Synthesis of vitamin D3 and calcitriol dimers as potential chemical inducers of vitamin D receptor dimerization

Article abstract of DOI:10.1021/jo001084x

The design and synthesis of vitamin D₃ dimers 2 and 3 and, 1α,25-dihydroxyvitamin D₃ (calcitriol) dimers 4 and 5 are described. The dimers were designed with a view to doubly binding the vitamin D receptor (VDR) and inducing the receptor homodimerization. In the dimers the units are linked through the C-11 position in ring C by an alkyl side chain of six or 10 carbon atoms, far from the hydroxy groups responsible for the VDR binding. The linker is formed by olefin metathesis of an olefinic side chain at the C-11 position introduced by stereoselective cuprate addition. The syhthesis, which is both short and convergent, uses the Wittig-Horner approach to construct the vitamin D triene system and allows the preparation of dimers with a linker of modulated length with the purpose of optimizing the vitamin D₃-VDR interaction.

Full text of DOI:10.1021/jo001084x

8290
J . Org. Chem. 2000, 65, 8290-8296
Syn th esis of Vita m in D3 a n d Ca lcitr iol Dim er s a s P oten tia l
Ch em ica l In d u cer s of Vita m in D Recep tor Dim er iza tion
J ose´ Pe´rez Sestelo,† Antonio Mourin˜o,‡ and Luis A. Sarandeses*,†
Departamento de Quı´mica Fundamental, Universidade da Corun˜a, E-15071 A Corun˜a, Spain, and
Departamento de Quı´mica Orga´nica y Unidad Asociada al C.S.I.C., Universidade de Santiago de
Compostela, E-15706 Santiago de Compostela, Spain
qfsarand@udc.es
Received J uly 17, 2000
The design and synthesis of vitamin D3 dimers 2 and 3 and 1R,25-dihydroxyvitamin D3 (calcitriol)
dimers 4 and 5 are described. The dimers were designed with a view to doubly binding the vitamin
D receptor (VDR) and inducing the receptor homodimerization. In the dimers the units are linked
through the C-11 position in ring C by an alkyl side chain of six or 10 carbon atoms, far from the
hydroxy groups responsible for the VDR binding. The linker is formed by olefin metathesis of an
olefinic side chain at the C-11 position introduced by stereoselective cuprate addition. The synthesis,
which is both short and convergent, uses the Wittig-Horner approach to construct the vitamin D
triene system and allows the preparation of dimers with a linker of modulated length with the
purpose of optimizing the vitamin D3-VDR interaction.
In tr od u ction
Vitamin D3 (1a ), through its hormonally active form
1R,25-(OH)2-vitamin D3 (calcitriol, 1c), is responsible for
a broad-ranging of biological activity that includes the
regulation of calcium and phosphorus metabolism, the
promotion of cellular differentiation processes, the inhibi-
tion of the proliferation of various tumor cells and some
functions related to the immune system.1 The biological
activity of vitamin D3 is associated with the interaction
of calcitriol with the vitamin D3 protein receptor (VDR),
a member of the nuclear receptor superfamily,2 through
a genomic pathway. Calcitriol interacts with the DNA
in the cell nucleus as a complex with the VDR and this
activates the signal transduction processes. During the
interaction, the VDR can exist as a homodimer (VDR-
VDR) or as a heterodimer with the retinoid X receptor
(VDR-RXR).3 The synthesis of vitamin D3 analogues that
can selectively induce the homo- or heterodimerization
of the VDR is of interest to understand the role of dimeric
VDR structures in the activation of gene transcription.4
which leads to the activation of different signal trans-
duction pathways by proximity or allosteric interac-
tions.5,6 These compounds have been coined by Schreiber
and Crabtree as chemical inducers of dimerization
(CIDs)7 and representative examples are the dimers of
the immunosuppressive agents FK506 (FK1012) and
cyclosporin A [(CyA)2], which are able to activate several
cellular processes such apoptosis.8 Molecular dimers have
also been useful to produce selective chemical responses
in the case of phorbol9 and to study divalent interactions
in other structures such as cyclodextrins10 or vancomy-
cin.11 In the vitamin D research area we envisioned the
synthesis of vitamin D3 dimers as chemical inducers of
VDR homodimerization with a view to exploring and
It has recently been shown that dimeric molecular
ligands with the ability to bind two protein receptors
simultaneously can induce the receptor’s dimerization,
(4) (a) Cheskis, B.; Lemon, B. D.; Uskokovic, M.; Lomedico, P. T.;
Freedman, L. P. Mol. Endocrinol. 1995, 9, 1814. (b) Forman, B. M.;
Umesono, K.; Chen, J .; Evans, R. M. Cell 1995, 81, 541. (c) Freedman,
L. P.; Arce, V.; Pe´rez Ferna´ndez, R. Mol. Endocrinol. 1994, 8, 265.
(5) Spencer, D. M.; Wandless, T. J .; Schreiber, S. L.; Crabtree, G.
R. Science 1993, 262, 1019.
(6) Austin, D. J .; Crabtree, G. R.; Schreiber, S. L. Chem. Biol. 1994,
1, 131.
(7) (a) Diver, S. T.; Schreiber, S. L. J . Am. Chem. Soc. 1997, 119,
5106. (b) Ho, S. N.; Biggar, S. R.; Spencer, D. M.; Schreiber, S. L.;
Crabtree, G. R. Nature 1996, 382, 822. (c) Schultz, L. W.; Clardy, J .
Bioorg. Med. Chem. Lett. 1998, 8, 1.
(8) (a) Pruschy, M. N.; Spencer, D. M.; Kapoor, T. M.; Miyaki, H.;
Crabtree, G. R.; Schreiber, S. L. Chem. Biol. 1994, 1, 163. (b) Belshaw,
P. J .; Spencer, D. M.; Crabtree, G. R.; Schreiber, S. L. Chem. Biol. 1996,
3, 731.
(9) (a) Sodeoka, M.; Arai, M. A.; Adachi, K.; Uotsu, K.; Shibasaki,
M. J . Am. Chem. Soc. 1998, 120, 457. (b) Wender, P. A.; Koehler, M.
F. T.; Wright, D. L.; Irie, K. Synthesis 1999, 1401.
† Universidade da Corun˜a.
‡ Universidade de Santiago de Compostela.
(1) For general reviews of vitamin D chemistry and biology, see: (a)
Vitamin D: Chemistry, Biology and Clinical Applications of the Steroid
Hormone; Norman, A. W., Bouillon, R., Thomasset, M., Eds.; Vitamin
D Workshop, Inc.: Riverside, CA, 1997. (b) Zhu, G.-D.; Okamura, W.
H. Chem. Rev. 1995, 95, 1877. (c) Vitamin D; Feldman, D., Glorieux,
F. H., Pike, J . W., Eds.; Academic Press: San Diego, 1997. (d) Bouillon,
R.; Okamura, W. H.; Norman, A. W. Endocr. Rev. 1995, 16, 200. (e)
Calverley, M. J .; J ones, J . In Antitumor Steroids; Blickenstaff, R. T.,
Ed.; Academic Press: San Diego, 1992; Chapter 7, p 193-270. (e)
Norman, A. W.; Litwack, G. Hormones; Academic Press: San Diego,
1997. (f) Walters, M. R. Endocr. Rev. 1992, 13, 719.
(2) Mangelsdorf, D. J .; Thummel, C.; Beato, M.; Herrlich, P.; Schu¨tz,
G.; Umesono, K.; Blumberg, B.; Kastner, P.; Mark, M.; Chambon, P.;
Evans, R. M. Cell 1995, 83, 835.
(3) (a) Freedman, L. P.; Lemon, B. D. In Vitamin D; Feldman, D.,
Glorieux, F. H., Pike, J . W., Eds.; Academic Press: San Diego, 1997;
Chapter 9, pp 127-148 and references therein. (b) Carlberg, C. Eur.
J . Biochem. 1995, 231, 517. (c) Carlberg, C. Endocrine 1996, 4, 91.
(10) Breslow, R.; Zhang, B. J . Am. Chem. Soc. 1996, 118, 8495.
(11) Rao, J .; Whitesides, G. M. J . Am. Chem. Soc. 1997, 119, 10286.
10.1021/jo001084x CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/01/2000

Synthesis of Vitamin D3 and Calcitriol Dimers
J . Org. Chem., Vol. 65, No. 24, 2000 8291
Sch em e 1
possibly exploiting their role in transcription control. In
this, a full account,12 we report in detail the synthesis of
dimeric vitamin D3 and calcitriol structures linked through
the C-11 position by a carbon side chain of modulated
size.
by cuprate addition to a suitable enone.15 This strategy
serves to incorporate side chains of different lengths, to
optimize the protein binding. The synthesis was focused
toward vitamin D3 dimers (2 and 3) and calcitriol dimers
(4 and 5) with variable linker lengths (n ) 1 and 3). A
vitamin D dimer could be transformed into calcitriol
dimer in the metabolic route. The retrosynthetic analysis
is depicted in Scheme 1. Route A involves dimerization
by metathesis of vitamin D3 analogue 6 conveniently
functionalized at C-11. The vitamin D triene unit is
formed by a Wittig-Horner reaction16 between ketone 8
which contains the C-D fragment and the anion of
phosphine oxide 917 or 1018 which contains the A ring.
The alternative route B involves direct Wittig-Horner
coupling of dimeric ketone 7 with the anion of phosphine
oxide 9 or 10. The dimeric ketone 7 can be prepared by
olefin metathesis of ketone 8 and subsequent hydrogena-
tion.
Resu lts a n d Discu ssion
In the design of vitamin D3 dimeric structures that
could be capable of doubly binding the VDR, we consid-
ered some essential structure/function relationships: (a)
the hydroxy groups at the C-3, C-1R and C-25 positions
are part of the VDR binding domain,1e (b) the triene
system is a fundamental structural feature,13 and (c) the
introduction of polar groups dramatically alters the
biological activity.1d In addition, we reasoned that the
linker should be sufficiently flexible to permit complete
interaction of each monomer with the VDR. For this
reason, we were interested in a synthetic route that
would allow the preparation of linkers of variable length
to optimize the binding with the VDR. In the past,
different types of linkers have been used for the prepara-
tion of molecular dimers and these include a carbamate
bond formed by reaction of a free hydroxy group with
p-xylylenediamine and phosgene in the dimer of cy-
closporine,4 an ester group formed by a hydroxy group of
phorbol and a diacid of variable length,7 or a carbon-
carbon bond from metathesis of a terminal olefin, e.g.,
in FK1012.14
With these findings in mind, and considering the
absence of functionality in the vitamin D structure to
effect a direct dimerization, we envisaged the synthesis
of a dimeric vitamin D3 molecule consisting of two
moieties linked by a carbon chain attached to each
calcitriol at ring C, thus providing a nonpolar linker
attached far from the hydroxy groups responsible in the
interaction with the VDR.1e The linker could be made by
metathesis of a terminal olefin conveniently inserted at
the C-11 position. The C-11 position can be functionalized
Syn th esis of Vita m in D3 Dim er s. In our synthetic
venture, we first decided to explore route A to prepare a
dimer of vitamin D3 (1a ). The synthesis starts with
Grundmann’s ketone 11 (Scheme 2),19 which was con-
verted to enone 1220 (80% yield) by known procedures.15a,c
Treatment of 12 with the cuprate prepared from 4-bromo-
1-butene by treatment with t-BuLi and the complex CuI/
n-Bu3P at -78 °C, gave 13 in high yield (85%) as a single
1
stereoisomer, as detected by H NMR spectroscopy. The
conjugate addition of the cuprates derived from 6-bromo-
1-hexene or bromoethylene to enone 12 led to the
stereoselective formation of ketones 14 and 15 (95% and
85% yields, respectively). These compounds possess,
respectively, olefinic side chains two carbons longer and
two carbons shorter than in 13.
(15) (a) Torneiro, M.; Fall, Y.; Castedo, L.; Mourin˜o, A. Tetrahedron
Lett. 1992, 33, 105. (b) D’Halleweyn, C.; Van Haver, D.; Van der
Eycken, J .; De Clerq, P.; Vandewalle, M. Bioorg. Med. Chem. Lett.
1992, 2, 477. (c) Torneiro, M.; Fall, Y.; Castedo, L.; Mourin˜o, A.
Tetrahedron 1997, 53, 10851.
(16) (a) Lythgoe, B.; Moran, T. A.; Nambudiry, M. E. N.; Ruston,
S.; Tideswell, J .; Wright, P. W. Tetrahedron Lett. 1975, 3863. (b)
Lythgoe, B. Chem. Soc. Rev. 1981, 449.
(12) For
a
preliminary communication, see: Pe´rez Sestelo, J .;
(17) Toth, H. T.; Okamura, W. H. J . Org. Chem. 1983, 48, 1414.
(18) Mourin˜o, A.; Torneiro, M.; Vitale, C.; Ferna´ndez, S.; Pe´rez
Sestelo, J .; Anne´, S.; Gregorio, C. Tetrahedron Lett. 1997, 38, 4713.
(19) Windaus, A.; Grundmann, W. Liebigs Ann. Chem. 1936, 524,
295.
Mourin˜o, A.; Sarandeses, L. A. Org. Lett. 1999, 1, 1005.
(13) Bouillon, R.; Sarandeses, L. A.; Allewaert, K.; Zhao, J .; Mas-
caren˜as, J . L.; Mourin˜o, A.; Vrielynck, S.; De Clercq, P.; Vandewalle,
M. J . Bone Miner. Res. 1993, 8, 1009.
(14) Clark, T. D.; Gadhiri, M. R. J . Am. Chem. Soc. 1995, 117, 12364
and ref 7a.
(20) Okamura, W. H.; Aurrecoechea, J . M.; Gibbs, R. A.; Norman,
A. W. J . Org. Chem. 1989, 54, 4072.

8292 J . Org. Chem., Vol. 65, No. 24, 2000
Pe´rez Sestelo et al.
Sch em e 2
Sch em e 4
Having obtained the C-11 functionalized ketones 13-
15, we proceeded to construct the vitamin D triene
system following approach A. Wittig-Horner reaction of
13 (Scheme 3) with the anion derived from treatment of
phosphine oxide 9 with n-BuLi at -78 °C afforded the
vitamin D3 analogue 16 in 86% yield. Treatment of 16
with a catalytic amount of the ruthenium carbene (Cy3P)2-
Cl2RuCHPh (10 mol %)21 at room temperature for 4 h
gave the dimer 18 (with loss of ethylene) as a mixture of
geometric isomers along with unreacted vitamin 16 in a
1:1 ratio. It was gratifying to see that the labile vitamin
D triene system survives the olefin metathesis reaction.
Treatment of the mixture 16-18 with n-Bu4NF (TBAF)
allowed the isolation of the vitamin D3 dimer 19 in 74%
yield (two steps) as a mixture of geometric isomers (8:1
ratio), and vitamin 17 in 18% yield. Unfortunately,
attempts to selectively hydrogenate the nonconjugate
double bond in 19 using different catalysts and reaction
conditions led to saturated products. Despite this prob-
lem, this synthetic route allowed us to synthesize 19 as
the first known vitamin D3 dimer.
Sch em e 3
lyst21 (10 mol %) at room temperature for 24 h gave the
dimeric ketone 20 in 63% yield as a mixture of geometric
isomers without any detectable epimerization at C-14 by
1H NMR. The recovered unreacted ketone 13 (30%) was
again submitted to olefin metathesis. The ratio of 20
isomers varies from 2:1 to 8:1 depending on the concen-
tration and temperature used. Similarly, metathesis of
ketone 14, with an olefinic side chain two carbons longer,
afforded dimeric ketone 21 in similar yield and stereo-
selectivity. Interestingly, when vinyl ketone 15 (Scheme
2) was subjected to the same olefin metathesis reaction
conditions, the reaction failed leading to the recovery of
starting material presumably due to steric hindrance.
Hydrogenation of dimeric ketone 20 at atmospheric
pressure in the presence of catalytic amounts of Rh/Al2O3
(5 wt %) for 12 h gave 22 in 91% yield. Wittig-Horner
reaction between ketone 22 and the anion generated by
treatment of phosphine oxide 10 (4.0 equiv) with n-BuLi
at -78 °C, provided the protected vitamin 24 in 85%
yield. Desilylation of 24 with n-Bu4NF (3 equiv), in the
absence of light, at room temperature for 24 h gave the
desired vitamin D3 dimer 2 (90%). Following the same
protocol as for 2, vitamin D3 dimer 3 was prepared in
three steps from dimeric ketone 21 in 82% overall yield.
These results led us to explore route B (Scheme 1), as
an alternative way to prepare our target compounds 2-5.
Treatment of ketone 13 (Scheme 4) with Grubbs cata-
Syn th esis of Ca lcitr iol Dim er s. Bearing in mind the
experience gained during the preparation of the vitamin
(21) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100.

Synthesis of Vitamin D3 and Calcitriol Dimers
J . Org. Chem., Vol. 65, No. 24, 2000 8293
Sch em e 5
linked at the C-11 position, far from the hydroxy groups
involved in the VDR binding, with an alkyl chain of
modulated length with the purpose of optimizing the
calcitriol-VDR interaction. The synthetic strategy, which
is both short and convergent, uses the Wittig-Horner
approach for the construction of the vitamin D triene
system, a stereoselective cuprate addition and a key
ruthenium olefin metathesis for the linker construction.
This work opens the door to new vitamin D homo- and
heterodimers.
Exp er im en ta l Section
Gen er al Mater ials an d Meth ods. Unless otherwise stated,
all reactions were conducted in flame-dried glassware under
a positive pressure of argon. Reaction temperatures refer to
external bath temperatures. All dry solvents were distilled
under argon immediately prior to use. Tetrahydrofuran (THF)
and ether (Et2O) were distilled from the sodium ketyl of
benzophenone. Dichloromethane (CH2Cl2) and acetonitrile
were distilled from P2O5. For the metathesis reactions
CH2Cl2 was degassed and filtered through basic alumina prior
to use. (Cy3P)2Cl2RuCHPh was purchased from Strem Chemi-
cals and used directly. Absolute MeOH was distilled from Mg
turnings. Copper iodide was purified by recrystallization from
saturated potasium iodide solution.25 Organic extracts were
dried over anhydrous MgSO4, filtered, and concentrated using
a rotary evaporator at aspirator pressure (20-30 mmHg). For
reactions where a component was added by cannula, the total
volume of solvent is given. Usually the compound was dis-
solved in 80% of that volume and the flask was then rinsed
with the remaining 20% of fresh solvent. Thin-layer chroma-
tography was effected on silica gel 60 F254 (layer thickness 0.2
mm) and components were located by observation under UV
light and/or by treating the plates with a phosphomolybdic acid
or p-anisaldehyde reagent followed by heating. Flash column
chromatography was performed on silica gel 60 (230-400
mesh) by Still’s method.26 1H NMR spectra were recorded on
a 200 MHz spectrometer and 13C NMR spectra at 50 MHz.
11r-(3-Bu ten -1-yl)-d e-A,B-ch olesta n -8-on e (13). A solu-
tion of 4-bromo-1-butene (145 µL, 1.43 mmol) in Et2O (3 mL)
was added dropwise over a 15 min period to a cooled (-85 °C)
solution of t-BuLi (1.7 mL, 1.75 M). After 40 min of stirring, a
solution of the complex CuI/n-Bu3P in Et2O [previously pre-
pared by addition of n-Bu3P (176 µL, 0.72 mmol) to a solution
of CuI (137 mg, 0.72 mmol) in Et2O (4 mL) at room temper-
ature] was transferred by cannula into the reaction mixture.
The mixture was warmed to -50 °C during 1 h and cooled to
-78 °C, and a solution of the enone 12 (94 mg, 0.36 mmol) in
Et2O (5 mL) was added by cannula over a 10 min. The reaction
was allowed to reach -20 °C (1 h) and quenched with a few
drops of a saturated solution of NH4Cl. The mixture was
poured into a separatory funnel with Et2O (50 mL), washed
with a saturated solution of NH4Cl (30 mL), and the organic
phase was dried, filtered and concentrated in vacuo. The
residue was purified by flash chromatography (2% AcOEt/
hexanes) to give 97 mg of ketone 13 [85%, Rf ) 0.4 (10% AcOEt/
hexanes), colorless oil]: [R]27D ) +21.5 (c 0.6, CHCl3); IR (neat)
3020, 2950, 1750, 1425 cm-1; 1H NMR (CDCl3) δ 0.64 (s, 3H),
0.87 (d, J ) 6.4 Hz, 6H), 0.97 (d, J ) 5.9 Hz, 3H), 2.40 (m,
2H), 4.95 (d, J ) 13.2 Hz, 1H), 5.02 (d, J ) 17.1 Hz, 1H), 5.78
(ddt, J ) 17.1, 13.2, 6.8 Hz, 1H); 13C NMR (CDCl3) δ 13.2, 18.5,
18.7, 22.3, 22.6, 24.0, 27.5, 27.7, 31.2, 35.3, 35.7, 35.8, 36.6,
39.4, 46.2, 47.5, 49.1, 56.6, 61.9, 114.8, 138.3, 211.3; MS (EI,
70 eV) m/z 318 (M+, 6); HRMS calcd for C22H38O 318.2923 (M+),
found 318.2913.
D3 dimers, we focused our efforts on the preparation of
calcitriol dimers following approach B. The synthesis of
dimers 4 and 5 (Scheme 1) requires the introduction of
C-25 and C-1R hydroxyl groups. The synthesis starts with
known ester 26 (Scheme 5).22 Addition of MeLi (3 equiv),
followed by oxidation with PDC and protection with Et3-
SiOTf (TESOTf) at -78 °C, afforded ketone 2823 (86%
three steps) (Scheme 5). Treatment of 28 under Saegusa
reaction conditions,15a,c,24 led to the formation of enone
29 in 84% yield. Stereoselective conjugate addition of the
respective cuprates derived from 4-bromo-1-butene and
6-bromo-1-hexene to enone 29 afforded ketones 30 or 31
in high yield (84-94%) as the only stereoisomers detected
1
by H NMR. Olefin metathesis of 30 or 31 with Grubbs
catalyst in CH2Cl2 at room temperature for 24 h afforded
the dimeric ketones 32 or 33 as a mixture of geometric
1
isomers without detectable epimerization at C-14 by H
NMR. As above, the stereoselectivity observed in the
reaction products (2:1 to 8:1) depends on the reaction
conditions such as concentration and temperature. The
mixture of isomers was converted to a single product (34
or 35) in 89-94% yield by catalytic hydrogenation at
atmospheric pressure using Rh/Al2O3 (5 wt %).
With the dimeric ketones 34 and 35 in hand, we
proceeded to the stereoselective construction of the
vitamin D triene system (Scheme 4). A double Wittig-
Horner reaction of 34 with the anion formed from the
1R-hydroxylated phosphine oxide 10 (3.0 equiv), gave
protected dimer 36 in 71% yield. Removal of the six silyl
protecting groups of 36, in the absence of light, with
n-Bu4NF (9 equiv) in THF at room temperature during
24 h afforded calcitriol dimer 4 in 67% yield. Calcitriol
dimer 5 was prepared as above by Wittig-Horner reac-
tion of 35 with the anion of 10 followed by one step
deprotection with n-Bu4NF (40% two steps). Overall, the
synthesis of the first known calcitriol dimers 4 and 5 were
achieved from known ketone 28 in six steps and 25%
overall yield.
Con clu sion s
We have designed and synthesized the first generation
of vitamin D3 and calcitriol dimers. The moieties are
11r-(5-Hexen -1-yl)-d e-A,B-ch olesta n -8-on e (14). Follow-
ing the same experimental procedure as for 13, enone 12 (183
mg, 0.70 mmol) was treated with the cuprate prepared from
6-bromo-1-hexene (0.37 mL, 2.79 mmol), t-BuLi (1.69 mL, 1.65
(22) Mascaren˜as, J . L.; Pe´rez Sestelo, J .; Castedo, L.; Mourin˜o, A.
Tetrahedron Lett. 1991, 32, 2813.
(23) Sicinski, R. R.; Perlman, K. L.; DeLuca, H. F. J . Med. Chem.
1994, 37, 3730.
(24) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011.
(25) Kauffman, G. B.; Teter, L. A. Inorg. Synth. 1963, 7, 9.
(26) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

8294 J . Org. Chem., Vol. 65, No. 24, 2000
Pe´rez Sestelo et al.
M), and CuI (218 mg, 1.15 mmol) to give, after purification by
(d, J ) 6.4 Hz, 12H), 0.96 (d, J ) 5.4 Hz, 6H), 2.39 (m, 4H),
5.38 (t, J ) 3.6 Hz, 2H); 13C NMR (CDCl3) δ 13.2, 18.8, 18.9,
22.5, 22.8, 23.7, 27.8, 28.0, 30.0, 35.5, 35.9, 36.0, 37.2, 39.4,
46.2, 47.6, 49.2, 56.5, 61.9, 130.1, 211.5; MS (EI, 70 eV) m/z
609 (M+ + 1, 3) 608 (M+, 7), 173 (100); HRMS calcd for
flash chromatography (2% AcOEt/hexanes), 229 mg of 14 [95%,
Rf ) 0.5 (15% AcOEt/hexanes), colorless oil]: [R]28 ) +15.7
D
(c 0.4, CHCl3); IR (neat) 3030, 2980, 1750, 1510, 1425 cm-1
;
1H NMR (CDCl3) δ 0.64 (s, 3H), 0.87 (d, J ) 6.4 Hz, 6H), 0.97
(d, J ) 5.9 Hz, 3H), 2.45 (m, 2H), 4.95 (d, J ) 10.5 Hz, 1H),
5.04 (d, J ) 17.1 Hz, 1H), 5.80 (ddt, J ) 17.1, 10.5, 6.8 Hz,
1H); 13C NMR (CDCl3) δ 13.2, 18.8, 18.9, 22.5, 22.8, 23.7, 26.5,
27.6, 28.0, 29.0, 33.6, 35.5, 36.0, 36.6, 37.3, 39.4, 46.5, 47.7,
C
42H72O2 608.5532 (M+), found 608.5540.
11r,11′r-(5-Decen e-1,10-d iyl)b is-d e-A,B-ch olest a n -8-
on e (21). Following the same experimental procedure as for
20, a solution of ketone 14 (50 mg 0.144 mmol) in CH2Cl2 (2
mL) afforded, after purification by flash chromatography (10%
AcOEt/hexanes), 32 mg of 21 as a 5:1 isomeric mixture [67%,
Rf ) 0.4 (10% AcOEt/hexanes), colorless oil]. 21 (major
isomer): IR (neat) 2940, 1720, 1460, 1380, 960 cm-1; 1H NMR
(CDCl3) δ 0.64 (s, 6H), 0.87 (d, J ) 6.4 Hz, 12H), 0.96 (d, J )
5.4 Hz, 6H), 2.41 (m, 4H), 5.37 (t, J ) 3.6 Hz, 2H); 13C NMR
(CDCl3) δ 13.2, 18.8, 18.9, 22.5, 22.8, 23.7, 26.5, 27.8, 27.9,
29.6, 32.5, 35.5, 36.0, 36.7, 37.4, 39.4, 46.5, 47.7, 49.2, 56.5,
61.9, 130.3, 211.7; HRMS (FAB) calcd for C46H82O2 664.6172
(M+ + 1), found 664.6158.
49.2, 56.6, 61.9, 114.4, 138.8, 211.5; HRMS calcd for C24H42
O
346.3236 (M+), found 346.3236.
(5E,7Z)-3â-[(ter t-Bu tyld im eth ylsilyl)oxy]-11r-(3-bu ten -
1-yl)-9,10-secoch olesta -5,7,10(19)-tr ien e (16). To a solution
of the phosphine oxide 9 (150 mg, 0.31 mmol) in THF (7 mL)
at -78 °C was added dropwise a solution of n-BuLi in hexanes
(118 µL, 0.28 mmol). The reaction was warmed to 0 °C and,
after 15 min, cooled again to -78 °C. A solution of 13 (50 mg,
0.157 mmol) in THF (3 mL) was added by cannula. The
mixture was stirred and warmed to -35 °C. The reaction was
quenched with a saturated solution of NH4Cl (1 mL) and then
poured into a separatory funnel with Et2O (30 mL). The
organic layer was washed with a saturated solution of NH4Cl
(20 mL), dried, filtered and concentrated with protection from
light. The residue was purified by flash chromatography (10%
Et2O/hexanes) to afford 73 mg of vitamin 16 [84%, Rf ) 0.8
11r,11′r-(1,6-H exa n ed iyl)b is-d e-A,B-ch olest a n -8-on e
(22). To a solution of diketone 20 (60 mg, 0.1 mmol) in MeOH
(7 mL) under an H2 atmosphere was added a catalytic amount
of the complex Rh/Al2O3 (5 wt %). The mixture was stirred
overnight, concentrated in vacuo and purified by flash chro-
matography (4% AcOEt/hexanes) to afford 55 mg of ketone 22
[91%, Rf ) 0.5 (10% AcOEt/hexanes)]: IR (neat) 2950, 1710,
(10% AcOEt/hexanes), colorless oil]: [R]25 ) +45.6 (c 1.5,
D
CHCl3); 1H NMR (CD2Cl2) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.52 (s,
3H), 0.86 (d, J ) 7.3 Hz, 6H), 0.88 (s, 9H), 0.94 (d, J ) 5.8 Hz,
3H), 2.89 (m, 1H), 3.84 (m, 1H), 4.76 and 5.01 (2 br s, 2H),
4.91, 4.96 and 5.06 (3 m, 2H), 5.83 (ddt, J ) 17.1, 10.3, 6.8
1420, 960 cm-1; H NMR (CDCl3) δ 0.63 (s, 6H), 0.86 (d, J )
1
6.8 Hz, 12H), 0.95 (d, J ) 5.7 Hz, 6H), 2.38 (m, 4H); 13C NMR
(CDCl3) δ 13.2, 18.8, 18.9, 22.5, 22.8, 23.7, 27.0, 27.8, 28.0,
29.7, 35.5, 35.9, 36.7, 37.5, 39.4, 46.4, 47.7, 49.2, 56.5, 61.9,
211.7; MS (FAB) m/z 611 (M+ + 1, 100), 593 (M+ - CH3, 17);
HRMS (FAB) calcd for C42H75O2, 611.5767 (M+ + 1), found
611.5739.
Hz, 1H), 6.00 and 6.19 (2 d, AB system, J ) 11.2 Hz, 2H); 13
C
NMR (CD2Cl2) δ -4.6, -4.5, 12.9, 18.4, 19.1, 22.3, 22.7, 22.9,
24.2, 26.0, 28.3, 28.4, 31.9, 33.0, 34.5, 36.1, 36.5, 36.7, 37.2,
39.9, 46.1, 47.1, 47.8, 56.7, 56.9, 70.8, 112.2, 114.2, 118.1, 121.7,
136.8, 139.7, 141.2, 146.0; HRMS calcd for C37H64OSi 552.4726
(M+), found 552.4715.
11r,11′r-(1,10-Deca n ed iyl)b is-d e-A,B-ch olest a n -8-on e
(23). Following the same experimental procedure as for 22,
hydrogenation of diketone 21 (25 mg, 0.038 mmol) with Rh/
Al2O3 (5 wt %) in MeOH (5 mL) afforded, after purification
(7% AcOEt/hexanes), 23 mg of 23 [91%, Rf ) 0.6 (15% AcOEt/
(5E,7Z)-11r,11′r-(3-Hexen e-1,6-diyl)bis-9,10-secoch oles-
ta -5,7,10(19)-tr ien -3â-ol (19). To a solution of the vitamin
16 (35 mg, 0.063 mmol) in CH2Cl2 (1 mL), protected from light
in a Schlenk tube, was added (Cy3P)2Cl2RuCHPh (6 mg, 10%).
The resulting mixture was stirred for 2 h and purified by flash
chromatography (5% Et2O/hexanes) to give 35 mg of a mixture
of dimer 18 and starting vitamin 16 (1:1 ratio). The mixture
was dissolved in THF (3 mL) and treated with a solution n-Bu4-
NF in THF (88 µL, 1 M). After being stirred for 24 h, the
mixture was concentrated in vacuo and the residue was
purified by flash chromatography (25% AcOEt/hexanes) to
afford 20 mg of dimer 19 [74%, Rf ) 0.2 (40% AcOEt/hexanes),
white foam] and 5 mg of the vitamin 17 (18%). 19: 1H NMR
(CD2Cl2) δ 0.51 (s, 6H), 0.85 (d, J ) 6.8 Hz, 12H), 0.93 (d, J )
5.9 Hz, 6H), 2.87 (m, 2H), 3.89 (m, 2H), 4.78 and 5.02 (2 br s,
4H), 5.42 (m, 2H), 6.01 and 6.24 (2 d, AB system, J ) 11.2 Hz,
4H); 13C NMR (CD2Cl2) δ 12.9, 19.1, 22.4, 22.7, 22.9, 24.2, 28.3,
28.4, 30.6, 32.4, 34.5, 35.7, 36.2, 36.5, 37.9, 39.8, 46.2, 46.3,
47.7, 56.8, 56.9, 69.5, 112.4, 117.8, 122.5, 130.7, 135.8, 141.8,
145.8; HRMS (FAB) calcd for C60H96O2 848.7410 (M+), found
hexanes), white solid]: IR (neat) 2940, 1725, 1460, 1380 cm-1
;
1H NMR (CDCl3) δ 0.64 (s, 6H), 0.87 (d, J ) 6.4 Hz, 12H),
0.96 (d, J ) 5.4 Hz, 6H), 1.26 (s, 23H), 2.39 (m, 4H); 13C NMR
(CDCl3) δ 13.2, 18.8, 18.9, 22.5, 22.8, 23.7, 27.1, 27.8, 28.0,
29.6, 29.7, 35.5, 36.0, 36.7, 37.5, 39.4, 46.5, 47.8, 49.2, 56.5,
61.9, 211.6; MS (FAB) m/z 668 (M+ + 2, 10), 667 (M+ + 1, 21),
288 (100); HRMS (FAB) calcd for C46H82O2 666.6315 (M+),
found 666.6318.
(5E,7Z)-1r,11′r-(1,6-Hexa n ed iyl)bis-9,10-secoch olesta -
5,7,10(19)-tr ien -3â-ol (2). To a solution of the phosphine oxide
9 (90 mg, 0.2 mmol) in THF (7 mL), at -78 °C, was added
dropwise a solution of n-BuLi in hexanes (100 µL, 2.0 M, 0.20
mmol). The reaction was warmed to 0 °C and, after 15 min,
cooled again to -78 °C. A solution of 22 (30 mg, 0.049 mmol)
in THF (3 mL) was then added by cannula. The mixture was
stirred and warmed to -50 °C. The reaction was quenched
with a saturated solution of NH4Cl (1 mL). The mixture was
poured into a separatory funnel with Et2O (50 mL) and washed
with a saturated solution of NH4Cl (30 mL). The organic layer
was dried, filtered and concentrated in vacuo with protection
from the light. The residue was purified by flash chromatog-
raphy (1% AcOEt/hexanes) to afford 45 mg of the protected
vitamin D3 dimer 24 [85%, Rf ) 0.8 (10% AcOEt/hexanes),
colorless oil]: 1H NMR (CD2Cl2) δ 0.06 (s, 6H), 0.07 (s, 6H),
0.53 (s, 6H), 0.86 (d, J ) 7.0 Hz, 12H), 0.88 (s, 18H), 0.94 (d,
J ) 5.9 Hz, 6H), 2.55 (m, 2H), 2.84 (m, 2H), 3.84 (m, 2H), 4.78
(d, J ) 2.4 Hz, 2H), 5.03 (d, J ) 2.4 Hz, 2H), 6.00 and 6.20 (2
d, AB system, J ) 11.2 Hz, 4H); 13C NMR (CD2Cl2) δ -4.57,
-4.51, 12.9, 18.4, 19.1, 22.4, 22.7, 22.9, 24.2, 26.0, 27.6, 28.3,
28.4, 30.4, 32.9, 35.1, 36.3, 36.5, 36.7, 38.2, 39.9, 46.1, 47.1,
48.0, 56.8, 56.9, 70.8, 112.2, 118.0, 121.8, 136.6, 141.4, 146.0.
To a solution of 24 (45 mg) in THF (5 mL), with protection
from the light, was added n-Bu4NF‚H2O (42 mg, 0.16 mmol).
The solution was stirred for 24 h, poured into a separatory
funnel with AcOEt (30 mL) and washed with a saturated
solution of NaCl (30 mL). The organic layer was dried, filtered
and concentrated in vacuo. The residue was purified by flash
848.7412. 17: [R]28 ) +18.3 (c 0.6, CHCl3); 1H NMR (CD2-
D
Cl2) δ 0.52 (s, 3H), 0.85 (d, J ) 6.3 Hz, 6H), 0.93 (d, J ) 6.3
Hz, 3H), 2.89 (m, 1H), 3.87 (m, 1H), 4.78 and 5.04 (2 br s, 2H),
4.90, 4.96 and 5.05 (3 m, 2H), 5.83 (ddt, J ) 17.1, 10.3, 6.8
Hz, 1H), 6.01 and 6.24 (2 d, AB system, J ) 11.2 Hz, 2H); 13
C
NMR (CD2Cl2) δ 12.8, 19.1, 22.4, 22.7, 22.9, 24.2, 25.8, 28.3,
28.4, 31.9, 32.4, 34.6, 35.7, 36.1, 36.4, 36.5, 37.2, 39.8, 46.1,
46.3, 47.8, 56.8, 56.9, 69.5, 112.4, 114.2, 117.9, 122.4, 135.9,
139.7, 141.7, 145.8; MS (FAB) m/z 439 (M+ + 1, 87), 438 (M+,
100); HRMS calcd for C31H50O 438.3862 (M+), found 438.3870.
11r,11′r-(3-H e xe n e -1,6-d iyl)b is-d e -A,B-ch ole st a n -8-
on e (20). To a solution of 13 (30 mg, 0.094 mmol) in CH2Cl2
(5 mL) in a Schlenk tube was added (Cy3P)2Cl2RuCHPh (9 mg,
10%). The mixture was stirred for 24 h, concentrated, and
purified by flash chromatography (5% AcOEt/hexanes) to
afford 18 mg of dimeric ketone 20 [63%, Rf ) 0.5 (10% AcOEt/
hexanes), colorless oil] as mixture of isomers in 5:1 ratio, and
9 mg of starting ketone 13 (30%). 20 (major isomer): IR (neat)
1
2950, 1720, 1425 cm-1; H NMR (CDCl3) δ 0.63 (s, 6H), 0.87

Synthesis of Vitamin D3 and Calcitriol Dimers
J . Org. Chem., Vol. 65, No. 24, 2000 8295
chromatography (30% AcOEt/hexanes) to afford 32 mg of
temperature. The mixture was poured into a separatory funnel
with CH2Cl2 (50 mL), and successively washed with 2%
H2SO4 (50 mL), a saturated solution of NaHCO3 (50 mL) and
water (50 mL). The organic phase was dried, filtered and
concentrated in vacuo, and the resulting crude was purified
by flash chromatography (6% EtOAc/hexanes) to afford 613
mg of 28 [99%, Rf ) 0.7 (50% AcOEt/hexanes), colorless oil]:
vitamin D3 dimer 2 [90%, Rf ) 0.4 (60% AcOEt/hexanes), white
foam]: [R]26 ) +14.1 (c 0.2, CHCl3); 1H NMR (CD2Cl2) δ 0.53
D
(s, 6H), 0.86 (d, J ) 6.3 Hz, 12H), 0.93 (d, J ) 5.9 Hz, 6H),
1.31 (m, 12H), 2.55 (m, 2H), 2.89 (m, 2H), 3.87 (m, 2H), 4.78
(d, J ) 2.9 Hz, 2H), 5.03 (d, J ) 2.4 Hz, 2H), 6.24 and 6.01 (2
d, AB system, J ) 11.2 Hz, 4H); 13C NMR (CD2Cl2) δ 12.9,
19.1, 22.4, 22.7, 22.9, 24.2, 27.5, 28.3, 30.3, 32.4, 35.2, 35.7,
36.3, 36.5, 38.2, 39.8, 46.2, 46.3, 48.1, 56.8, 57.0, 69.5 112.4,
117.8, 122.5, 135.8, 141.9, 145.8; MS (FAB) m/z 850 (M+, 75);
HRMS (FAB) calcd for C60H98O2 850.7567 (M+), found 850.7601.
[R]28 ) +6.5 (c 1.7, CHCl3); IR (neat) 2950, 1730, 750 cm-1
.
D
1H NMR (CDCl3) δ 0.59 (q, J ) 7.9 Hz, 6H), 0.65 (s, 3H), 0.91
(t, J ) 7.9 Hz, 9H), 0.93 (d, J ) 5.6 Hz, 3H),1.16 (s, 6 H), 2.27
(m, 1 H), 2.45 (m, 1H); 13C NMR (CDCl3) δ 6.7, 7.1, 12.4, 18.6,
19.0, 20.6, 24.0, 27.4, 29.7, 29.9, 35.4, 36.2, 38.9, 40.9, 45.4,
49.9, 56.7, 61.9, 73.3, 212.2.
(5E,7Z)-1r,11′r-(1,10-Deca n ed iyl)bis-9,10-secoch olesta -
5,7,10(19)-tr ien -3â-ol (3). Following the same experimental
procedure as for 2, reaction of diketone 23 (56 mg, 0.084 mmol)
with the anion prepared from phosphine oxide 9 (152 mg, 0.34
mmol) and n-BuLi in hexanes (187 µL, 1.71 M, 0.31 mmol)
afforded, after purification by flash chromatography (1%
AcOEt/hexanes), 88 mg of 25 [92%, Rf ) 0.8 (15% AcOEt/
hexanes), colorless oil]: 1H NMR (CD2Cl2) δ 0.06 (s, 12H), 0.53
(s, 6H), 0.86 (d, J ) 7.3 Hz, 12H), 0.88 (s, 18H), 0.93 (d, J )
5.9 Hz, 6H), 2.42 (m, 2H), 2.85 (m, 2H), 3.86 (m, 2H), 4.75 (d,
J ) 3 Hz, 2H), 5.00 (d, J ) 3 Hz, 2H), 5.99 and 6.19 (2 d, AB
system, J ) 11.2, Hz, 4H); 13C NMR (CD2Cl2) δ -4.6, -4.5,
12.9, 18.4, 19.1, 22.4, 22.7, 22.9, 24.2, 26.0, 27.6, 28.3, 28.4,
30.1, 30.4, 32.9, 35.1, 36.3, 36.5, 36.7, 38.2, 39.9, 46.1, 47.1,
48.0, 56.8, 57.0, 70.8, 112.2, 118.0, 121.7, 136.7, 141.4, 146.0.
Deprotection of 25 (32 mg, 0.028 mmol) with n-Bu4NF‚H2O
(35 mg, 0.11 mmol), following the same experimental proce-
dure as for 2, afforded, after purification by flash chromatog-
raphy (AcOEt), 25 mg of 3 [98%, Rf ) 0.8 (70% AcOEt/
hexanes), white foam]: [R]29D ) +11.1 (c 0.6, CHCl3); 1H NMR
(CD2Cl2) δ 0.53 (s, 6H), 0.86 (d, J ) 6.3 Hz, 12H), 0.93 (d, J )
5.9 Hz, 6H), 2.55 (m, 2H), 2.89 (m, 2H), 3.87 (m, 2H), 4.78 (d,
J ) 2.9 Hz, 2H), 5.03 (d, J ) 2.4 Hz, 2H), 6.24 and 6.01 (2 d,
AB system, J ) 11.2, Hz, 4H); 13C NMR (CD2Cl2) δ 19.1, 199,
22.4, 22,7, 22.9, 23.1, 24.2, 27.6, 28.3, 28.4, 30.1, 30.4, 32.3,
32.4, 35.2, 35.7, 36.3, 36.4, 36.5, 38.2, 39.9, 46.2, 46.3, 48.1,
56,8, 57.0, 69.5, 112.4, 117.8, 122.5, 135.7, 142.0, 145.8; MS
(FAB) m/z 907 (M+, 25); HRMS (FAB) calcd for C64H107O2
907.8271 (M+ + 1), found 907.8260.
25-[(Tr ieth ylsilyl)oxy]de-A,B-ch olest-9(11)-en -8-on e (29).
A solution of ketone 28 (500 mg, 1.27 mmol) in THF (6 mL)
was added dropwise (30 min) by cannula to a cooled (-75 °C)
solution of LDA (1.52 mmol) in THF (4 mL). After stirring for
30 min, TMSCl (210 µL, 1.64 mmol) was added by syringe and
the reaction mixture was warmed to room temperature and
concentrated in vacuo. The residue was dissolved in Et2O (25
mL), the solution was dried, filtered and concentrated in vacuo.
The residue was dissolved in CH3CN/THF (10 mL, 3:2), and
Pd(OAc)2 (285 mg, 1.27 mmol) was added. The resulting
mixture was stirred for 24 h, filtered through Celite and
concentrated in vacuo. The residue was purified by flash
chromatography (5% AcOEt/hexanes) to afford 420 mg of enone
29 [84%, Rf ) 0.4 (15% AcOEt/hexanes), colorless oil]: [R]28
D
) +8.7 (c 0.8, CHCl3); 1H NMR (CDCl3) δ 0.56 (q, J ) 7.8 Hz,
6H), 0.76 (s, 3H), 0.92 (d, J ) 6.8 Hz, 3H), 0.94 (t, J ) 7.5 Hz,
9H), 1.19 (s, 6H), 2.3-2.7 (m, 3H), 5.98 (dd, J ) 9.0, 2.9 Hz,
1H), 6.75 (m, 1H); 13C NMR (CDCl3) δ 6.2, 6.8, 7.1, 7.4, 11.9,
18.4, 19.4, 20.6, 27.4, 29.8, 30.0, 35.0, 35.4, 36.1, 42.9, 45.4,
47.5, 56.7, 59.2, 63.5, 73.3, 129.5, 135.2, 147.6, 202.0; HRMS
calcd for C24H44O2Si 392.3111 (M+ + 1), found 449.3123.
11r-(3-Bu t en -1-yl)-25-[(t r iet h ylsilyl)oxy]d e-A,B-ch o-
lesta n -8-on e (30). Following the same experimental proce-
dure as for 13, reaction of enone 29 (250 mg, 0.64 mmol) with
the cuprate generated from 4-bromo-1-butene (260 mL, 2.55
mmol), t-BuLi (1.54 mL, 2.55 mmol) and CuI/n-Bu3P (1.275
mmol) afforded, after purification by flash chromatography (2%
AcOEt/hexanes), 240 mg of 30 [84%, Rf ) 0.5 (15% AcOEt/
hexanes), colorless oil]: [R]25D ) +7.2 (c 0.5, CHCl3); IR (neat)
25-Hyd r oxy-d e-A,B-ch olesta n -8-on e (27).27 To a -45 °C
cooled solution of ester 26 (502 mg, 1.78 mmol) in THF (15
mL) a solution of MeLi in Et2O (3.9 mL, 1.5 M, 5.94 mmol)
was added dropwise (10 min). The reaction mixture was stirred
for 30 min, quenched by addition of MeOH (1 mL), and then
warmed to room temperature. The reaction mixture was
poured into a separatory funnel with Et2O (30 mL) and washed
successively with a saturated solution of NaHCO3 (30 mL) and
NaCl (30 mL). The organic layer was dried, filtered and
concentrated in vacuo, and the crude was purified by flash
chromatography (30% EtOAc/hexanes) to afford 445 mg [89%,
Rf ) 0.4 (50% AcOEt/hexanes), white solid] of a diol which was
inmediately oxidized to ketone 27: 1H NMR (CDCl3) δ 0.92
(d, J ) 7.1 Hz, 3H), 0.94 (s, 3H), 1.22 (s, 6H), 4.08 (m, 1H).
A mixture of the freshly prepared diol (445 mg, 1.58 mmol)
and PDC (1.92 g, 5.11 mmol) in CH2Cl2 (30 mL) was stirred
for 6 h. Et2O (50 mL) was added and the resulting mixture
was stirrred for 10 min. The mixture was filtered through
Celite and the solids were washed with Et2O (2 × 40 mL). The
filtrate was concentrated in vacuo and residue was purified
by flash chromatography (25% EtOAc/hexanes), to afford 432
mg of 27 [98%, Rf ) 0.5 (50% AcOEt/hexanes), colorless oil]:
1H NMR (CDCl3) δ 0.62 (s, 3H), 0.95 (d, J ) 6.2 Hz, 3H), 1.20
(s, 6H), 2.45 (m, 1H); 13C NMR (CDCl3) δ 12.5, 18.7, 19.0, 20.7,
24.1, 27.5, 29.2, 29.4, 35.5, 36.2, 39.0, 41.0, 42.3, 49.9, 56.6,
62.0, 71.0, 212.2.
1
3070, 2950, 1715, 1470, 1390, 910 cm-1; H NMR (CDCl3) δ
0.56 (q, J ) 8.3 Hz, 6H), 0.94 (t, J ) 6.8 Hz, 9H), 0.96 (d, J )
6.4 Hz, 3H), 1.19 (s, 3H), 2.40 (m, 2H), 4.96 (d, J ) 13.2 Hz,
1H), 5.01 (d, J ) 17.1 Hz, 1H), 5.79 (ddt, J ) 17.1, 13.2, 6.8
Hz, 1H); 13C NMR (CD2Cl2) δ 6.8, 7.1, 13.2, 13.8, 18.7, 18.9,
20.7, 27.0, 27.8, 29.8, 30.0, 31.3, 35.5, 36.0, 36.2, 36.5, 45.4,
46.2, 47.6, 49.1, 56.5, 61.9, 73.4, 114.7, 138.3, 211.4; MS (FAB)
m/z 449 (M+ + 1, 13), 317 (100); HRMS (FAB) calcd for
C
28H53O2Si 449.3815 (M+ + 1), found 449.3828.
11r-(5-Hexen e-1-yl)-25-[(tr ieth ylsilyl)oxy]-d e-A,B-ch o-
lesta n -8-on e (31). Following the same experimental proce-
dure as for 13, reaction of enone 29 (190 mg, 0.48 mmol) with
the cuprate generated from 6-bromo-1-hexene (260 mL, 1.94
mmol), t-BuLi (1.17 mL, 2.55 mmol) and CuI/n-Bu3P (0.97
mmol) afforded, after purification by flash chromatography (2%
AcOEt/hexanes), 218 mg of 31 [94%, Rf ) 0.5 (15% AcOEt/
hexanes), colorless oil]: [R]26D ) +10.7 (c 0.3, CHCl3); IR (neat)
1
3080, 2950, 1725, 1460, 1380, 1230, 1050, 740 cm-1. H NMR
(CDCl3) δ 0.58 (q, J ) 7.6 Hz, 6H,), 0.64 (s, 3H), 0.93 (t, J )
7.8 Hz, 12H), 0.96 (d, J ) 6.4 Hz, 3H), 1.19 (s, 6H), 4.95 (d, J
) 10.3 Hz, 1H), 5.04 (d, J ) 17.6 Hz, 1H), 5.81 (ddt, J ) 17.6,
10.3, 6.7 Hz, 1H); 13C NMR (CDCl3) δ 6.7, 7.1, 13.2, 18.8, 18.9,
20.7, 25.0, 25.1, 26.5, 27.7, 29.0, 29.8, 30.0, 33.6, 35.4, 35.8,
36.2, 36.6, 37.3, 45.4, 46.4, 47.7, 49.2, 114.4, 138.8, 211.5; MS
(FAB) m/z 477 (M+ + 1, 54), 475 (M+ - 1, 100); HRMS (FAB)
calcd for C30H57O2Si 477.4128 (M+ + 1), found 477.4138.
11r,11′r-(3-Hexen e-1,6-d iyl)bis-25-[(tr ieth ylsilyl)oxy]-
d e-A,B-ch olesta n -8-on e (32). A solution of ketone 30 (50 mg
0.11 mmol) in CH2Cl2 (2 mL) was treated following the same
experimental procedure as for 20, to afford, after purification
by flash chromatography (8% AcOEt/hexanes), 34 mg of 32
[70%, Rf ) 0.4 (20% AcOEt/hexanes), colorless oil] as a 5:1
isomeric mixture. 32 (major isomer): IR (neat) 3000, 1720,
25-[(Tr ieth ylsilyl)oxy]d e-A,B-ch olesta n -8-on e (28). To
a solution of 27 (440 mg, 1.57 mmol) in CH2Cl2 (30 mL), at
-78 °C, was added dropwise 2,6-lutidine (0.74 mL, 6.29 mmol)
and Et3SiOTf (0.53 mL, 2.36 mmol) and the resulting mixture
was stirred for 30 min at -78 °C and warmed to room
(27) Curci, R.; Detomaso, A.; Prencipe, T.; Carpenter, G. J . Am.
Chem. Soc. 1994, 116, 8112.

8296 J . Org. Chem., Vol. 65, No. 24, 2000
Pe´rez Sestelo et al.
1450 cm-1; 1H NMR (CDCl3) δ 0.56 (q, J ) 7.8 Hz, 12H), 0.64
(s, 6H), 0.94 (t, J ) 7.8 Hz, 18H), 0.97 (d, J ) 7.3 Hz, 6H),
1.19 (s, 12H), 2.40 (m, 4H), 5.38 (t, J ) 3.6 Hz, 2H); 13C NMR
(CDCl3) δ 6.8, 7.1, 13.2, 18.8, 18.9, 20.7, 27.7, 29.7, 30.0, 30.1,
35.5, 36.0, 37.2, 45.4, 46.2, 47.6, 49.1, 56.5, 61.9, 73.4, 129.5,
130.1, 211.5; HRMS (FAB) calcd for C52H95O4Si2 839.6769 (M+
- C2H5), found 839.6751.
0.87 (s, 18H), 0.93 (t, J ) 8.3 Hz, 18H), 1.18 (s, 12H), 2.42 (m,
2H), 2.87 (m, 2H), 4.19 (m, 2H), 4.38 (m, 2H), 4.83 (d, J ) 3
Hz, 2H), 5.18 (d, J ) 3 Hz, 2H), 6.01 and 6.2 (2 d, AB system,
J ) 11.2 Hz, 4H).
To a solution of 36 (21 mg, 0.013 mmol) in THF (7 mL),
with protection from the light, was added n-Bu4NF‚H2O (41
mg, 0.13 mmol) in one portion. After stirring for 24 h, the
reaction mixture was poured into a separatory funnel with
AcOEt (30 mL) and washed with a saturated solution of NaCl
(30 mL). The organic layer was dried, filtered and concentrated
in vacuo. The residue was purified by flash chromatography
(AcOEt) to afford 8 mg of the calcitriol dimer 4 [67%, Rf ) 0.2
11r,11′r-(5-Decen e-1,10-d iyl)bis-25-[(tr ieth ylsilyl)oxy]-
d e-A,B-ch olesta n -8-on e (33). Following the same experi-
mental procedure as for 20, ketone 31 (60 mg, 0.126 mmol) in
CH2Cl2 (2 mL) afforded, after purification by flash chroma-
tography (5% AcOEt/hexanes), 28 mg of 33 [48%, Rf ) 0.4 (10%
AcOEt/hexanes), colorless oil] as a isomeric mixture. 33 (major
(100% AcOEt), white solid]: [R]26 ) +34.2 (c 0.2, CHCl3); 1H
D
isomer): IR (neat) 2950, 1710, 1450, 730 cm-1 1H NMR
;
NMR (CD3OD) δ 0.57 (s, 6H), 0.98 (d, J ) 5.8 Hz, 6H), 1.16 (s,
12H), 2.52 (m, 2H), 2.91 (m, 2H), 4.12 (m, 2H), 4.34 (t, J ) 5.3
Hz, 2H), 4.90 (s, 2H), 5.29 (s, 2H), 6.06 and 6.32 (2 d, AB
system, J ) 11.3 Hz, 4H); 13C NMR (CD3OD) δ 13.2, 19.5, 21.9,
22.9, 28.1, 29.1, 29.2, 30.8, 35.9, 37.1, 37.5, 37.7, 38.8, 43.7,
45.3, 46.1, 46.9, 57.8, 67.4, 71.4, 111.9, 118.9, 124.8, 135.8,
141.8, 149.8; MS (FAB) m/z 938 [(M + Na)+, 3]; HRMS (FAB)
calcd for C60H98O6Na 937.7261 [(M + Na)+], found 937.7232.
(5E,7Z)-11r,11′r-(1,10-Decan ediyl)bis-9,10-secoch olesta-
5,7,10(19)-tr ien e-1r,3â,25-tr iol (5). Following the same ex-
perimental procedure as for 4, reaction of diketone 35 (19 mg,
0.021 mmol) with the anion formed from phosphine oxide 10
(55 mg, 0.09 mmol) and n-BuLi in hexanes (35 µL, 2.24 M,
0.08 mmol) afforded, after purification by flash chromatogra-
phy (1% AcOEt/hexanes), 22 mg of 37 [65%, Rf ) 0.8 (15%
AcOEt/hexanes), colorless oil]: 1H NMR (CD2Cl2) δ 0.06 (s,
12H), 0.52 (s, 6H), 0.56 (q, J ) 8.3 Hz, 12H), 0.86 (d, J ) 7.3
Hz, 6H), 0.87 (s, 18H), 0.93 (t, J ) 8.3 Hz, 18H), 1.18 (s, 12H),
2.42 (m, 2H), 2.87 (m, 2H), 4.19 (m, 2H), 4.38 (m, 2H), 4.83 (d,
J ) 3 Hz, 2H), 5.18 (d, J ) 3 Hz, 2H), 6.01 and 6.2 (2 d, AB
system, J ) 11.2 Hz, 4H).
Deprotection of 37 (22 mg, 0.013 mmol) with n-Bu4NF‚H2O
(50 mg, 0.12 mmol), following the same experimental proce-
dure as for 4, afforded, after purification by flash chromatog-
raphy (AcOEt), 8 mg of 5 [62%, Rf ) 0.4 (10% MeOH/AcOEt),
colorless oil]: 1H NMR (CD3OD) δ (0.57 (s, 6H), 0.98 (d, J )
5.9 Hz, 6H), 1.16 (s, 12H), 2.56 (m, 2H), 2.91 (m, 2H), 4.12 (m,
2H), 4.35 (t, J ) 5.8 Hz, 2H), 4.90 (br s, 2H), 5.29 (br s, 2H),
6.07 and 6.32 (2 d, AB system, J ) 11.2 Hz, 4H); 13C NMR
(CD3OD) δ 11.8, 18.0, 20.4, 21.6, 26.7, 27.6, 27.8, 29.1, 29.4,
34.5, 35.6, 36.0, 36.5, 37.4, 42.2, 43.8, 44.6, 45.5, 46.2, 56.4,
65.9, 69.9, 70.0, 110.5, 117.5, 123.3, 134.3, 140.3, 148.3; HRMS
(FAB) calcd for C64H106O6 970.7989 (M+), found 970.8223.
(CDCl3) δ 0.58 (q, J ) 7.6 Hz, 12H), 0.64 (s, 6H), 0.93 (t, J )
7.6 Hz, 18H), 0.97 (d, J ) 7.3 Hz, 6H), 1.19 (s, 12H), 2.35 (m,
4H), 5.38 (t, J ) 3.9 Hz, 2H); 13C NMR (CDCl3) δ 6.8, 13.2,
18.8, 18.9, 20.7, 26.5, 27.1, 27.7, 29.7, 29.8, 30.0, 32.5, 35.5,
36.3, 36.8, 37.4, 45.4, 46.5, 47.7, 49.2, 56.6, 61.9, 73.4, 130.3,
211.6; MS (FAB) m/z 948 [(M + Na)+, 1], 896 (M+ - C2H5, 1),
297 (100).
11r,11′r-(1,6-Hexa n ed iyl)bis-25-[(tr ieth ylsilyl)oxy]-d e-
A,B-ch olesta n -8-on e (34). Following the same experimental
procedure as for 22, dimeric ketone 32 (18 mg, 0.021 mmol)
afforded, after purification (4% AcOEt/hexanes), 16 mg of 34
[89%, Rf ) 0.5 (15% AcOEt/hexanes), colorless oil]: [R]27
)
D
+9.4 (c 0.2, CHCl3); IR (neat) 2950, 1720, 1410, 1230, 750 cm-1
;
1H NMR (CDCl3) δ 0.56 (q, J ) 7.6 Hz, 12H), 0.64 (s, 6H),
0.95 (t, J ) 7.6 Hz, 18H), 0.96 (d, J ) 5.6 Hz, 6H), 1.19 (s,
12H), 2.40 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 6.8, 7.1, 13.2,
18.8, 18.9, 20.7, 27.2, 27.8, 29.7, 29.8, 30.0, 35.5, 36.2, 36.7,
37.5, 45.4, 46.4, 47.8, 49.2, 56.5, 61.9, 73.4, 211.7; HRMS (FAB)
calcd for C52H97O4Si2 841.6925 (M+ - C2H5), found 841.6898.
11r,11′r-(1,10-Deca n ed iyl)b is-25-[(t r iet h ylsilyl)oxy]-
d e-A,B-ch olesta n -8-on e (35). Following the same experi-
mental procedure as for 20, dimeric ketone 33 (50 mg, 0.054
mmol) afforded after purification (6% AcOEt/hexanes), 47 mg
of 35 [94%, Rf ) 0.5 (15% AcOEt/hexanes), colorless oil]: IR
1
(neat) 2925, 1720, 1410, 1230, 775 cm-1; H NMR (CDCl3) δ
0.57 (c, J ) 7.8 Hz, 12H), 0.65 (s, 6H), 0.92 (t, J ) 7.8 Hz,
18H), 0.95 (d, J ) 7.8 Hz, 6H), 1.19 (s, 12H), 2.41 (m, 4H); 13
C
NMR (CDCl3) δ 6.8, 7.1, 13.2, 18,8, 18.9, 20.7, 27.1, 27.8, 29.6,
29.7, 29.8, 30.0, 35.5, 36.3, 36.7, 37.6, 45.4, 46.5, 47.8, 49.2,
56.6, 61.9, 73.4, 211.6; HRMS (FAB) calcd for C56H105O4Si2
897.7551 (M+ - C2H5), found 897.7555.
(5E,7Z)-11r,11′r-(1,6-Hexa n ed iyl)bis-9,10-secoch olesta -
5,7,10(19)-tr ien e-1r,3â,25-tr iol (4). To a solution of the
phosphine oxide 10 (40 mg, 0.06 mmol) in THF (5 mL) at -78
°C, was added dropwise a solution of n-BuLi in hexanes (40
µL, 1.75 M, 0.07 mmol). The reaction was warmed to 0 °C and,
after 15 min, cooled again to -78 °C. A solution of 34 (16 mg,
0.018 mmol) in THF (3 mL) was added by cannula. The
mixture was stirred and warmed to -50 °C. The reaction was
quenched with MeOH (1 mL). The mixture was poured into a
separatory funnel with AcOEt (40 mL) and washed with a
saturated solution of NaCl (30 mL). The organic layer was
dried, filtered and concentrated under reduced pressure with
protection from the light. The residue was purified by flash
chromatography (2% Et2O/hexanes) to afford 21 mg of the
protected calcitriol dimer 36 [71%, Rf ) 0.8 (10% Et2O/
hexanes), colorless oil]: 1H NMR (CD2Cl2) δ 0.06 (s, 12H), 0.52
(s, 6H), 0.56 (q, J ) 8.3 Hz, 12H), 0.86 (d, J ) 7.3 Hz, 6H),
Ack n ow led gm en t. J .P.S. thanks the Spanish Min-
istry of Education and Culture for a research grant. We
thank the DGES (Spain, PM97-0166), Xunta de Galicia
(XUGA 10305A98) and University of A Corun˜a for
financial support. We also thank Mrs. Paulina Freire
for reproducing some experiments and Mr. Carlos
Gregorio for the preparation of an advanced intermedi-
ate of the A ring phosphine oxide 10.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O001084X