; Chugai)
H
OH
OH
OH
A
1 (S)
OH
MC903 (2; Leo)
ILX-23-7553 16-ene
(1S,24R)-1,24-Dihydroxy-
calciol (4; Teijin)
HO
(6; ILEX)
One of our goals is directed toward the development of calcitriol analogues with
high antiproliferative activity against a broad spectrum of cancer cells without causing
significant calcemic effects. It has been postulated that 1 mediates a wide range of
biological effects through a multi-step mechanism that includes binding of the vitamin
1
)
)
Present address: Bayer AG Leverkusen, ZF-LSc-SH, Building Q18, D-51368 Leverkusen.
Present address: Astra Zeneca R&D, Medical Chemistry, S-43183 Mˆlndal.
2

3252
Helvetica Chimica Acta Vol. 85 (2002)
D receptor (VDR), heterodimerization of the VDR with the retinoic X receptor
(RXR), and binding of the VDRÀ1ÀRXR complex to vitamin D responsive element
(VDRE) sequences followed by transcription [3][10]. However, a more-detailed
understanding of the mode of action of the natural hormone 1 is required in order to
rationally design new analogues with selective properties [4].
A few years ago, precise information on the shape of the biologically active
conformation of 1 was unavailable due to problems encountered in the crystallization
of the 1ÀVDR complex. In addition, the study of the shape of the biologically active
conformation of 1 was a difficult task due to the flexibility of the side chain, which can
adopt numerous conformations of similar low-energy values. The gap in knowledge of
structureÀfunction relationships led us to systematically investigate structural
modifications of 1 focusing the improvement of its activity as cancer-cell-growth
inhibitor and as inducer of cancer-cell differentiation. More recently, X-ray-crystallo-
graphic studies have elicited the ligand-binding domain of VDR complexed to 1 and
the plasma vitamin D binding protein (DBP) complexed to calcidiol. These structural
features provide important tools for the design of a new generation of drugs with
selective action [5].
To indirectly study the side-chain shape of the active calcitriol conformation, we
started a research program directed toward the synthesis of analogues of 1 that possess
side chains with locked spatial orientations. Our initial studies began with the synthesis
of calcitriol analogues with either a double bond or the corresponding cyclopropane
ring at C(17)ÀC(20), both of which lock the rotation of the side chain near the five-
membered ring [6]. Some of these analogues were found to improve the biological
profile of the natural vitamin D hormone for potential therapeutic applications, leading
us to synthesize structurally related analogues of 1 with even higher degrees of unsatura-
tion at the side chain [7] as well as a new class of calcitriol analogues with fixed torsion
angles (C(16)ÀC(17)ÀC(20)ÀC(22) or C(16)ÀC(17)ÀC(20)ÀC(22)ÀC(23)ÀC(24)).
As examples of the latter class of compounds, we describe here the synthesis of 7a and
7b, the structures of which are characterized by the presence of an additional five-
membered ring (E) formed by linking C(18) and C(21) and side chains with locked
spatial orientations at C(20).
21
OH
20
18
OH
E
H
H
C
D
H
H
7a
7b
A
1S
OH
HO
OH
HO
General Retrosynthetic Analysis.
Our proposed route for the convergent
synthesis of calcitriol analogues 7 is shown in Scheme 1. The projected approach for
the introduction of the (E)ÀC(7)ˆC(8) bond is based on a WittigÀHorner coupling

Helvetica Chimica Acta Vol. 85 (2002)
3253
Scheme 1
O
R
H
O
H
R
H
O
H
E
C
D
H
H
H
8
O
HO
HO
H
10
11
8a (R' = H)
8b (R' = MOM)
7
7(R' = H)
A
(O)PPh2
Li
HO
OH
Vitamin D2
a, R =
b, R =
OR'
OR'
O
(R)-Carvone
TBSO
OTBS
9
MOM = MeOCH2; TBS = t-BuMe2Si
connecting the calcitriol subunit 8 with the known phosphine oxide anion 9 [1k,m]. This
mild and popular approach to the vitamin D triene system was originally developed by
Lythgoe [8] and subsequently improved by F. Hoffmann-La Roche [9]. It was envisaged
that the ketone fragments 8a and 8b could be prepared from the a,b-unsaturated
ketone 10 according to methods of Sonogashira [10] and Stille [11]. The formation of
the sterically congested tricyclic ketone 10, which is required for the convergent route,
presents a more demanding challenge, particularly with regard to the formation of the
five-membered ring E, which confers great conformational rigidity to the molecule.
Ketal 11 has already been prepared in our laboratory from commercially available
vitamin D2 [12]. On this basis, we proceeded to attempt the synthesis of ketone 10.
Synthesis of the a,b-Unsaturated Ketone 10. Our plan for the construction of 10
involved an intramolecular aldol-type condensation on the masked aldehyde 12
(Scheme 2). Two approaches were then envisaged for the preparation of lactol 12 from
ketal 11. The first approach consisted of a four-step sequence: formation of
intermediate 14 (X ˆ I or AcO) by means of long-distance radical reaction on 11
(Pb(OAc)4, CaCO3, I2, hn) [13][14]3); oxidation of 14 to lactone 13 (CrO3), and
reduction of 13 followed by deprotection to 12. The second option involved formation
of lactol 12 by hydrolysis and deprotection of intermediate 14 (X ˆ AcO). Consider-
ing the possibility of direct formation of lactol acetate 14 (X ˆ AcO) by long-
distance radical functionalization on 11, we initially decided to explore this shorter
route to 12.
3
)
Some authors propose that long-distance radical functionalization provides iodides or lactols as
intermediates [14a,b]. Other authors propose the direct formation of lactol acetates [14c].

3254
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 2
O
O
O
H
HO
O
O
H
H
O
O
H
H
H
HO
10
12
13
O
X
O
O
H
O
H
O
H
H
HO
14 (X = I or OAc)
11
Irradiation of alcohol 11 (Scheme 3) in the presence of Pb(OAc)4, I2, and CaCO3 in
cyclohexane at 808 gave a mixture (ca. 3 :1) of the desired acetates (R)-14 and (S)-14 in
a combined yield of 77%. The stereochemistry at C(10), of the two compounds was
assigned on the basis of the steric interaction between the corresponding AcO group
and the dioxolane ring.
Scheme 3
Interestingly, treatment of this mixture of acetates with a catalytic amount of
pyridinium p-toluenesulfonate in wet acetone induced deketalization to produce,
1
presumably via 12, lactol 15, whose structure was proposed on the basis of H-NMR
data. Lactol 15, which was prone to decomposition in the presence of silica gel, was
immediately treated with t-BuOK to give in an intramolecular aldol condensation

Helvetica Chimica Acta Vol. 85 (2002)
3255
followed by dehydration the key a,b-unsaturated ketone 10 (32% from acetate 14).
Attempts to improve the yield in 10 by following the sequence of reactions shown in
Scheme 4 were unsuccessful, presumably due to the extreme strain imposed by the
tricyclic system. Similar results have recently been obtained during a triquinane-type
synthesis [15].
Scheme 4
O
O
AcO
O
HO
O
H
LiOH, MeOH,
H2O, CH2Cl2
O
H
t-BuOK,
THF
HF/MeCN
or
O
10
12
TsOH
90%
H
H
14
17
Synthesis of Calcitriol Analogues 7a and 7b. Having obtained ketone 10, our
attention turned to the preparation of vinyl triflate 22 (Scheme 5), which is required for
the introduction of the requisite side chains of target analogues 7a and 7b. Silylation of
10 with (t-Bu)Me2SiCl [16] followed by catalytic hydrogenation of the cyclopentene
double bond provided ketone 19 (two steps, 66%). Treatment of 19 with (i-Pr)2NLi and
reaction of the resulting kinetic enolate with N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-
N-(trifluoromethylsulfonyl)methanesulfonamide [17] afforded vinyl triflate 20, which
was converted to ketone 22 by sequential deprotection with HF and oxidation with
pyridinium dichromate [18] (4 steps from 10, 54% overall yield). Pd-Mediated
Sonogashira cross-coupling of vinyl triflate 22 with 2-methyl-4-pentyn-2-ol (23)
afforded the desired ketone 8a in 92% yield. Vinyl triflate 22 was also coupled with
known vinyl stannane 25 [19] under Stille conditions to produce the other fragment 8b
in 66% yield. The fragments 8a and 8b were individually coupled at À788 with
phosphine oxide anion 9 [20] to form stereoselectively the corresponding protected
calcitriol analogues 24 and 26 (86% yield in both cases). These compounds were
deprotected conventionally to the desired calcitriol analogues 7a (88%) and 7b.
Experimental Part
General Methods. All reactions involving oxygen- or moisture-sensitive compounds were carried out under
dry Ar. Reaction temps. refer to external bath temps. All anh. solvents were distilled under Ar immediately
prior to use. THF was distilled from Na/benzophenone, cyclohexane was distilled from LiAlH4, AcOEt and (i-
Pr)2NH were distilled from CaH2, and CH2Cl2 was distilled from P2O5. The anal. grade cation-exchange resin
AG 50W-X40 was supplied by BioRad and was washed with MeOH prior to use. Liquid reagents or solns. of
reagents were added by syringe or cannula. Org. extracts were dried over anh. Na2SO4, filtered, and
concentrated with a rotary evaporator at aspirator pressure (20 30 mmHg). Reactions were monitored by TLC
with aluminium-backed Merck 60 silica-gel plates (0.2 mm); the chromatograms were visualized first with UV
(254 nm) and then by immersion in a soln. of phosphomolybdic acid in MeOH (5%), followed by heating. Flash
column chromatography (FC) [21] was performed with Merck 60 (230 400 mesh) silica gel. M.ps.: measured in
open capillary tubes, uncorrected. NMR Spectra: recorded at 250 (1H) and 63 (13C) MHz, in CDCl3 solns., unless
otherwise stated; chemical shifts (d) in ppm, CDCl3 (7.26 (1H) or 77.0 (13C)) as internal standard; coupling
constants (J) in Hz. Distorsionless Enhancement by Polarization Transfer (DEPT) was used to assign C-atom
types. MS: m/z (rel. %); EI: 70 eV.

3256
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 5
1. (i-Pr)2NLi, THF, –78o
2. Cl
O
H
O
H
OTf
H
H2, Pd/C
AcOEt
N
NTf2
100%
86%
H
H
H
TBSO
X
X
19
HF,
20 (X = OTBS)
21 (X = OH)
TBSCl,
DMF
10 (X=OH)
MeCN
66%
96%
18 (X=OTBS)
OH
PDC,
CH2Cl2
100%
H
OTf
9, THF
H
Bu4NF,
THF
OH
H
–78o
23
7a
8a
88%
Pd(PPh3)4,
Pyrrolidine
86%
H
24
O
22
92%
TBSO
OTBS
OMOM
H
1. Bu4NF, THF
9, THF
–78o
Bu3Sn
2. AG 50W-X4
resin, MeOH
H
OMOM
25
8b
7b
86%
100%
TBSO
Pd(PPh3)4, LiCl
THF, 75o
66%
26
OTBS
MOM = MeOCH2; PDC: pyridinium dichromate, TBS = t-BuMe2Si; Tf = CF3SO2
(1R,2S,5R,6R,10R)- and (1R,2S,5R,6R,10S)-2-(2-Methyl-1,3-dioxolan-2-yl)-11-oxatricyclo[4.3.2.01,5]un-
dec-10-yl Acetate ((R)-14 and (S)-14). A suspension of Pb(OAc)4 (16.6 g, 37.45 mmol, 3 equiv.) and anh.
CaCO3 (3.75 g, 37.45 mmol, 3 equiv.) in anh. cyclohexane (150 ml) was stirred at 808 for 5 min. I2 (4.12 g,
16.22 mmol, 1.3 equiv.) and a soln. of (1S,3aR,4S,7aS)-2,3,3a,4,5,6,7,7a-octahydro-7a-methyl-1-(2-methyl-1,3-
dioxolan-2-yl)inden-4(1H)-ol (11; 3 g, 12.48 mmol, 1 equiv.) in anh. cyclohexane (30 ml) were added. The
stirred violet mixture was irradiated (300-W tungstenlamp) for 3 h and thereupon turned colorless. The mixture
was filtered, and the solid was washed with cyclohexane. The soln. was concentrated under vacuum to half
volume and washed with sat. aq. Na2S2O3 (200 ml) and H2O (150 ml). The combined aq. phase was extracted
with Et2O (2 Â 150 ml). The combined org. phase was dried, filtered, and concentrated under vacuum. FC of the
residue (SiO2, 3 Â 10 cm, AcOEt/hexanes 1:9 3 :7) provided (R)-14 (2 g, 55%; Rf 0.45 (AcOEt/hexanes 4 :6);
colorless oil), and (S)-14 (0.83 g, 22%; Rf 0.52 (AcOEt/hexanes 4 :6); colorless oil).
Data of (R)-14: 1H-NMR: 6.19 (s, HÀC(10)); 4.14 (d, J ˆ 4.5, HÀC(6)); 3.80 (m, OCH2CH2O); 2.40
(dd, J ˆ 13.0, 6.3, HÀC(5)); 2.03 (s, MeCˆO); 1.20 (s, Me). 13C-NMR: 170.2 (C); 110.5 (C); 98.6 (CH);
79.3 (CH); 64.5 (CH2); 63.4 (CH2); 58.0 (CH); 53.8 (CH); 53.7 (C); 33.3 (CH2); 30.9 (CH2); 24.3 (CH2);
‡
‡
24.1 (CH2); 23.8 (Me); 21.0 (Me); 18.2 (CH2). EI-MS: 281 (5, [M À Me] ), 253 (2, [M À Ac] ), 237 (12,
‡
‡
[M À OCH2CH2O] ), 209 (11), 193 (38, [M À OCH2CH2O À Ac] ), 121 (100).

Helvetica Chimica Acta Vol. 85 (2002)
3257
Data of (S)-14: 1H-NMR: 6.11 (s, HÀC(10)); 4.38 (d, J ˆ 4.8, HÀC(6)); 3.85 (m, OCH2CH2O); 2.00
(s, MeCˆO); 1.22 (s, Me). 13C-NMR: 169.3 (C); 110.2 (C); 98.0 (CH); 79.4 (CH); 63.7 (CH2); 63.0 (CH2); 55.7
(C); 55.3 (CH); 54.7 (CH); 34.7 (CH2); 30.9 (CH2); 26.2 (CH2); 24.5 (CH2); 23.5 (Me); 21.3 (Me); 18.2 (CH2).
‡
FAB-MS: 237 (26, [M À AcO] ), 194 (13), 193 (100), 176 (9).
(3aS,5aR,6S,9aR)-3a,4,5,5a,6,7,8,9-Octahydro-6-hydroxycyclopenta[c]inden-3(3H)-one (10). A stirred
soln. of a mixture of (S)- and (R)-14 (2.45 g, 8.35 mmol, 1 equiv.) and pyridinium p-toluenesulfonate 0.43 g,
2.12 mmol, 0.25 equiv.) in wet acetone (120 ml) was refluxed for 2 h. The cooled mixture was concentrated
under vacuum, and the residue was dissolved in Et2O (100 ml) and poured in H2O (75 ml). The aq. phase was re-
extracted with Et2O (2 Â 50 ml). The combined org. phase was dried, filtered, and concentrated under vacuum
to give (1R,3RS,4S,7R,8R,12S)-3-methyl-2,13-dioxatetracyclo[6.5.0.04,8.07,12 ]tridecan-3-ol (15). 1H-NMR: 5.57
(s, HÀC(1)); 4.68 (br. s, HÀC(12)); 1.44 (s, Me).
To a freshly prepared soln. of 15 in anh. THF (110 ml) t-BuOK (1.8 g, 16.01 mmol, 1.9 equiv.) was added.
The mixture was stirred for 10 min, treated with a few drops of H2O and then concentrated under vacuum. The
residue was dissolved in Et2O (60 ml) and washed with sat. aq. NaCl (40 ml). The combined org. phase was
dried, filtered, and concentrated under vacuum. FC of the residue (SiO2, 2 Â 10 cm, AcOEt/hexanes 2 :8 5 :5)
gave 10 (0.51 g, 2% for the two steps; Rf 0.45 (AcOEt/hexanes 6 :4)). Colorless oil. 1H-NMR: 8.20 (d, J ˆ 5.8,
HÀC(1)); 6.02 (d, J ˆ 5.8, HÀC(2)); 4.26 (m, HÀC(6)); 2.21 (br. s, OH); 2.19 (dd, J ˆ 11.6, 1.6, HÀC(3a)).
13C-NMR: 212.5 (C); 171.5 (CH); 132.6 (CH); 67.9 (CH); 55.6 (C); 54.2 (CH); 51.4 (CH); 36.2 (CH2); 33.3
‡
(CH2); 27.7 (CH2); 24.9 (CH2); 18.5 (CH2). FAB-MS: 193 (100, [M ‡ H] ). EI-HR-MS: 192.1150 (calc. for
C12H16O2; found: 192.1144).
(3aS,5aR,6S,9aR)-6-{[(tert-Butyl)(dimethyl)silyl]oxy}-3a,4,5,5a,6,7,8,9-octahydrocyclopenta[c]inden-
3(3H)-one (18). A soln. of 10 (2.1 g, 10.92 mmol, 1 equiv.), t-BuMe2SiCl (2.14 g, 14.20 mmol, 1.3 equiv.), and
1H-imidazole (1.7 g, 25.12 mmol, 2.3 equiv.) in anh. DMF (50 ml) was stirred at 608 for 24 h. The reaction was
quenched by addition of H2O (4 ml), and the resulting mixture was poured in ice-H2O (250 ml). The aq. phase
was extracted with Et2O/hexanes 1:1 (5 Â 100 ml). The combined org. phase was dried, filtered, and
concentrated under vacuum. FC of the residue (SiO2; 3 Â 10 cm, AcOEt/hexanes 1:9 2 :8) afforded 18 (2.19 g,
66%; Rf 0.52 (AcOEt/hexanes 1:4)). White solid. M.p. 70 728. 1H-NMR: 8.20 (d, J ˆ 5.8, HÀC(1)); 6.05
(d, J ˆ 5.8, HÀC(2)); 4.24 (m, HÀC(6)); 2.23 (dd, J ˆ 11.6, 1.7, HÀC(3a)); 0.90 (s, t-Bu); 0.06 (s, MeSi); 0.91
(s, MeSi). 13C-NMR: 212.4 (C); 171.6 (CH); 132.3 (CH); 68.9 (CH); 55.8 (C); 54.3 (CH); 52.1 (CH); 36.3
(CH2); 33.9 (CH2); 27.9 (CH2); 25.8 (Me); 25.5 (CH2); 18.7 (CH2); 18.0 (C); À4.8 (Me); À5.2 (Me). EI-MS:
‡
‡
‡
306 (4, M ), 291 (2, [M À Me] ), 250 (27), 249 (100, [M À t-Bu] ), 157 (18), 129 (16), 91 (13), 75 (44). EI-HR-
MS: 306.2015 (calc. for C18H30O2Si; found: 306.2021). Anal. calc. for C18H30O2Si: C 70.53, H 9.86; found:
C 70.44, H 9.75.
(3aS,5aR,6S,9aR)-6-{[(tert-Butyl)(dimethyl)silyl]oxy}decahydrocyclopenta[c]inden-3(3H)-one (19). A
stirred suspension of 18 (85 mg, 0.28 mmol) and a catalytic amount of Pd/C (5%) in anh. AcOEt (15 ml) was
deoxygenated under vacuum and hydrogenated (balloon pressure) for 2 h. The mixture was filtered (Celite) and
the residue was washed with AcOEt. The combined filtrate was concentrated under vacuum. FC of the residue
(SiO2; 1 Â 7 cm, AcOEt/hexanes 1:9) gave 19 (85 mg, 100%; Rf 0.52 (AcOEt/hexanes)). White solid. M.p. 35
378. 1H-NMR (300 MHz): 4.12 (m, HÀC(6)); 0.89 (s, t-Bu); 0.04 (s, MeSi); 0.02 (s, MeSi). 13C-NMR (75 MHz):
222.8 (C); 68.6 (CH); 59 (CH); 51.8 (CH); 50.7 (C); 37.4 (CH2); 34.2 (CH2); 26.1 (CH2); 26.0 (CH2); 25.8 (Me);
‡
‡
24.9 (CH2); 18.0 (C); 17.6 (CH2); À4.8 (Me); À5.0 (Me). FAB-MS: 309 (37, [M ‡ H] ), 308 (16, [M À OH] ),
‡
‡
291 (64, [M À H2O] ), 251 (14, [M À t-Bu] ), 177 (21), 159 (100). Anal. calc. for C18H32O2Si: C 70.07, H 10.45;
found: C 70.01, H 10.75.
(3aS,5aR,6S,9aR)-6-{[(tert-Butyl)(dimethyl)silyl]oxy}-3a,4,5,5a,6,7,8,9-octahydro-1H-cyclopenta[c]inden-
3-yl Trifluoromethanesulfonate (20). Anh. (i-Pr)2NH (60 ml, 0.44 mmol, 1.5 equiv.) was added dropwise under
stirring to a cold (À 788) soln. of BuLi in hexanes (180 ml, 0.44mmol, 2.4m, 1.5 equiv.). The white solid of (i-
Pr)2NLi was dissolved in anh. THF (1 ml). The soln. was stirred for 10 min, and a soln. of 19 (90 mg, 0.29 mmol,
1 equiv.) in anh. THF (3 ml) was added. The mixture was stirred at À788 for 2 h and than treated with N-(5-
chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (140 mg, 0.35 mmol,
1.2 equiv.). The deep-red mixture was warmed to r.t., and then stirred for 20 min. The reaction was quenched
by addition of a few drops of H2O. The mixture was concentrated under vacuum, and the residue was purified by
FC (SiO2; 1 Â 10 cm, hexanes) to afford 20 (110 mg, 86%; Rf 0.85 (hexanes)). Colorless oil. 1H-NMR: 5.48
(m, HÀC(2)); 4.16 (m, HÀC(6)); 2.83 (d, J ˆ 17.6, HÀC(1)); 2.47 (m, HÀC(3a)); 2.04 (dd, J ˆ 17.6, 2.9,
HÀC(1)); 0.89 (s, t-Bu); 0.04 (s, MeSi); 0.02 (s, MeSi). 13C-NMR: 151 (C); 118.6 (q, J ˆ 320.7, CF3); 116.6 (CH);
68.9 (CH); 52.8 (CH); 51.6 (CH); 51.4 (C); 37.4 (CH2); 35.3 (CH2); 34.4 (CH2); 30.2 (CH2); 27.5 (CH2); 25.8
‡
‡
(Me); 18.0 (C); 17.1 (CH2); À4.9 (Me); À5.1 (Me). FAB-MS: 441 (6, [M ‡ H] ), 440 (10, M ), 439 (36,

3258
Helvetica Chimica Acta Vol. 85 (2002)
‡
‡
‡
‡
[M À H] ), 421 (6, [M À F] ), 383 (19, [M À t-Bu] ), 307 (36, [M À SO2CF3] ), 175 (70), 159 (100), 154 (55),
136 (75),117 (64). Anal. calc. for C19H31F3O4SSi: C 51.82, H 7.05; found: C 52.22, H 7.11.
(3aS,5aR,6S,9aR)-3a,4,5,5a,6,7,8,9-Octahydro-6-hydroxy-1H-cyclopenta[c]inden-3-yl Trifluoromethanesul-
fonate (21). An aq. soln. of HF (48%, 4 drops) was added to a soln. of 20 (65 mg, 0.15 mmol, 1 equiv.) in MeCN
(2 ml). The mixture was stirred for 2 h and then poured in an aq. sat. soln. of NaHCO3 (5 ml). The aq. phase was
extracted with Et2O (3 Â 5 ml). The combined org. phase was dried, filtered, and concentrated under vacuum.
FC of the residue (SiO2; 1 Â 12 cm, AcOEt/hexanes 15 :85) gave 21 (46 mg, 96%; Rf 0.50 (AcOEt/hexanes
3 :7)). Colorless oil. 1H-NMR: 5.46 (m, HÀC(2)); 4.23 (m, HÀC(6)); 2.77 (d, J ˆ 17.4, HÀC(1)); 2.50
(m, HÀC(3a)); 2.12 (dd, J ˆ 17.4, 2.9, HÀC(1)). 13C-NMR: 151.2 (C); 118.6 (q, J ˆ 320.7, CF3); 116.3 (CH); 68.6
(CH); 52.8 (CH); 51.3 (CH); 51.0 (C); 37.3 (CH2); 35.3 (CH2); 33.9 (CH2); 30.3 (CH2); 27.0 (CH2); 17.0 (CH2).
‡
EI-MS: 308 (2, [M À H2O] ), 280 (30), 175 (52), 157 (21), 147 (58), 69 (100). EI-HR-MS: 325.0721 (calc. for
C13H16F3O4S; found: 325.0721).
(3aS,5aR,9aS)-3a,4,5,5a,6,7,8,9-Octahydro-6-oxo-1H-cyclopenta[c]inden-3-yl Trifluoromethanesulfonate
(22). Pyridinium dichromate (80 mg, 0.21 mmol, 4.2 equiv.) and a catalytic amount of pyridinium p-
toluenesulfonate were successively added to a soln. of 21 (15 mg, 0.05 mmol, 1 equiv.) in anh. CH2Cl2
(1.5 ml). The mixture was stirred in the dark for 5 h and then filtered (Celite), and the residue was washed
with AcOEt. The filtrate was concentrated under vacuum, and the residue was purified by FC (SiO2; 1 Â 5 cm,
AcOEt/hexanes 15 :85) to give 22 (14 mg, 100%; Rf 0.60 (AcOEt/hexanes 3 :7)). Colorless oil. 1H-NMR: 5.48
(m, HÀC(2)); 2.83 (d, J ˆ 8.2, HÀC(3a)); 2.58 (dd, J ˆ 12.0, 4.0, HÀC(5a)). 13C-NMR: 210.2 (C); 149.5 (C);
118.5 (q, J ˆ 320.7, CF3); 115.3 (CH); 61.3 (CH); 57.0 (C); 52.5 (CH); 40.6 (CH2); 35.9 (CH2); 34.4 (CH2); 29.9
‡
‡
(CH2); 23.7 (CH2); 23.1 (CH2). EI-MS: 324 (18, M ), 307 (8, [M À OH] ), 192 (20), 191 (100), 163 (40). EI-
HR-MS: 324.0643 (calc. for C13H15F3 O4S; found: 324.0641).
(3aS,5aR,9aS)-3a,4,5,5a,8,9-Hexahydro-3-(4-hydroxy-4-methylpent-1-ynyl)-1H-cyclopenta[c]inden-6(7H)-
one (8a). 2-Methyl-pent-4-yn-2-ol (23; 27 mg, 0.28 mmol, 3 equiv.) and a catalytic amount of Pd(PPh3)4 were
succesively added to a soln. of 22 (30 mg, 0.09 mmol, 1 equiv.) in pyrrolidine (1 ml). The mixture was stirred for
30 min and then poured in a sat. aq. soln. of NH4Cl (7 ml). The aq. phase was extracted with Et2O (3 Â 10 ml).
The combined org. phase was dried, filtered, and concentrated under vacuum. FC of the residue (SiO2; 1 Â
10 cm, AcOEt/hexanes 2 :8 4 :6) 8a (23 mg, 92%; Rf 0.50 (AcOEt/hexanes 1:1)). Colorless oil. 1H-NMR
(300 MHz): 5.78 (m, HÀC(2)); 2.79 (d, J ˆ 8.8, HÀC(3a)); 2.59 (dd, J ˆ 12.2, 4.4, HÀC(14)); 2.51
(s, 2 HÀC(3')); 1.32 (s, 2 Me). 13C-NMR (75 MHz): 211.2 (C); 133.9 (CH); 126.4 (C); 87.1 (C); 79.8 (C);
70.0 (C); 61.5 (CH); 58.6 (C); 58.2 (CH); 40.6 (CH2); 39.3 (CH2); 36.1 (CH2); 34.9 (CH2); 31.3 (CH2); 28.5
‡
(Me); 24.4 (CH2); 22.9 (CH2). EI-MS: 272 (4, M ), 257 (3), 215 (17), 214 (100), 213 (5), 171 (26), 143 (29), 129
(38), 128 (34), 59 (86). EI-HR-MS: 272.1776 (calc. for C18H24O2; found: 272.1768).
(3aS,5aR,9aS)-3a,4,5,5a,8,9-Hexahydro-3-[(1E)-4-(methoxymethoxy)-4-methylpent-1-enyl]-1H-cyclopen-
ta[c]inden-6(7H)-one (8b). A soln. of 22 (25 mg, 0.08 mol, 1 equiv.), tributyl[(E)-4-(methoxymethoxy)-4-
methylpent-1-enyl]stannane (25, 43 mg, 0.10 mmol, 1.25 equiv.), anh. LiCl (33 mg, 0.77 mmol, 9.5 equiv.), and a
catalytic amount of Pd(Ph3P)4 in anh. THF (2 ml) was stirred at 758 for 4 h. The reaction was quenched by
addition of H2O (7 ml). The aq. phase was extracted with Et2O (3 Â 7 ml). The combined org. phase was dried,
filtered, and concentrated under vacuum. The residue was purified by FC (SiO2; 1 Â 13 cm, AcOEt/hexanes
1:9 2 :8) to give 8b (16 mg, 66%; Rf 0.55 (AcOEt/hexanes 3 :7)). Colorless oil. 1H-NMR (300 MHz): 6.12
(d, J ˆ 15.7, HÀC(1')); 5.53 (m, HÀC(2')); 5.38 (br. s, HÀC(2)); 4.73 (s, OCH2O); 3.36 (s, MeO); 2.88
(br. d, J ˆ 9.9, HÀC(3a)); 2.60 (dd, J ˆ 11.5, 4.5, HÀC(5a)); 1.21 (s, 2 MeÀC(4')). 13C-NMR (75 MHz): 211.5
(C); 145.1 (C); 128.8 (CH); 127.2 (CH); 126.2 (CH); 91.0 (CH2); 76.4 (C); 61.3 (Me); 59.6 (C); 55.0 (CH); 54.0
(CH); 45.5 (CH2); 40.9 (CH2); 38.7 (CH2); 36.5 (CH2); 31.6 (CH2); 26.3 (Me); 26.2 (Me); 24.7 (CH2); 23.3
(CH2). EI-MS: 260 (51), 257 (21), 228 (32), 215 (35), 214 (100), 202 (23). EI-HR-MS: 318.2195 (calc. for
C20H30O3; found: 318.2196).
(1S,3R,5Z,7E)-1,3-Bis{[(tert-butyl)(dimethyl)silyl]oxy}-20,21,22,22,23,23-hexadehydro-18,21-cyclo-9,10-
secocholesta-5,7,10(19)-trien-25-ol (24). A soln. of the lithium salt of (2Z)-2-((3S,5R)-3,5-bis{[(tert-butyl)(di-
methyl)silyl]oxy}-2-methylenecyclohexyliden)ethyl(diphenyl)phosphine oxide (9) in THF was prepared by
dropwise addition of a soln. of BuLi in hexanes (0.24 ml, 0.58 mmol) to a cooled (À 788), stirred soln. of 9
(409 mg, 0.70 mmol, 6 equiv.) in anh. THF (6.8 ml). The deep-red soln. was stirred for 1.5 h. To this cold soln. a
soln. of 8a (30 mg, 0.11 mmol, 1 equiv.) in anh. THF (3 ml) was added dropwise. The mixture was stirred in the
dark at À788 for 9 h and at À408 for 1 h. The reaction was quenched by addition of H2O (5 ml) and AcOEt
(10 ml). The aq. phase was extracted with AcOEt (3 Â 5 ml). The combined org. phase was washed with sat. aq.
NaCl (5 ml), dried, filtered, and concentrated under vacuum. The residue was purified by FC (SiO2; 1.5 Â 14 cm,
1
AcOEt/hexanes 1:99 5 :95) to give 24 (60 mg, 86%; Rf 0.50 (AcOEt/hexanes 1:9)). Colorless oil. H-NMR:

Helvetica Chimica Acta Vol. 85 (2002)
3259
6.17, 6.02 (AB, J ˆ 11.3, HÀC(6), HÀC(7)); 5.77 (m, HÀC(21)); 5.19 (m, HÀC(19)); 4.86 (d, J ˆ 2.3,
HÀC(19)); 4.39 (m, HÀC(1)); 4.18 (m, HÀC(3)); 2.76 (m, HÀC(14)); 2.62 (d, J ˆ 9.2, HÀC(17)); 2.51
(s, 2 HÀC(24)); 2.44 (dd, J ˆ 13.3, 3.6, HÀC(18)); 2.21 (dd, J ˆ 13.1, 7.1, HÀC(18)); 2.21 (dd, J ˆ 13.1, 7.1,
HÀC(18)); 1.32 (s, Me(26), Me(27)); 0.88 (s, 2t-Bu); 0.06 (s, 2 Me2Si). 13C-NMR: 148.3 (C); 141.1 (C); 135.5
(C); 135.3 (CH); 127.5 (C); 122.9 (CH); 117.2 (CH); 111.2 (CH2); 86.1 (C); 81.0 (C); 71.9 (CH); 70.1 (C); 67.5
(CH); 58.2 (CH), 56.5 (CH); 55.5 (C); 45.9 (CH2); 44.8 (CH2); 39.8 (CH2); 37.7 (CH2); 35.2 (CH2); 31.9 (CH2);
28.6 (Me); 28.5 (CH2); 25.8 (Me); 25.8 (Me); 25.3 (CH2); 24.4 (CH2); 18.2 (C); 18.1 (C); À4.6 (Me); À4.7
(Me); À4.8 (Me); À5.1 (Me).
(1S,3R,5Z,7E)-20,21,22,22,23,23-Hexadehydro-18,21-cyclo-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol
(7a). A soln. of 24 (50 mg, 0.08 mmol, 1 equiv.) in anh. THF (9 ml) was treated with a soln. of Bu4NF in THF
(1m, 2 ml, 2 mmol, 25 equiv.). The mixture was stirred in the dark for 9 h. The reaction was quenched by addition
of sat. aq. NH4Cl (20 ml). The aq. phase was extracted with AcOEt (3 Â 10 ml). The combined org. phase was
dried, filtered, and concentrated under vacuum. FC of the residue (SiO2; 1 Â 10 cm, AcOEt/hexanes 2 :3 4 :1)
1
gave 7a (23 mg, 88%; Rf 0.60 (AcOEt)). White solid. H-NMR: 6.31, 6.02 (AB, J ˆ 11.3, HÀC(6), HÀC(7));
5.77 (m, HÀC(21)); 5.32 (m, HEÀC(19)); 4.99 (m, HZÀC(19)); 4.43 (m, HÀC(1)); 4.23 (m, HÀC(3)); 2.77
(m, HÀC(14)); 2.60 (m, HÀC(17), HÀC(18)); 2.50 (s, 2 HÀC(24)); 2.31 (dd, J ˆ 13.3, 6.3, HÀC(18)); 1.32
(s, Me(26), Me(27)). 13C-NMR: 147.6 (C); 143.2 (C); 135.2 (CH); 133.4 (C); 127.5 (C); 124.6 (CH); 116.3 (CH);
111.7 (CH2); 86.2 (C); 80.9 (C); 70.6 (C); 70.1 (CH); 66.8 (CH); 58.2 (CH); 56.5 (CH); 55.6 (C); 45.1 (CH2);
42.8 (CH2); 39.8 (CH2); 37.6 (CH2); 35.1 (CH2); 31.9 (CH2); 28.7 (Me); 28.6 (CH2); 25.4 (CH2); 24.5 (CH2). EI-
‡
MS: 408 (6, M ), 391 (11), 390 (16), 372 (14), 279 (17), 171 (11), 167 (30), 149 (100). EI-HR-MS: 408.2664
(calc. for C27H36O3; found: 408.2681).
(1S,3R,5Z,7E,22E)-3-[(tert-Butyl)(dimethyl)silyl]oxy-20,21,22,23-tetradehydro-25-(methoxymethyoxy)-
18,21-cyclo-9,10-secocholesta-5,7,10(19)-trien-1-yl (tert-Butyl)(dimethyl)silyl Ether (26). A soln. of the lithium
salt of 9 in THF was prepared by the dropwise addition of a soln. of BuLi in hexanes (0.16 ml, 0.40 mmol) to a
cooled (À 788), stirred soln. of 9 (290 mg, 0.50 mmol, 3 equiv.) in anh. THF (4.8 ml). The deep-red soln. was
stirred for 2 h. To this cold soln. was added dropwise a soln. of 8b (50 mg, 0.17 mmol, 1 equiv.) in anh. THF
(6 ml). The mixture was stirred in the dark at À788 for 4 h and at À408 for 1 h. The reaction was quenched by
addition of H2O (5 ml) and AcOEt (10 ml). The aq. phase was extracted with AcOEt (3 Â 5 ml). The combined
org. phase was washed with sat. aq. NaCl (5 ml), dried, filtered, and concentrated under vacuum. The residue
was purified by FC (SiO2; 1.5 Â 9 cm, AcOEt/hexanes 1:99 5 :95) to give 26 (97 mg, 86%; Rf 0.50 (AcOEt/
hexanes 1:9)). Colorless oil. 1H-NMR: 6.12 (m, HÀC(6), HÀC(7), HÀC(22)); 5.53 (m, HÀC(23)); 5.39
(m, HÀC(21)); 5.20 (m, HÀC(19E)); 4.88 (m, HÀC(19Z)); 4.75 (s, OCH2O); 4.39 (m, HÀC(1)); 4.19
(m, HÀC(3)); 3.38 (s, MeO); 2.76 (m, HÀC(17), HÀC(14)); 2.44 (dd, J ˆ 13.3, 3.3, HÀC(18)); 2.22 (dd, J ˆ
13.3, 6.9, HÀC(18)); 1.23 (s, Me(26), Me(27)); 0.89 (s, t-Bu); 0.88 (s, t-Bu); 0.07 (s, Me2Si); 0.06 (s, Me2Si).
13C-NMR: 148.4 (C); 145.4 (C); 141.4 (C); 135.2 (C); 129.3 (CH); 127.3 (CH); 126.4 (CH); 123.0 (CH); 116.8
(CH); 111.1 (CH2); 91.0 (CH2); 71.8 (CH); 67.5 (CH); 56.2 (C); 56.1 (CH); 55.1 (CH); 53.7 (CH); 45.9 (CH2);
45.5 (CH2); 44.8 (CH2); 39.1 (CH2); 38.0 (CH2); 32.1 (CH2); 28.6 (CH2); 26.3 (Me); 26.2 (Me); 25.8 (Me); 25.8
(Me); 25.7 (CH2); 24.5 (CH2); 18.3 (C); 18.1 (C); À4.7 (Me); À4.8 (Me); À5.1 (Me).
(1S,3R,5Z,7E,22E)-20,21,22,23-tetradehydro-18,21-cyclo-9,10-secocholesta-5,7,10(19)-triene-1,3-diol (7b).
A soln. of 26 (45 mg, 0.07 mmol, 1 equiv.) in anh. THF (10 ml) was treated with a soln. of Bu4NF in THF
(1m, 1.5 ml, 1.5 mmol, 21 equiv.). The mixture was stirred in the dark for 15 h. The reaction was quenched by
addition of sat. aq. NH4Cl (20 ml). The aq. phase was extracted with AcOEt (3 Â 10 ml). The combined org.
phase was dried, filtered, and concentrated under vacuum. The residue was diluted with anh. MeOH (15 ml) and
treated with cationic resin AG 50W-X4 (800 mg). The mixture was stirred in the dark for 3 h and then filtered.
The solids were washed with anh. AcOEt (4 Â 20 ml). The soln. was concentrated under vacuum, and the
residue was purified by FC (SiO2; 1.5 Â 10 cm, AcOEt/hexanes 2 :8 7:3) to give 7b (27 mg, 100%; Rf 0.50
(AcOEt/hexanes 8 :2)). White solid. 1H-NMR: 6.33, 6.03 (AB, J ˆ 11.3, HÀC(6), HÀC(7)); 6.17 (d, J ˆ 15.7,
HÀC(22), 5.53 (m, HÀC(23)); 5.42 (m, HÀC(21)); 5.32 (m, HÀC(19E)); 5.00 (m, HÀC(19Z)); 4.42
(m, HÀC(1)); 4.22 (m, HÀC(3)); 2.76 (m, HÀC(17), HÀC(14)); 2.58 (dd, J ˆ 13.3, 3.1, HÀC(18)); 2.34
(dd, J ˆ 13.3, 6.4, HÀC(18)); 2.25 (d, J ˆ 7.5, 2 HÀC(24)); 1.22 (s, Me(26), Me(27)). 13C-NMR: 147.6 (C); 145.2
(C); 143.4 (C); 133.2 (C); 130.4 (CH); 127.8 (CH); 125.8 (CH); 124.7 (CH); 116.0 (CH); 111.6 (CH2); 70.9
(CH); 70.6 (C); 66.8 (CH); 56.4 (C); 56.0 (CH); 53.7 (CH); 47.2 (CH2); 45.1 (CH2); 42.8 (CH2); 39.1 (CH2); 37.8
‡
(CH2); 32.0 (CH2); 29.2 (Me); 29.1 (Me); 28.8 (CH2); 25.8 (CH2); 24.6 (CH2). EI-MS: 410 (4 M ), 393 (16), 392
(49), 374 (18), 334 (26), 200 (30), 155 (39), 129 (42), 59 (100). EI-HR-MS: 410.2820 (calc. for C27H38O3; found:
410.2820).

3260
Helvetica Chimica Acta Vol. 85 (2002)
We are grateful to the DIGICYT (Spain, projects SAF 92-0572, 95-0878 and PM97-0166) for financial
support and to Solvay Pharmaceuticals (Weesp, The Netherlands) for a gift of starting materials. C. V. thanks the
Spanish MEC for an FPI research grant. K. N. thanks the Swedish National Board for Industrial and Technical
Development (NUTEK) and the Spanish MEC for research grants. Mr. Juan Muras is acknowledged for
technical assistance.
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Received June 5, 2002