Synthesis of new aromatic (C17-C20)-locked side-chain analogues of calcitriol (1α,25-dihydroxyvitamin D3)

Article abstract of DOI:10.1021/jo000579j

The synthesis of four new analogues of calcitriol (1α,25-(OH)₂-D₃) possessing aromatic and conjugated double bond units at the side chain are described. The triene system is introduced using the Lythgoe-Hoffmann La Roche convergent Wittig-Horner approach. The key steps in the preparation of the requisite upper fragments are the introduction of the side chain with the E-conjugated aromatic system and its photochemical conversion to the Z counterpart.

Full text of DOI:10.1021/jo000579j

6978
J . Org. Chem. 2000, 65, 6978-6983
Syn th esis of New Ar om a tic (C17-C20)-Lock ed Sid e-Ch a in
An a logu es of Ca lcitr iol (1r,25-Dih yd r oxyvita m in D3)†,1
Ana Ferna´ndez-Gacio, Cristian Vitale, and Antonio Mourin˜o*
Departamento de Quı´mica Orga´nica y Unidad Asociada al CSIC,
Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain
qomourin@usc.es
Received April 17, 2000
The synthesis of four new analogues of calcitriol (1R,25-(OH)2-D3) possessing aromatic and
conjugated double bond units at the side chain are described. The triene system is introduced using
the Lythgoe-Hoffmann La Roche convergent Wittig-Horner approach. The key steps in the
preparation of the requisite upper fragments are the introduction of the side chain with the
E-conjugated aromatic system and its photochemical conversion to the Z counterpart.
In tr od u ction
2
1R,25-Dihydroxyvitamin D3 [1, 1R,25-(OH)2-D3, cal-
citriol], the hormonally active form of vitamin D3 (2,
cholecalciferol), besides its important role in calcium
homeostasis,2a also promotes cell differentiation and
inhibits cell proliferation of various tumor cells, a fact
that suggests its possible use in the treatment of cancer.3
Unfortunately, the therapeutic value of 1R,25-(OH)2-D3
as an antitumor agent found serious limitations due to
its potent calcemic effects.2n,o,p For this reason, there is
continued and increasing interest aimed at the rational
design of new analogues of 1R,25-(OH)2-D3 with selective
biological functions as possible drugs for medical use.
However, the incomplete understanding of the conforma-
tion or conformations that the hydroxylated side chain
of 1R,25-(OH)2-D3 adopt upon binding to its receptor
(VDR) or receptors (VDRs)4 has led to the synthesis of
numerous side-chain modified analogues of which only
F igu r e 1.
a few have been identified as promising drugs for the
treatment of certain cancers2n,p and psoriasis.5
As part of our efforts to understand the side-chain
conformation of calcitriol in its bioactive form, we recently
reported6,7 the synthesis and conformational analysis of
four side-chain analogues of 1R,25-(OH)2-D3. The four
compounds in question incorporate conformationally
locked units in the form of a double bond or a cyclopro-
pane ring at C17-C20.8 Here we report the synthesis of
four new analogues in which the side chain features both
an aromatic ring at C20 and a conjugated double bond
at C17-C20.9,10
† This paper is dedicated to the memory of Prof. Pascual Teresa.
(1) ) This work was taken in part from the doctoral thesis of Ana
Isabel Ferna´ndez Gacio (1999, University of Santiago de Compostela).
(2) For reviews on the chemistry and/or biochemistry of vitamin D,
see: (a) Norman, A. W. Vitamin D the Calcium Homeostatic Steroid
Hormone; Academic Press: New York, 1979. (b) DeLuca, H. F.; Paaren,
H. E.; Schnoes, H. K. Top. Curr. Chem. 1979, 83, 1. (c) Pardo, R.;
Santelli, M. Bull. Soc. Chim. Fr. 1985, 98. (d) J ones, G., guest Ed.
Steroids 1987, 49, 1. (e) Ikekawa, N. Med. Res. Rev. 1987, 7, 333. (f)
Quinkert, G. Vitamin D Active Compounds. Part I. Synform 1985, 3,
41. Part II. Ibid. 1986, 4, 131. Part III. Ibid. 1987, 5, 1. (g) Ostrem, V.
K.; DeLuca, H. F. Steroids 1987, 49, 73. (h) Wilson, S. R.; Yasmin, A.
Stereoselective Synthesis of Vitamin D. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1992; Vol. 10,
p 43. (i) Calverley, M. J .; J ones, G. Antitumor Steroids; Blikenstaff, R.
T., Ed.; Academic Press: New York, 1992. (j) Uskokovic, M. R. Bioorg.
Med. Chem. Lett. 1993, 3, 1783. (k) Dai, H.; Posner, G. H. Synthesis
1994, 1383. (l) Schmalz, H.-G. Nachr. Chem. Technol. Lab. 1994, 42,
397. (m) Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877. (n)
Bouillon, R.; Okamura, W. H.; Norman, A. W. Structure-Function
Relationships in the Vitamin D Endocrine System. Endocr. Rev. 1995,
16, 200. (o) 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. (p) Feldman,
D.; Glorieux, F. H.; Pike, J . W. Vitamin D; Academic Press: San Diego,
1997.
(4) Yamamoto, K.; Masuno, H.; Choi, M.; Nakashima, K.; Taga, T.;
Ooizumi, H.; Umesono, K.; Sicinska, W.; VanHooke, J .; DeLuca, H.
F.; Yamada, S. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 1473 and
references therein.
(5) (a) Calcipotriol, an analogue of 1R,25-(OH)2-D3, has been com-
mercialized under the name of Dovonex by Leo Pharmaceuticals for
the local treatment of psoriasis. Binderup, L.; Kragballe, K. Rev.
Contemp. Pharmacother. 1992, 3, 357. (b) For Vitamin D analogues
in the treatment of psoriasis, see: Kragballe K. J . Cell. Biochem. 1992,
49, 46.
(6) Mart´ınez-Pe´rez, J . A.; Sarandeses, L.; Granja, J .; Palenzuela, J .
A.; Mourin˜o, A. Tetrahedron Lett. 1998, 39, 4725.
(7) The binding affinities of these analogues to VDR in vitro have
been presented at the GESA meeting (Obernai, Alsace, May 1999). As
compared with the natural hormone 1R,25-(OH)2-D3 (100%), the
analogue with Z stereochemistry binds more efficiently to VDR (190%)
and is more effective at promoting cell differentiation (HL-60 cells)
(300%) than the natural hormone. The corresponding cyclopropanic
derivative of the above Z olefinic analogue does not bind significantly
to VDR (<1%) but induces cell differentiation (HL-60 cells) (1000%)
better than the natural hormone. The E olefinic analogue binds poorly
(5%) to VDR but is as effective (100%) as the natural hormone at
promoting cell differentiation (HL-60).
(3) (a) Zhou, J . Y.; Norman, A. W.; Chen, D.; Sun, G.; Uskokovic,
M. R.; Koeffler. H. P. Proc. Natl. Acad. Sci U.S.A. 1990, 87, 3929. (b)
Colston, K. W.; Chander, S. K.; Mackay, A. G.; Coombe, R. C. Biochem.
Pharmacol. 1992, 44, 693. (c) Abe-Hashimoto, J .; Kikuchi, T.; Matsu-
moto, T.; Nishii, Y.; Ogata, E.; Ikeda, K. Cancer Res. 1993, 53, 2534.
(d) Anzano, M. A.; Smith, J . M.; Uskokovic, M. R.; Peer, C. W.; Mullen,
L. T.; Letterio, J . J .; Welsh, M. C.; Shrader, M. W.; Logsdon, D. L.;
Driver, C. L.; Brown, C. C.; Roberts, A. B.; Sporn, M. B. Cancer Res.
1994, 54, 1653.
(8) For conformational analysis of nonlocked side-chain analogues
of 1R,25-(OH)2-D3, see: Yamada, S.; Yamamoto, K.; Masuno, H.; Ohta,
M. J . Med. Chem. 1998, 41, 1467 and references therein.
10.1021/jo000579j CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/21/2000

New Analogues of Calcitriol
J . Org. Chem., Vol. 65, No. 21, 2000 6979
Sch em e 1
Resu lts a n d Discu ssion
Sch em e 2a
Gen er a l Syn th etic Ap p r oa ch . The synthesis of
analogues 3 (E configuration at C20) and 4 (Z configu-
ration at C20) (Scheme 1) follows the mild convergent
Wittig-Horner approach originally developed by Lythgoe
and later improved by the Hoffmann La Roche group.2m,11
In this route, 5 or 6 is coupled with the anion of
phosphine oxide 7 to provide, after alkylation and depro-
tection, analogues 3 or 4, respectively. Ketone 8 (TBS )
Sit-BuMe2), which is readily prepared by degradation of
vitamin D2, serves as the key compound to synthesize
the upper fragments 5 and 6. The key steps are the
introduction of aromatic units in the upper fragments,
especially in the case of 6. This route allows the incor-
poration of organic residues at C25 in the last steps of
the synthesis.
Syn th esis of An a logu es 3. The synthesis of the
corresponding upper fragments 5 is shown in Scheme 2.
The known ketone 8, readily prepared from vitamin D2,12
was separately treated with potassium carbanions of
phosphonates 1013 to give the E olefins 11 (∼70%) and
the corresponding Z-isomers (∼12%). The E/Z stereo-
chemistry of these compounds was established by 1H
NMR NOE experiments and by comparison of their 1H
NMR spectra with those of similar compounds.14 Pal-
ladium-catalyzed carbomethoxylation of bromides 11 in
MeOH/DMSO under an atmosphere of CO provided the
desired esters 12 (∼85%).15 Cleavage of the silyl ether
protecting groups to give alcohols 13 was followed by PDC
oxidation to afford the desired ketones 5 (∼88% over the
two steps).
a
m ) meta-series, p ) para-series. (a) KH, THF, ∆ (11m , 69%;
11p , 70%); (b) CO, Pd(OAc)2, Et3N, dppp, MeOH, DMSO, ∆ (12m ,
86%, 12p , 80%); (c) (HF, MeCN (13m , 92%; 13p , 96%); (d) PDC,
CH2Cl2 (5m , 95%; 5p , 91%).
Scheme 3 shows the remaining steps leading to ana-
logues 3. Treatment of the phosphine oxide 72m,16 with
butyllithium followed by reaction of the resulting anion
with ketones 5 according to known procedures,11 provided
the protected vitamin D analogues 14 (∼91%) with a
methoxycarbonyl group at C25 for further functionaliza-
tion. Treatment of esters 14 with methyllithium and
subsequent removal of the silyl groups with tetrabutyl-
ammonium fluoride afforded the desired vitamin D
analogues 3 (∼80% over the two steps, ∼33% overall yield
from ketone 8, seven steps).
Syn th esis of An a logu es 4. The introduction of the
C17-C20 Z double bond proved to be more challenging
than anticipated. Initial efforts to introduce the Z geom-
etry by reaction of the ylide prepared from phosphonium
salt 16 (KOt-Bu or NaH) with ketone 8 resulted in the
recovery of starting material, presumably for steric
reasons (Scheme 4). Attempts to isomerize olefin 12 to
19 by employing the Vedejs protocol17,18 were unsuccess-
ful due to difficulties in isolating epoxide 18.
(9) For the synthesis and biological evaluation of side-chain ana-
logues of 1R,25-(OH)2-D3 with aromatic units at C22, see Figade`re, B.;
Norman, A. W.; Henry, H. L.; Koeffler H. P.; Zhou, J .-Y.; Okamura,
W. H. J . Med. Chem. 1991, 34, 2452.
(10) For other analogues of 1R,25-(OH)2-D3, possesing a double bond
at C17-C20, see: Bretting, C.; Hansen, C. M.; Anderson, N. R. Vitamin
D, A Pluripotent Steroid Hormone: Structural Studies, Molecular
Endocrinology and Clinical Applications; Norman, A. W., Bouillon, R.,
Thomasset, M., Eds.; Walter de Gruyter: Berlin, 1994; pp 73-74.
(11) (a) Lythgoe, B. Chem. Soc. Rev. 1980, 9, 449 and references
therein. (b) Baggiolini, E. G.; Iacobelli, J . A.; Hennessy, B. M.; Batcho,
A. D.; Sereno, J . F.; Uskokovic, M. R. J . Org. Chem. 1986, 51, 3098.
(12) (a) Sardina, F. J .; Mourin˜o, A.; Castedo, L. J . Org. Chem. 1986,
51, 1264. (b) Ferna´ndez, B.; Mart´ınez-Pe´rez, J . A.; Granja, J . R.;
Castedo, L.; Mourin˜o, A. J . Org. Chem. 1992, 57, 3173.
(13) (a) Savignac, P.; Lavielle, G. Bull. Soc. Chim. Fr. 1974, 1506.
(b) Brettle, R.; Dunmur, D. A.; Hindley, N. J .; Marson, C. M. J . Chem.
Soc., Chem. Commun. 1992, 410. (c) Kennedy, G.; Perboni, A. D.
Tetrahedron Lett. 1996, 37, 7611. (d) Katz, H. E.; Bent, S. F.; Wilson,
W. L.; Schilling, M. L.; Ungashe, S. B. J . Am. Chem. Soc. 1994, 116,
6631.
(16) Compound 7 was prepared as per Mourin˜o, A.; Torneiro, M.;
Vitale, C.; Ferna´ndez, S.; Pe´rez-Sestelo, J .; Anne`, S.; Gregorio, C.
Tetrahedron Lett. 1997, 38, 4713.
(17) Vedejs, E.; Fuchs, P. L. J . Am. Chem. Soc. 1971, 93, 4070.
(18) This procedure has been successfully used in these laboratories
for the introduction of olefinic side chains (ref 14).
(14) Rey, M. A.; Mart´ınez-Pe´rez, J . A.; Ferna´ndez-Gacio, A.; Halkes,
K.; Fall, Y.; Granja, J .; Mourin˜o, A. J . Org. Chem. 1999, 64, 3196.
(15) Initial attempts to functionalize bromide 11 through its anion
to give ester 12 using different electrophiles [MeOAc, AcCl, MeOC-
(O)Cl] resulted in poor yields (25-65%) due to extensive protonation.

6980 J . Org. Chem., Vol. 65, No. 21, 2000
Ferna´ndez-Gacio et al.
Sch em e 3a
Sch em e 4a
a
n-BuLi, THF, -78 °C; 5m or 5p (14m , 94%; 14p , 89%); (b)
MeLi, THF, -78 °C (15m , 90%; 15p , 95%); (c) n-Bu4NF, THF (3m ,
90%; 3p , 80%).
At this point we decided to explore photochemical
isomerization as an alternative strategy to obtain the Z
analogues. After much experimentation we were pleased
to find that direct irradiation (THF, medium pressure-
Hg, Pyrex reactor, 90 min) of (E)-ester 12 proceeded
cleanly to provide a separable 4:1 mixture of the desired
(Z)-ester 19 (∼75%) and starting material (17%).19,20
Desilylation and oxidation afforded ketones 6 (∼96%),
which were required for the Wittig-Horner coupling.
The remaning steps to vitamin D analogues 4 are
depicted in Scheme 5 and are similar to those described
for the preparation of vitamin D analogues 3 ( two steps,
overall yield from ketone 8, 28%).
Biologica l Eva lu a tion . The new analogues failed to
bind significantly to the calf thymus vitamin D receptor
(VDR) in in vitro competitive binding assay (RCI assay).21
The RCIs values of 3m , 3p , and 4p were all <1, whereas
the RCI value for 4m was 1.5 as compared for the
reference compound 1R,25-(OH)2-D3. This poor binding
in relation to structurally related analogues6,7 may be
attributed to steric hindrance by the aromatic unit.
Promotion of cell differentiation (in HL-60 human
leukemia cells) and intestinal Ca absorption (in CaCo
cells) have so far been tested only in the case of 4m .22,2n
This analogue proved to be as active as the natural
a
(a) hν, THF (19m , 75%; 19p , 78%); (b) HF, MeCN (20m , 94%;
20p , 92%); (c) PDC, CH2Cl2 (6m , 97%; 6b, 96%).
hormone 1R,25-(OH)2-D3 regarding cell differentiation
and was found to not stimulate the Ca-transport.
The results of broader biological screening of com-
pounds 3m , 3p , 4m , and 4p will be reported in due
course. Small samples of these analogues are available
upon request for further biological evaluation.
In summary, we used the Lythgoe-Hoffmann La Roche
approach to synthesize four new analogues of the hor-
mone 1R,25-(OH)2-D3 with partially locked side chains
(seven to eight steps, overall yield ∼30%). Key steps of
the synthesis are the stereoselective installation of the
E and Z olefinic side-chain fragments and the photo-
chemical step to isomerize E double bonds to Z double
bonds. This route allows the easy preparation of related
vitamin D analogues by simple funcionalization at C25
in the last steps of the synthesis.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions involving oxygen- or
moisture-sensitive compounds were carried out under a dry
argon atmosphere. Reaction temperatures refer to external
bath temperatures. All dry solvents were distilled under argon
immediately prior to use. Tetrahydrofuran (THF), ether (Et2O),
and benzene were distilled from Na/benzophenone. Dichlo-
romethane (CH2Cl2) was distilled from P2O5. Absolute metha-
nol and ethanol were distilled from Mg/I2. Pyridine was
distilled from KOH and CaH2. Hexane, diisopropylamine (i-
Pr2NH), and triethylamine (Et3N) were distilled from CaH2.
(19) Irradiation of (E)-bromide 11 produces a 4:1 mixture of Z- and
E-bromides with significant amounts of the corresponding protonated
compounds. Difficulties were encountered in separating the Z- and
E-bromides by chromatography, and this led us to carry out the
photochemical experiments on the (E)-esters 12.
(20) Attempts to improve the Z/E ratio (4:1) of isomers using various
triplet sensitizers (acetophenone, fluorenone, anthracene, tetracene)
were unsuccessful.
(21) (a) Procsal, D. A.; Okamura, W. H.; Norman, A. W. J . Biol.
Chem. 1975, 250, 8382. (b) Wecksler, W. R.; Norman, A. W. Methods
Enzymol. (Vitamins and Coenzymes) 1980, 67, 488.
(22) The differentiation was expressed as the maturation parameter
nitroblue tetrazolium reduction. The cells were cultured in serum free
medium (i.e., without vitamin D binding protein).

New Analogues of Calcitriol
Sch em e 5a
J . Org. Chem., Vol. 65, No. 21, 2000 6981
m), 5.94 (1 H, s), 4.13 (1 H, m), 2.74-2.47 (3 H, m), 1.20 (1 H,
s), 0.92 (9 H, s), 0.06 (6 H, 2 s). 13C NMR: 157.0 (C), 141.0 (C),
131.1 (CH), 129.7 (CH), 128.4 (CH), 126.8 (CH), 122.0 (C),
115.3 (CH), 69.2 (CH), 50.5 (CH), 45.0 (C), 36.8 (CH2), 34.6
(CH2), 28.3 (CH2), 25.8 (3 CH3), 24.1 (CH2), 21.6 (CH3), 18.0
(C), 17.6 (CH2), -4.8 (CH3), -5.2 (CH3). MS [m/e, (%)]: 436
(MH+, 35), 435 (MH+, 39), 379 [M+ - C(CH3)3, 45], 303 (M+
-
OTBS, 100). Anal. Calcd for C23H35OBrSi: C, 63.57; H, 8.13;
found: C, 63.52; H, 8.19.
(17E)-[8â-(ter t-Bu tyld im eth ylsilyloxy)-1-(4-br om op h e-
n yl)m eth ylid en e]-d e-A,B-a n d r osta n e (11p ). Procedure as
above. 11p [13%, Rf ) 0.7 (hexanes), colorless oil] and 2.1 g of
17p [70%, Rf ) 0.6 (hexanes), colorless oil].
8â-ter t-Bu tyld im eth ylsilyloxy-(17E)-{1-[3-(m eth yloxy-
car bon yl)ph en yl]m eth yliden e}-de-A,B-an dr ostan e (12m ).
Et3N (185 µL, 1.44 mmol), dppp (131 mg, 0.32 mmol), and Pd-
(OAc)2 (65 mg, 0.29 mmol) were added to a solution of 11m
(628 mg, 1.44 mmol) in DMSO (30 mL) and MeOH (10 mL).
The resulting suspension was purged with CO and stirred at
80 °C in a CO atmosphere (balloon pressure). After 12 h of
stirring, H2O was added, and the aqueous portion was
extracted with EtOAc. The combined organic fractions were
dried, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (hexanes) to give 512 mg of
12m [86%, Rf ) 0.33 (3% Et2O/hexanes), colorless oil]. 1H
NMR: 8.01 (1 H, s), 7.82 (1 H, d, J ) 7.69 Hz), 7.48 (1 H, d,
J ) 7.87 Hz), 7.34 (1 H, t, J ) 7.69 Hz, H-Ar), 6.03 (1 H, s,
H-20), 4.09 (1 H, m), 3.89 (3 H, s), 2.80-2.48 (2 H, m), 1.12 (3
H, s), 0.93 (9 H, s), 0.05 (6 H, s). 13C NMR: 167.0 (C), 157.2
(C), 138.9 (C), 132.3 (CH), 129.8 (C), 129.2 (CH), 128.0 (CH),
126.4 (CH), 115.4 (CH), 69.0 (CH), 51.8 (CH3), 50.3 (CH), 45.0
(C), 36.7 (CH2), 34.5 (CH2), 28.2 (CH2), 25.7 (3 CH3), 23.9 (CH2),
21.5 (CH3), 17.9 (CH2), 17.5 (C), -4.9 (CH3), -5.26 (CH3). MS
a
(a) n-BuLi, THF, -78 °C; 6m or 6p (21m , 94%; 21p , 82%); (b)
[m/e, (%)]: 437 (M+ + Na, 19), 415 (MH+, 100), 383 (M+
-
MeLi, THF, -78 °C (22m , 98%; 22p , 93%); (c) n-Bu4NF, THF (4m ,
85%; 4p , 85%).
OMe, 56), 357[M+ - C(CH3)3, 35], 283 (M+ - OTBS, 77).
HRMS: calcd for C25H39O3Si: 415.2668; found: 415.2667. UV
(EtOH) λmax 254 nm; λmin 228 nm.
Dimethyl sulfoxide (DMSO) was stored over 4 Å molecular
sieves. KH was purified by successive washes with hexane and
THF, evaporation of the solvents, and drying of the resulting
solid in vacuo. Dppp [1,3-bis-(diphenylphoshino)propane] was
purchased from Aldrich and used without further purification.
Liquid reagents or solutions of reagents were added by syringe
or cannula. Photochemical reactions were performed with a
Hanovia lamp (450 W) of medium mercury pressure in a Pyrex
glass reactor. Organic extracts were dried over anhydrous Na2-
SO4, filtered, and concentrated using a rotary evaporator at
aspirator pressure (20-30 mmHg). Reactions were monitored
by thin-layer chromatography (TLC) using aluminum-backed
Merck 60 silica gel plates (0.2 mm thickness). After viewing
with ultraviolet illumination at 254 nm, the plates were
visualized by immersion in a solution of phosphomolybdic acid
in MeOH (5%), followed by heating. Flash column chromatog-
raphy was performed with Merck 60 (230-400 mesh) silica
gel. All NMR spectra were measured using solutions in CDCl3
unless otherwise stated. Chemical shifts are reported on the
δ scale (ppm) downfield from tetramethylsilane (δ ) 0.0) using
the residual solvent signal as an internal standard: 7.26 (1H),
77.0 triplet (13C). All coupling constants are measured in hertz
(Hz). Distortionless enhancement by polarization transfer
(DEPT) was used to assign carbon types. Unless otherwise
stated, mass spectra were measured using electron-impact
ionization at 70 eV. Melting points (open capillary tubes) are
uncorrected.
8â-ter t-Bu tyldim eth ylsilyloxy-(17E)-[1-(3-br om oph en yl)-
m eth ylid en e]-d e-A,B-a n d r osta n e (11m ). A solution of ke-
tone 8 (1.88 g, 6.65 mmol) and diethyl 3-bromobenzylphos-
phonate 10m (7.15 g, 23.28 mmol) in dry THF (40 mL) was
added by cannula to a suspension of KH (0.85 g, 21.2 mmol)
in dry THF (20 mL). The mixture was refluxed for 4 h and
the reaction quenched with HCl (5%). The mixture was washed
with water, dried, filtered, and concentrated in vacuo. The
residue, an E/Z mixture (4:1), was purified by flash chroma-
tography (hexanes) to give 0.34 g of 11m [12%, Rf ) 0.7
(hexanes), colorless oil] and 1.97 g of 17m [69%, Rf ) 0.63
(hexanes), colorless oil]. 1H NMR: 7.47 (1 H, m), 7.20 (3 H,
8â-ter t-Bu tyld im eth ylsilyloxy-(17E)-{1-[4-(m eth yloxy-
ca r bon yl)p h en yl]m eth ylid en e}-d e-A,B-a n d r osta n e (12p ).
Procedure as above. 12p [80%, Rf ) 0.31 (3% Et2O/hexanes),
white solid, mp 82-84 °C].
(17E)-{1-[3-(Meth yloxyca r bon yl)p h en yl]m eth ylid en e}-
d e-A,B-a n d r osta n -8â-ol (13m ). An aqueous solution of HF
(48%, 60 drops) was added dropwise to a solution of 12m (440
mg, 1.06 mmol) in acetonitrile (15 mL). The resulting hetero-
geneous mixture was stirred at room temperature for 3 h and
then treated with saturated aqueous NaHCO3. The aqueous
portion was extracted with Et2O. The combined organic
fractions were dried, filtered, and concentrated in vacuo. Flash
chromatography (35% Et2O/hexanes) afforded 294 mg of 13m
1
[92%, Rf ) 0.32 (50% Et2O/hexanes), colorless oil]. H NMR:
7.92 (1 H, s), 7.75 (1 H, d, J ) 7.7 Hz), 7.42 (1 H, d, J ) 7.8
Hz), 7.29 (1 H, dd, J ) 7.7, 7.7 Hz), 5.98 (1 H, s), 4.13 (1 H,
m), 3.83 (3 H, s), 2.78 (1 H, m), 2.46 (1 H, m), 1.07 (3 H, s). 13
C
NMR: 167.3 (CdO), 156.7 (C), 138.8 (C), 132.5 (CH), 129.9
(C), 129.2 (CH), 128.1 (CH), 126.6 (CH), 115.8 (CH), 68.9 (CH),
52.1 (CH), 50.0 (CH3), 44.8 (C), 36.5 (CH2), 33.8 (CH2), 28.2
(CH2), 23.5 (CH2), 21.2 (CH3), 17.4 (CH2). MS [FAB, m/e, (%)]:
322 (M+ - H + Na, 100), 283 (M+ - OH, 44), 251 (MH+
-
CO2Me, 21). HRMS: calcd for C19H25O3: 301.1804; found:
301.1803.
(17E)-{1-[4-(Meth yloxyca r bon yl)p h en yl]m eth ylid en e}-
d e-A,B-a n d r osta n -8â-ol (13p ). Procedure as above. 13p
[96%, Rf ) 0.32 (40% Et2O/hexanes), colorless oil].
(17E)-{1-[3-(Meth yloxyca r bon yl)p h en yl]m eth ylid en e}-
d e-A,B-a n d r osta n -8-on e (5m ). PDC (221 mg, 0.59 mmol) was
added to a solution of 13m (117 mg, 0.39 mmol) in CH2Cl2 (20
mL). After being stirred 8 h, the resulting suspension was
filtered through Celite and concentrated. The resulting residue
was purified by flash chromatography (20% Et2O/hexanes) to
afford 111 mg of pure 5m [95%, Rf ) 0.34 (40% Et2O/hexanes),
1
white solid, mp 65-67 °C]. H NMR: 7.97 (1 H, s), 7.83 (1 H,
d, J ) 7.6 Hz), 7.47 (1 H, d, J ) 7.81 Hz), 7.36 (1 H, dd, J )
7.68, 7.81 Hz), 6.16 (1 H, s), 3.89 (3 H, s), 2.81-2.52 (3 H, m,
H-14, 2 H-16), 0.83 (3 H, s, Me-18). 13C NMR: 210.8 (C), 166.9

6982 J . Org. Chem., Vol. 65, No. 21, 2000
Ferna´ndez-Gacio et al.
(C), 153.6 (C), 138.0 (C), 132.4 (CH), 130.0 (C), 129.2 (CH),
128.2 (CH), 127.0 (CH), 117.5 (CH), 58.9 (CH), 52.0 (CH3), 51.9
(C), 40.9 (CH2), 35.0 (CH2), 27.9 (CH2), 23.5 (CH2), 20.4 (CH2),
19.5 (CH3). Anal. Calcd for C19H22O3: C, 76.47; H, 7.38;
found: C, 76.24; H, 7.59.
(17E)-{1-[4-(Meth yloxyca r bon yl)p h en yl]m eth ylid en e}-
d e-A,B-a n d r osta n -8-on e (5p ). Procedure as above. 5p [91%,
Rf ) 0.4 (40% Et2O/hexanes), white solid, mp 102-103 °C].
(17E)-1r-20-[3-(Dim et h ylh yd r oxym et h yl)p h en yl]-17,-
20-d id eh yd r o-21,22,23,24,25,26,27-h ep t a n or vit a m in D3
(3m ). A solution of TBAF (1.11 M in THF, 0.53 mL, 0.59 mmol)
was added by syringe to a solution of 15m (39 mg, 0.059 mmol)
in THF (3 mL). After the mixture was stirred at room
temperature for 26 h in the dark, a solution of NH4Cl was
added, and the resulting mixture was extracted with Et2O.
The combined organic extracts were dried, filtered, and
concentrated in vacuo to give a residue that was purified by
flash chromatography (80-100% Et2O/hexanes) to afford 23
mg of pure vitamin D analogue 3m [90%, Rf ) 0.55 (100%
EtOAc/hexanes), white solid, mp 100 °C (dec)]. 1H NMR
(MeOD, 300 MHz, δ): 7.49 (1 H, s), 7.28 (3 H, m), 6.39, 6.21
(2 H, AB, J ) 11.1 Hz), 6.17 (1 H, s), 5.35 (1 H, broad s), 4.97
(1 H, broad s), 4.41 (1 H, m), 4.17 (1 H, m), 2.89 (1 H, m), 1.57
(6 H, s), 0.80 (3 H, s). 13C NMR (MeOD, 75.40 MHz, δ): 156.0
(C), 151.0 (C), 150.2 (C), 142.2 (C), 140.0 (C), 136.7 (C), 129.3
(CH), 127.7 (CH), 126.1 (CH), 125.1 (CH), 123.5 (CH), 120.0
(CH), 119.9 (CH), 112.5 (CH2), 73.4 (C), 71.9 (CH), 67.8 (CH),
55.8 (CH), 46.6 (CH2), 44.1 (CH2), 38.4 (CH2), 32.4 (2 CH3),
30.5 (CH2), 30.1 (CH2), 24.9 (2 CH2), 19.8 (CH3). MS [m/e, (%)]:
434 (M+, 7), 416 (M+ - H2O, 48), 398 (M+ - 2 H2O, 96), 111
(100). HRMS: calcd for C29H38O3: 434.2821; found: 434.2801.
(17E)-1r-20-[4-(Dim et h ylh yd r oxym et h yl)p h en yl]-17,-
20-d id eh yd r o-21,22,23,24,25,26, 27-h ep t a n or vit a m in D3
(3p ). Procedure as above. 3p [80%, Rf ) 0.25 (80% EtOAc/
(17E)-1r-ter t-Bu tyld im eth ylsilyloxy-20-[3-(m eth yloxy-
ca r b on yl)p h en yl]-17,20-d id eh yd r o-21,22,23,24,25,26,27-
h ep ta n or vita m in D3 ter t-bu tyld im eth ylsilyl eth er (14m ).
A solution of n-BuLi (2.25 M in hexanes, 190 µL, 0.428 mmol)
was added dropwise by syringe to a solution of the phosphine
oxide 7 (277 mg, 0.476 mmol) in THF (6 mL) at -78 °C. The
resulting deep red solution was stirred at -78 °C for 1 h
followed by the slow addition of a solution of ketone 5m (71
mg, 0.238 mmol) in THF (3 mL). The red solution was stirred
in the dark at -78 °C for 4 h and then warmed to -40 °C over
2 h. The reaction was quenched with H2O. The mixture was
extracted with Et2O, and the combined organic fractions were
washed with brine, dried, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography (2-80%
Et2O/hexanes) to give 146 mg of pure 14m [94%, Rf ) 0.6 (10%
1
Et2O/hexanes), colorless oil]. H NMR (CD2Cl2, 250 MHz, δ):
8.01 (1 H, s,), 7.80 (1 H, d, J ) 7.7 Hz), 7.53 (1 H, d, J ) 7.69
Hz), 7.37 (1 H, dd, J ) 7.7, 7.69 Hz), 6.30, 6.14 (2 H, AB, J )
11.1 Hz), 6.16 (1 H, s), 5.23 (1 H, broad s), 4.90 (1 H, broad s),
4.42 (1 H, m), 4.22 (1 H, m), 3.89 (3 H, s), 2.77-2.52-2.18 (3
H, m), 0.91 (9 H, s), 0.90 (9 H, s), 0.76 (3 H, s), 0.10 (6 H, s),
0.09 (6 H, s). 13C NMR (CD2Cl2, 62.83 MHz, δ): 167.8 (C), 157.5
(C), 149.3 (C), 140.8 (C), 139.8 (C), 136.6 (C), 133.2 (CH), 131.0
(C), 130.0 (CH), 129.1 (CH), 127.4 (CH), 123.7 (CH), 119.4
(CH), 117.8 (CH), 112.0 (CH2), 72.8 (CH), 68.4 (CH), 54.7 (CH),
52.7 (CH3), 49.3 (C), 46.8 (CH2), 45.7 (CH2), 37.5 (CH2), 29.7
(2 CH2), 26.5 (6 CH3), 24.1 (2 CH2), 19.6 (CH3), 19.0 (C), 18.8
(C), -4.10 (CH3). MS [FAB, m/e, (%)]: 663 (MH+, 7), 661 (M+
- H, 7). HRMS: calcd for C40H63O4Si2: 663.4265; found:
663.4268.
1
hexanes), white solid, mp 122 °C (dec)]. H NMR (MeOD, 300
MHz): 7.45 (2 H, d, J ) 8.3 Hz), 7.31 (2 H, d, J ) 8.3 Hz),
6.39, 6.22 (2 H, AB, J ) 11.1 Hz), 6.13 (1 H, s), 5.35 (1 H,
broad s), 4.96 (1 H, broad s), 4.41 (1 H, m), 4.17 (1 H, m), 1.56
(6 H, s), 0.80 (3 H, s). 13C NMR (MeOD, 75.40 MHz): 155.4
(C), 149.8 (C), 148.2 (C), 141.8 (C), 138.1 (C), 136.3 (C), 129.0
(2 CH), 125.4 (2 CH), 124.7 (CH), 119.5 (CH), 118.9 (CH), 112.1
(CH2), 72.8 (C), 71.5 (CH), 67.4 (CH), 55.4 (CH), 49.8 (C), 46.1
(CH2), 43.7 (CH2), 38.0 (CH2), 31.8 (2 CH3), 30.0 (CH2), 26.7
(CH2), 24.5 (2 CH2), 19.4 (CH3). UV (i-PrOH) λmax (ꢀ) 260 nm
(44.000). MS [m/e, (%)]: 434 (M+, 51), 416 (M+ - H2O, 78),
398 (M+ - 2 H2O, 62). HRMS: calcd for C29H38O3: 434.2821;
found: 434.2831.
(17E)-1r-ter t-Bu tyld im eth ylsilyloxy-20-[4-(m eth yloxy-
ca r b on yl)p h en yl]-17,20-d id eh yd r o-21,22,23,24,25,26,27-
h ep ta n or vita m in D3 ter t-bu tyld im eth ylsilyl eth er (14p ).
Procedure as above. 14p [89%, Rf ) 0.83 (20% EtOAc/hexanes),
colorless oil].
8â-ter t-Bu tyld im eth ylsilyloxy-(17Z)-{1-[3-(m eth yloxy-
car bon yl)ph en yl]m eth yliden e}-de-A,B-an dr ostan e (19m ).
A solution of 12m (24 mg, 0.06 mmol) in THF (10 mL) was
irradiated during 1 h 30 min and then concentrated. The
residue, which consisted of a 4:1 Z/E mixture, was purified by
flash chromatography (1% Et2O/hexanes) to give 18 mg of 19m
[75%, RfZ ) 0.37 (3% Et2O/hexanes), colorless oil]. 4 mg of the
(17E)-1r-ter t-Bu t yld im et h ylsilyloxy-20-[3-(d im et h yl-
h yd r oxym eth yl)p h en yl]-17,20-d id eh yd r o-21,22,23,24,25,-
26,27-h ep ta n or vita m in D3 ter t-bu tyld im eth ylsilyl eth er
(15m ). A solution of MeLi (1.5 M in Et2O, 0.32 mL, 0.485
mmol) was added by syringe to a solution of 14m (64 mg, 0.097
mmol) in THF (10 mL) at -78 °C. After 45 min, the reaction
was quenched with H2O. The mixture was extracted with
EtOAc. The combined organic fractions were washed with HCl
(5%) and H2O, dried, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (20-40% Et2O/
hexanes) to give 58 mg of pure 15m [90%, Rf ) 0.58 (20%
1
starting ester 12m was recovered (16%). H NMR: 7.82 (2 H,
broad s), 7.31 (2 H, m), 6.17 (1 H, s), 4.03 (1 H, m), 3.88 (3 H,
s), 2.63 (1 H, m), 2.32 (1 H, m), 1.25 (3 H, s), 0.87 (9 H, s), 0.00
(3 H, s), -0.02 (3 H, s).13C NMR: 167.2 (C), 155.3 (C), 139.2
(C), 133.8 (CH), 130.4 (CH), 129.2 (C), 127.3 (CH), 127.0 (CH),
117.8 (CH), 69.6 (CH), 52.5 (CH), 51.9 (CH3), 44.5 (C), 37.2
(CH2), 34.2 (CH2), 31.0 (CH2), 25.7 (3 CH3), 23.0 (CH2), 20.7
(CH3), 17.9 (C), 17.5 (CH2), -4.9 (CH3), -5.2 (CH3). MS [FAB,
m/e, (%)]: 437 (M+ + Na, 19), 415 (MH+, 100), 383 (M+ - OMe,
44), 357 [M+ - C(CH3)3, 26], 283 (M+ - OTBS, 62). HRMS:
calcd for C25H39O3Si: 415.2668; found: 415.2662. UV (EtOH)
λmax 248 nm; λmin 228 nm.
1
EtOAc/hexanes), colorless oil]. H NMR (MeOD, 250 MHz, δ):
7.49 (1 H, s), 7.28 (3 H, m), 6.33, 6.18 (2 H, AB, J ) 11.2 Hz),
6.17 (1 H, s), 5.27 (1 H, broad s), 4.90 (1 H, broad s), 4.49 (1
H, m, H-1), 4.29 (1 H, m, H-3), 2.88 (1 H, m), 1.57 (6 H, s),
0.94 (18 H, s), 0.80 (3 H, s), 0.14 (6 H, s), 0.13 (6 H, 2 s). 13C
NMR (MeOD, 62.83 MHz, δ): 155.5 (C), 150.6 (C), 150.0 (C),
141.3 (C), 139.6 (C), 136.8 (C), 128.9 (CH), 127.3 (CH), 125.7
(CH), 124.2 (CH), 123.1 (CH), 119.6 (CH), 119.6 (CH), 111.9
(CH2), 73.4 (CH), 72.9 (C), 68.9 (CH), 55.3 (CH), 47.2 (CH2),
46.1 (CH2), 38.0 (CH2), 32.0 (2 CH3), 30.0 (CH2), 29.7 (CH2),
26.5 (3 CH3), 26.4 (3 CH3), 24.5 (CH2), 24.4 (CH2), 19.6 (CH3),
19.2 (C), 19.0 (C), -4.2 (CH3), -4.4 (CH3), -4.5 (CH3), -4.7
(CH3). MS [FAB, m/e, (%)]: 686 (MH+ + Na, 44), 663 (MH+,
44), 661 (M+ - H, 52), 645 (M+ - OH, 38), 531 (M+ - OTBS,
31). HRMS: calcd for C41H67O3Si2: 663.4629; found: 663.4630.
8â-ter t-Bu tyld im eth ylsilyloxy-(17Z)-{1-[4-(m eth yloxy-
ca r bon yl)p h en yl]m eth ylid en e}-d e-A,B-a n d r osta n e (19p ).
Procedure as above. 19p [78%, RfZ ) 0.36 (3% Et2O/hexanes),
white solid, mp 71-72 °C]. Ester 12p was recovered (18%).
(17Z)-{1-[3-(Meth yloxyca r bon yl)p h en yl]m eth ylid en e}-
d e-A,B-a n d r ost a n -8â-ol (20m ). Similar procedure to 13m
and 13p . 20m [94%, Rf ) 0.38 (50% Et2O/hexanes), colorless
oil]. 1H NMR: 7.87-7.84 (2 H, m), 7.36-7.26 (2 H, m), 6.22 (1
H, s), 4.13 (1 H, m), 3.91 (3 H, s), 2.69-2.39 (3 H, m), 1.28 (3
H, s). 13C NMR: 167.3 (C), 154.6 (C), 139.1 (C), 133.8 (CH),
130.4 (CH), 129.3 (C), 127.5 (CH), 127.1 (CH), 118.2 (CH), 69.5
(CH), 52.1 (CH3), 44.2 (C), 37.1 (CH2), 33.5 (CH2), 30.9 (CH2),
22.5 (CH2), 20.4 (CH3), 17.3 (CH2). MS [FAB, m/e, (%)]: 322
(M+ - H + Na, 100), 301 (MH+, 85), 283 (M+ - OH, 95), 269
(M+ - OMe, 36), 251 (MH+ - CO2Me, 21). HRMS: calcd for
(17E)-1r-ter t-Bu t yld im et h ylsilyloxy-20-[4-(d im et h yl-
h yd r oxym eth yl)p h en yl]-17,20-d id eh yd r o-21,22,23,24,25,-
26,27-h ep ta n or vita m in D3 ter t-bu tyld im eth ylsilyl eth er
(15p ). Procedure as above. 15p [95%, Rf ) 0.52 (20% EtOAc/
hexanes), colorless oil].
C
19H25O3: 301.1804; found: 301.1802.
(17Z)-{1-[4-(Meth yloxyca r bon yl)p h en yl]m eth ylid en e}-

New Analogues of Calcitriol
J . Org. Chem., Vol. 65, No. 21, 2000 6983
d e-A,B-a n d r osta n -8â-ol (20p ). Procedure as above. 20p [107
mg, 92%, Rf ) 0.37 (40% Et2O/hexanes), white solid, mp 122
°C].
(CH3), 29.8 (CH2), 26.5 (3 CH3), 26.4 (3 CH3), 24.3 (CH2), 23.6
(CH2), 19.3 (CH3), 19.2 (C), 19.0 (C), -4.2 (CH3), -4.4 (CH3),
-4.5 (CH3), -4.7 (CH3). HRMS: calcd for C41H67O3Si2: 663.4629;
found: 663.4624.
(17Z)-1r-ter t-Bu tyld im eth ylsilyloxy-20-[4-(d im eth ylh y-
d r oxym eth yl)p h en yl]-17,20-d id eh yd r o-21,22,23,24,25,26,-
27-h ep t a n or vit a m in D3 ter t-b u t yld im et h ylsilyl E t h er
(22p ). Procedure as above. 22p [93%, Rf ) 0.53 (20% EtOAc/
hexanes), colorless oil].
(17Z)-{1-[3-(Meth yloxyca r bon yl)p h en yl]m eth ylid en e}-
d e-A,B-a n d r osta n -8-on e (6m ). Procedure as 5m and 5p . 6m
1
[97%, Rf ) 0.34 (40% Et2O/hexanes)]. H NMR: 7.91-7.85 (2
H, m), 7.35 (2 H, m), 6.36 (1 H, s), 3.92 (3 H, s), 2.38-2.76 (3
H, m, H-14), 0.98 (3 H, s). 13C NMR: 211.2 (C), 167.1 (C), 152.3
(C), 138.6 (C), 133.5 (CH), 130.2 (CH), 129.6 (C), 127.8 (CH),
127.5 (CH), 120.0 (CH), 61.4 (CH), 52.1 (CH3), 50.8 (C), 40.9
(CH2), 35.5 (CH2), 30.8 (CH2), 23.6 (CH2), 19.5 (CH2), 19.4
(CH3). MS [FAB, m/e, (%)]: 321 (M+ + Na, 54), 299 (MH+, 100),
283 (M+ - CH3, 25), 267 (M+ - OMe, 74), 237 (37). HRMS:
calcd for C19H23O3: 299.1647; found: 299.1643.
(17Z)-1r-20-[3-(Dim et h ylh yd r oxym et h yl)p h en yl]-17,-
20-d id eh yd r o-21,22,23,24,25,26, 27-h ep t a n or vit a m in D3
(4m ). Procedure as for 3m and 3p . 4m [85%, Rf ) 0.27 (80%
EtOAc/hexanes), white solid, mp 92 °C (dec)]. 1H NMR (MeOD,
300 MHz, δ): 7.34 (1 H, d, J ) 7.5 Hz), 7.33 (1 H, s), 7.23 (1
H, t, J ) 7.5 Hz), 7.04 (1 H, d, J ) 7.4 Hz, H-Ar), 6.39 (1 H,
s), 6.34, 6.19 (2 H, AB, J ) 11.2 Hz), 5.36 (1 H, broad s), 4.96
(1 H, broad s), 4.41 (1 H, m), 4.17 (1 H, m), 1.56 [3 H, s], 1.55
[3 H, s], 0.96 (3 H, s). 13C NMR (MeOD, 75.40 MHz, δ): 154.4
(C), 149.9 (C), 149.8 (C), 141.8 (C), 139.8 (C), 136.2 (C), 128.2
(CH), 126.8 (CH), 124.7 (CH), 123.2 (CH), 122.2 (CH), 119.7
(CH), 112.1 (CH2), 72.8 (CH), 71.4 (CH), 67.4 (CH), 57.7 (CH),
48.4 (C), 46.1 (CH2), 43.7 (CH2), 38.1 (CH2), 32.2 (CH2), 32.0
(CH3), 31.9 (CH3), 29.8 (CH2), 24.3 (CH2), 23.5 (CH2), 19.1
(CH3). MS [m/e, (%)]: 434 (M+, 32), 416 (M+ - H2O, 88), 398
(M+ - 2H2O, 73). Anal. Calcd for C29O3H38: C, 80.13; H, 8.82;
found: C, 80.40; H, 8.74. UV (i-PrOH) λmax (ꢀ) 260 nm (25000).
(17Z)-1r-20-[4-(Dim et h ylh yd r oxym et h yl)p h en yl]-17,-
20-d id eh yd r o-21,22,23,24,25,26, 27-h ep ta n or vita m in D3
(4p ). Procedure as above. 4p [85%, Rf ) 0.5 (100% Et2O), white
(17Z)-{1-[4-(Meth yloxyca r bon yl)p h en yl]m eth ylid en e}-
d e-A,B-a n d r osta n -8-on e (6p ). Procedure as above. 6p [37
mg, 96%, Rf ) 0.5 (40% Et2O/hexanes), white solid, mp 91-
93 °C].
(17Z)-1r-ter t-Bu tyld im eth ylsilyloxy-20-[3-(m eth yloxy-
ca r b on yl)p h en yl]-17,20-d id eh yd r o-21,22,23,24,25,26,27-
h ep ta n or vita m in D3 ter t-bu tyld im eth ylsilyl eth er (21m ).
Procedure as for 14m and 14p . 21m [94%, Rf ) 0.67 (10%
1
Et2O/hexanes), colorless oil]. H NMR (CD2Cl2, 250 MHz, δ):
7.82 (2 H, m), 7.33 (2 H, m), 6.33 (1 H, s), 6.24, 6.10 (2 H, AB,
J ) 11.2 Hz), 5.22 (1 H, broad s), 4.87 (1 H, broad s), 4.40 (1
H, m), 4.18 (1 H, m), 3.87 (3 H, s), 0.90 (9 H, s), 0.87 (9 H, s),
0.87 (3 H, s), 0.09 (6 H, s), 0.06 (6 H, s). 13C NMR (CD2Cl2,
62.83 MHz, δ): 167.8 (CdO), 155.6 (C), 149.3 (C), 140.8 (C),
140.1 (C), 136.5 (C), 134.4 (CH), 131.0 (CH), 130.3 (C), 128.3
(CH), 127.8 (CH), 123.7 (CH), 120.2 (CH), 119.5 (CH), 112.0
(CH2), 72.8 (CH), 68.4 (CH), 57.1 (CH), 52.7 (CH3), 48.0 (C),
46.8 (CH2), 45.7 (CH2), 37.7 (CH2), 32.2 (CH2), 29.4 (CH2), 26.4
(6 CH3), 24.0 (CH2), 23.1 (CH2), 19.3 (CH3), 19.0 (C), 18.8 (C),
-4.1 (CH3), -4.2 (CH3), -4.3 (CH3), -4.4 (CH3). MS [FAB, m/e,
(%)]: 663 (MH+, 14), 661 (M+ - H, 13), 531 (M+ - OTBS, 6).
HRMS: calcd for C40H63O4Si2: 663.4265; found: 663.4263.
(17Z)-1r-ter t-Bu tyld im eth ylsilyloxy-20-[4-(m eth yloxy-
ca r b on yl)p h en yl]-17,20-d id eh yd r o-21,22,23,24,25,26,27-
h ep ta n or vita m in D3 ter t-bu tyld im eth ylsilyl eth er (21p ).
Procedure as above. 21p [82%, Rf ) 0.88 (20% EtOAc/hexanes),
colorless oil].
1
solid, mp 110 °C (dec)]. H NMR (MeOD, 300 MHz): 7.44 (2
H, d, J ) 8.26 Hz), 7.18 (2 H, d, J ) 8.07 Hz), 6.38 (1 H, s),
6.37, 6.22 (2 H, AB, J ) 11.2 Hz), 5.39 (1 H, broad s), 4.99 (1
H, broad s), 4.44 (1 H, m), 4.20 (1 H, m), 2.88 (1 H, m), 1.60 (6
H, s), 0.98 (3 H, s). 13C NMR (MeOD, 75.40 MHz): 154.4 (C),
149.8 (C), 148.6 (C), 141.8 (C), 138.3 (C), 136.2 (C), 129.9 (CH),
124.8 (CH), 124.7 (CH), 121.7 (CH), 119.7 (CH), 112.1 (CH2),
72.9 (C), 71.4 (CH), 67.4 (CH), 57.7 (CH), 46.1 (CH2), 43.7
(CH2), 38.1 (CH2), 32.3 (CH2), 31.9 (CH3), 31.9 (CH3), 29.8
(CH2), 24.3 (CH2), 23.5 (CH2), 19.0 (CH3). MS [m/e, (%)]: 434
(M+, 11), 416 (M+ - H2O, 67), 398 (M+ - 2H2O, 100), 380 (M+
- 3H2O, 44). HRMS: calcd for C29H38O3: 434.2821; found:
434.2848. UV (i-PrOH) λmax (ꢀ) 260 nm (20000).
(17Z)-1r-ter t-Bu tyld im eth ylsilyloxy-20-[3-(d im eth ylh y-
d r oxym eth yl)p h en yl]-17,20-d id eh yd r o-21,22,23,24,25,26,-
27-h ep t a n or vit a m in D3 ter t-b u t yld im et h ylsilyl et h er
(22m ). Procedure as for 15m and 15p . 22m [98%, Rf ) 0.54
(20% EtOAc/hexanes), oil]. 1H NMR (MeOD, 250 MHz, δ): 7.35
(1 H, d, J ) 7.9 Hz), 7.32 (1 H, s), 7.23 (1 H, t, J ) 7.5 Hz),
7.04 (1 H, d, J ) 7.4 Hz), 6.39 (1 H, s), 6.28, 6.16 (2 H, AB, J
) 11.0 Hz), 5.26 (1 H, broad s), 4.90 (1 H, broad s), 4.49 (1 H,
m), 4.28 (1 H, m), 2.73 (1 H, m), 2.20 (2 H, m), 1.56 [3 H, s],
1.55 [3 H, s], 0.95 (9 H, s), 0.94 (3 H, s), 0.93 (9 H, s), 0.15 (6
H, s), 0.12 (6 H, s). 13C NMR (MeOD, 62.83 MHz, δ): 154.3
(C), 149.9 (2 C), 141.3 (C), 139.7 (C), 136.7 (C), 128.2 (CH),
126.7 (CH), 124.2 (CH), 123.2 (CH), 122.2 (CH), 119.9 (CH),
112.0 (CH2), 73.4 (CH), 72.8 (C), 68.9 (CH), 57.7 (CH), 47.2
(CH2), 46.1 (CH2), 38.1 (CH2), 32.3 (CH2), 32.0 (CH3), 31.9
Ack n ow led gm en t. We thank the Spanish MEC for
financial support (Grant PM97-0166) and Solvay-
Pharmaceuticals B. V. for starting materials. A.F-G.
thanks the Spanish MEC for an FPU grant. We also
thank Prof. R. Suau, J .P van de Velde, S. Halkes, and
J . Zorgdrager for valuable suggestions.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
(including DEPT) spectra of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O000579J