Synthesis of new 18-substituted analogues of calcitriol using a photochemical remote functionalization

Article abstract of DOI:10.1021/jo020022z

A novel convergent synthetic approach to new analogues of calcitriol modified at the C-18 position is reported. The key step in the synthesis is the 20-hydroxyl-directed photochemical iodination of the 18-methyl group in the presence of (diacetoxyiodo)benzene. Using this methodology, two new analogues of calcitriol were prepared: the first contains a hydroxylated alkyl side chain attached at C-18 with the natural side chain replaced by an isopropylidene group; the second is a conformationally locked analogue due to an extra oxacycle between the C-18 and C-20 positions.

Full text of DOI:10.1021/jo020022z

Syn th esis of New 18-Su bstitu ted An a logu es of Ca lcitr iol Usin g a
P h otoch em ica l Rem ote F u n ction a liza tion
Iva´n Cornella,† 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 CSIC,
Universidade de Santiago de Compostela, E-15706 Santiago de Compostela, Spain
qfsarand@udc.es
Received J anuary 9, 2002
A novel convergent synthetic approach to new analogues of calcitriol modified at the C-18 position
is reported. The key step in the synthesis is the 20-hydroxyl-directed photochemical iodination of
the 18-methyl group in the presence of (diacetoxyiodo)benzene. Using this methodology, two new
analogues of calcitriol were prepared: the first contains a hydroxylated alkyl side chain attached
at C-18 with the natural side chain replaced by an isopropylidene group; the second is a
conformationally locked analogue due to an extra oxacycle between the C-18 and C-20 positions.
In tr od u ction
Calcitriol (1R,25-dihydroxyvitamin D3, 1b, Figure 1),
the hormonally active form of vitamin D3 (1a ), partici-
pates in a wide range of metabolic functions.1 Besides
the regulation of calcium and phosphorus metabolism,
this compound is involved in the promotion of cellular
differentiation processes, the inhibition of proliferation
of various tumor cell lines, and other functions related
to the immune system. However, the therapeutic value
of calcitriol is limited by the potent calcemic effects
associated with it, and for this reason, the synthesis of
analogues with a selective biological function is an
important goal.2 Calcitriol exerts its biological activity
after interaction with a protein receptor (vitamin D
receptor, VDR) or receptors (VDRs) in the nucleus cell
or in the cellular membrane.3
The vitamin D structure has been extensively modified
in order to explore structure-function relationships and
to find the ideal analogue to give the desired properties.4
Small modifications in the vitamin D structure and
changes in the conformation adopted during the interac-
tion with VDR can modify the biological activity dramati-
cally,4 and several analogues have been identified as
promising drugs for the treatment of certain cancers and
F IGURE 1. Vitamin D3 and calcitriol [1R,25-(OH)2-D3].
psoriasis.1 Most of the modifications have been made in
the flexible parts of the molecule, i.e., the side chain and
the A ring, while other topological regions such as the
triene system or the CD ring remain less explored due
to the absence of efficient synthetic approaches.2 In this
paper, we report a novel convergent synthetic approach
to new calcitriol derivatives modified in the CD ring
region based in the intramolecular photochemical remote
iodination of the 18-methyl group.
It has recently been discovered that inversion of the
stereochemistry at the C-20 position gives rise to highly
active and selective analogues.5 This suggests that in the
conformationally active form of calcitriol the 25-hydroxy
side chain is situated in the upper-left side of the vitamin
D structure.6 Indeed, a recent X-ray diffraction study of
the calcitriol-VDR complex confirmed this hypothesis.7
† Universidade da Corun˜a.
‡ Universidade de Santiago de Compostela.
(1) (a) Vitamin D; Feldman, D., Glorieux, F. H., Pike, J . W., Eds.;
Academic Press: New York, 1997. (b) Calverley, M. J .; J ones, J . In
Antitumor Steroids; Blickenstaff, R. T., Ed.; Academic Press: San
Diego, 1992; Chapter 7, pp 193-270. (c) Norman, A. W.; Litwack, G.
Hormones; Academic Press: San Diego, 1997.
(2) (a) Dai, H.; Posner, G. H. Synthesis 1994, 1383-1398. (b) Zhu,
G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877-1952. (c) Okamura,
W. H.; Zhu, G.-D. In Vitamin D; Feldman, D., Glorieux, F. H., Pike, J .
W., Eds.; Academic Press: New York, 1997; p 939-971.
(3) 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, p 127-148 and references therein.
(4) (a) Okamura, W. H.; Palenzuela, J . A.; Plumet, J .; Midland, M.
M. J . Cell Biochem. 1992, 49, 10-18. (b) Bouillon, R.; Okamura, W.
H.; Norman, A. W. Endocr. Rev. 1995, 16, 200-257.
(5) (a) Binderup, L.; Latini, S.; Binderup, E.; Bretting, C.; Calverley,
M.; Hansen, K. Biochem. Pharmacol. 1991, 42, 1569-1575. (b) Dil-
worth, F. J .; Calverley, M. J .; Makin, H. L.; J ones, G. Biochem.
Pharmacol. 1994, 47, 987-993. (c) Liu, Y.-Y.; Collins, E. D.; Norman,
A. W.; Peleg, S. J . Biol. Chem. 1997, 272, 3336-3345. (d) Yang, W.;
Freedman, L. P. J . Biol. Chem. 1999, 274, 16838-16845.
(6) (a) Yamamoto, K.; Ooizumi, H.; Umesono, K.; Verstuyf, A.;
Bouillon, R.; DeLuca, H. F.; Shinki, T.; Suda, T.; Yamada, S. Bioorg.
Med. Chem. Lett. 1999, 9, 1041-1046. (b) 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, 1467-1472. (c) Yamada, S.; Yamamoto, K.; Masuno,
H.; Choi, M. Steroids 2001, 66, 177-187.
10.1021/jo020022z CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/23/2002
J . Org. Chem. 2002, 67, 4707-4714
4707

Cornella et al.
SCHEME 1. Retr osyn th etic An a lysis
SCHEME 2. Syn th esis of Iod o Keton e 3a
For these reasons, the synthesis of analogues in which
the 25-hydroxy group has this orientation and also
analogues that have a conformationally restricted8 side
chain are now of great interest. In the work described
here, we devised a promising family of calcitriol ana-
logues (4, Scheme 1) in which a hydroxylated alkyl side
chain, similar to the calcitriol one, is placed at the C-18
position. By exploiting the C-18 functionalization, we also
envisioned the synthesis of calcitriol analogues (such as
5) with restricted mobility in the side chain by construct-
ing a new cycle between the C-18 and C-20 or C-21
positions.
a
Key: (a) NaBH4, MeOH, 0 °C [9a /9b (20S/20R) ) 3:7], 99%;
(b) DIB, I2, cyclohexane, hν, then J ones’ reagent, acetone, 0 °C,
84%.
carbons. In this reaction, a hydroxyl group reacts with
DIB in the presence of iodine to produce an alkoxy
radical, presumably via a hypoiodite intermediate, which
is able to abstract close hydrogen atoms intramolecularly
from suitable positioned nonactivated carbons.
The incorporation of an iodine atom offers several
synthetic advantages in terms of further transformations
such as nucleophilic substitutions, halogen-metal ex-
change reactions, as well as radical or transition-metal-
promoted reactions. To explore this possibility, we chose
the known C-20 methyl ketone 211 (Scheme 1), which
contains the CD rings of the vitamin D structure. The
ketone reduction should afford the necessary alkylic
alcohol for posterior photolysis under Sua´rez conditions
for iodination. Analogues of types 4 and 5 should be
available from iodo ketone 3.
The first step in our synthetic venture was therefore
the preparation of iodo ketone 3 (Scheme 2). Reduction
of methyl ketone 2 with NaBH4 afforded a mixture of
alcohols 9 (20R/20S ) 7:3).12 Irradiation of 9 with visible
light under Sua´rez conditions [DIB (1.1 equiv) and I2 (1.0
equiv) in cyclohexane] gave an unstable iodo alcohol that
was immediately oxidized with J ones’ reagent to give the
iodo ketone 3 (84%, 2 steps).
With iodo ketone 3 in hand, we explored its synthetic
utility for C-18 substituted calcitriol analogues. For
analogues of type 4 (Scheme 1, route A), we tried the
introduction of a hydroxylated side chain at C-18. The
halogen-metal exchange reaction with t-BuLi at low
Resu lts a n d Discu ssion
The C-18 position in the vitamin D structure has been
previously functionalized by the introduction of a hy-
droxyl group through a radical reaction with Pb(OAc)4
under thermal or photochemical conditions using an
alkoxy radical inductor placed in the C-8 position.9
Herein, we studied the introduction of an iodine atom
by reaction with (diacetoxyiodo)benzene (DIB) and iodine
under photochemical conditions using a hydroxyl group
at C-20 as the radical inductor. The use of DIB in
photochemical remote functionalization reactions was
first reported by Sua´rez some years ago in steroids.10
Irradiation of alkylic alcohols with visible light in the
presence of DIB and iodine can induce, under adequate
reaction conditions, the remote iodination of nonactivated
(7) (a) Rochel, N.; Wurtz, J . M.; Mitschler, A.; Klaholz, B.; Moras,
D. Mol. Cell 2000, 5, 173-179. (b) Tocchini-Valentini, G.; Rochel, N.;
Wurtz, J . M.; Mitschler, A.; Moras, D. Proc. Natl. Acad. Sci. U.S.A.
2001, 98, 5491-5496.
(8) For recent examples, see: (a) Mart´ınez-Pe´rez, J . A.; Sarandeses,
L.; Granja, J .; Palenzuela, J . A.; Mourin˜o, A. Tetrahedron Lett. 1998,
39, 4725-4728. (b) 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, 3196-3206. (c) Ferna´ndez-Gacio, A.; Vitale, C.; Mourin˜o, A. J . Org.
Chem. 2000, 65, 6978-6983.
(9) (a) Valle´s, M. J .; Castedo, L.; Mourin˜o, A. Tetrahedron Lett. 1992,
33, 1503-1506. (b) Maynard, D. F.; Norman, A. W.; Okamura, W. H.
J . Org. Chem. 1992, 57, 3214-3217. (c) Nilsson, K.; Valle´s, M. J .;
Castedo, L.; Mourin˜o, A.; Halkes, S. J .; van de Velde, J . P. Bioorg. Med.
Chem. Lett. 1993, 3, 1855-1858. (d) Grue-Sorensen, G.; Hansen, C.
H. Bioorg. Med. Chem. 1998, 6, 2029-2039.
(10) (a) Concepcio´n, J . I.; Francisco, C. G.; Herna´ndez, R.; Salazar,
J . A.; Sua´rez, E. Tetrahedron Lett. 1984, 25, 1953-1956. (b) de Armas,
P.; Concepcio´n, J . I.; Francisco, C. G.; Herna´ndez, R.; Salazar, J . A.;
Sua´rez, E. J . Chem. Soc., Perkin Trans. 1 1989, 405-411.
(11) Ferna´ndez, B.; Mart´ınez Pe´rez, J . A.; Granja, J . R.; Castedo,
L.; Mourin˜o, A. J . Org. Chem. 1992, 57, 3173-3178.
(12) (a) Kirk, D. N.; Mudd, A. J . Chem. Soc. C 1969, 968-974. (b)
Fall, Y. Tetrahedron Lett. 1997, 38, 4909-4912.
4708 J . Org. Chem., Vol. 67, No. 14, 2002

Synthesis of 18-Substituted Analogues of Calcitriol
SCHEME 3. Rea ctivity of Iod o Keton e 3a
SCHEME 4. Syn th esis of Ca lcitr iol An a logu e 19a
a
Key: (a) t-BuLi, THF, -78 °C, 75%; (b) methyl acrylate, Zn,
CuI, EtOH/H2O (7:3), sonication, 40%; (c) KO-t-Bu, THF, ∆, 91%;
(d) NaBH4, MeOH, then AgOAc, acetone, ∆, 75%.
temperatures followed by addition of electrophiles (such
as aldehydes or primary halides) failed; instead, the
cyclobutanol 10 (Scheme 3) was obtained.13 The nucleo-
philic substitution reaction of organocuprates with iodo
ketone 3 resulted in the recovery of the starting material.
At that time, we tried the zinc-copper sonochemical
induced conjugate addition reaction of iodides to R,â-
unsaturated systems, developed by Luche14 and later
used in our group for the synthesis of 25-hydroxyvitamin
D derivatives.15 The sonication of iodo ketone 3 and
methyl acrylate with Zn and CuI in aqueous ethanol (70%
v/v) gave the desired 1,4-conjugate addition product, the
ketoester 11, in moderate yield (40%, Scheme 3).16
Additionally, we tested the formation of a cycle be-
tween the position C-18 and C-20 or C-21, with a view
in the synthesis of calcitriol analogues with a conforma-
tionally restricted side chain. Attempts of intramolecular
cyclization of the kinetic enolate from 3 did not give any
reaction product. Alternately, when the iodo ketone 3 was
treated with KO-t-Bu under reflux, the cyclopropanol 12
was obtained stereoselectively and in good yield (91%).17
These results prompted us to explore the formation of
an oxygen bridge between the C-20 and C-18. Stereo-
selective reduction of 3 with NaBH4 and treatment of the
resulting alcohol with silver acetate afforded the ether
a
Key: (a) Ph3PCH3Br, n-BuLi, THF, 0 °C, 80%; (b) n-Bu4NF,
THF, ∆, 87%; (c) PDC, CH2Cl2, 88%; (d) 8, n-BuLi, THF, -78 °C,
65%; (e) MeLi, THF, -78 °C, 86%; (f) n-Bu4NF, THF, rt, 99%.
13 in 75% yield. The stereochemistry of this ether was
assigned by comparison with the 1H NMR chemical shifts
of analogous steroidal compounds.10b,18 The high stereo-
selectivity observed in the reduction step (20R/20S ≈
20:1) can be explained by the presence of the iodine atom
at C-18, blocking the re-face of the carbonyl group.19
At this point, we selected compounds 11 and 13 for the
synthesis of analogues of calcitriol modified at C-18. In
the case of ketoester 11, we planned the synthesis of
analogues of type 4 (Scheme 1, route A). The ester group
could be transformed to a hydroxyalkyl side chain
analogous to the natural in calcitriol and the methyl
ketone converted to a isopropylene group, a suitable
precursor for the natural side chain20 that could also
reduce the flexibility of the hydroxylated side chain at
C-18.9d The vitamin D triene system could be achieved
following the Lythgoe approach.21
(13) Suginome, H.; Nakayama, Y. J . Chem. Soc., Perkin Trans. 1
1992, 1843-1848.
(14) (a) Petrier, C.; Dupuy, C.; Luche, J . L. Tetrahedron Lett. 1986,
27, 3149-3152. (d) Dupuy, C.; Petrier, C.; Sarandeses, L. A.; Luche,
J . L. Synth. Commun. 1991, 21, 643-651. (e) Sarandeses, L. A.;
Mourin˜o, A.; Luche, J . L. J . Chem. Soc., Chem. Commun. 1992, 798-
799.
Wittig reaction of ketoester 11 with the ylide of meth-
ylene triphenylphosphonium bromide afforded regio-
selectively the ester 14 (Scheme 4) in good yield. Removal
of the silyl group at C-8 with n-Bu4NF (14 f 15) and
oxidation of the resulting alcohol 15 with PDC led to the
desired C-8 ketone 16 (76%, two steps). Wittig-Horner
(15) (a) Castedo, L.; Mascaren˜as, J . L.; Mourin˜o, A.; Sarandeses, L.
A. Tetrahedron Lett. 1988, 29, 1203-1206. (b) Mascaren˜as, J . L.;
Sarandeses, L. A.; Castedo, L.; Mourin˜o, A. Tetrahedron 1991, 47,
3485-3498. (c) Mascaren˜as, J . L.; Pe´rez Sestelo, J .; Castedo, L.;
Mourin˜o, A. Tetrahedron Lett. 1991, 32, 2813-2816. (d) Pe´rez Sestelo,
J .; Mascaren˜as, J . L.; Castedo, L.; Mourin˜o, A. J . Org. Chem. 1993,
58, 118-123. (e) Pe´rez Sestelo, J .; Mascaren˜as, J . L.; Castedo, L.;
Mourin˜o, A. Tetrahedron Lett. 1994, 35, 275-278.
(18) Choay, P.; Monneret, C.; Khuong-Huu, Q. Bull. Soc. Chim. Fr.
1973, 1456-1459.
(19) For stereochemical studies in the addition of Grignard reagents
to 20-keto steroids, see: (a) Chaudhuri, N. K.; Williams, J . G.;
Nickolson, R.; Gut, M. J . Org. Chem. 1969, 34, 3759-3766. (b) Makino,
T.; Shibata, K.; Rohrer, D. C.; Osawa, Y. J . Org. Chem. 1978, 43, 276-
280.
(20) The calcitriol side chain has already been prepared from the
isopropylene moiety at C-17; see: (a) Kwon, Y. C.; Midland, M. M. J .
Am. Chem. Soc. 1983, 105, 3725-3727. (b) Sas, B.; De Clercq, P.;
Vandewalle, M. Synlett 1997, 1167-1170.
(16) The major side product (40%) corresponds to the â-scission
compound 29; see the Experimental Section and ref 13.
(21) (a) Lythgoe, B.; Moran, T. A.; Namburidy, M. E. N.; Ruston,
S.; Tideswell, J .; Wright, P. W. Tetrahedron Lett. 1975, 3863-3866.
(b) Lythgoe, B. Chem. Soc. Rev. 1980, 449-475. (c) Baggiolini, E. G.;
Iacobelli, J . A.; Hennessy, B. M.; Batcho, A. D.; Sereno, J . F.; Uskokovic,
M. R. J . Org. Chem. 1986, 51, 3098-3108.
(17) Kirk, D. N.; Rajagopalan, M. S. J . Chem. Soc., Perkin Trans. 1
1976, 1064-1068.
J . Org. Chem, Vol. 67, No. 14, 2002 4709

Cornella et al.
SCHEME 5. Syn th esis of 28a
reaction of ketone 16 with the anion derived from
phosphine oxide 8,22 generated by treatment with n-BuLi
at low temperature, gave the silyl-protected vitamin D
analogue 17 in 65% yield. Addition of methyllithium
followed by treatment with n-Bu4NF gave the desired
calcitriol analogue 19 in 85% overall yield. In this way,
the synthesis of the first analogue of calcitriol with a
hydroxylated alkyl side chain, analogous to the natural
chain, attached at C-18 was achieved. Moreover, the
addition of other organometallics to the ester group in
the vitamin 17 would give a variety of 18-substituted
analogues.
Following with the use of the compounds obtained from
iodo ketone 3 in Scheme 3, we pursued the synthesis of
conformationally restricted side chain analogues of cal-
citriol type 5 (Scheme 1, route B). With the experience
gained in the preparation of ether 13, we planned the
synthesis of calcitriol analogue with an ether bridge
between the C-18 and C-20 positions.23 The retrosyn-
thetical analysis was based in the Lythgoe approach for
the construction of the vitamin D triene system and
intramolecular Williamson reaction of a iodo alcohol
furnished with the calcitriol side chain.
Regioselective alkylation of iodo ketone 3 with LDA
and 3,3-dimethylallyl bromide gave 20 in 89% yield,
which contains a precursor of the 25-hydroxycalcitriol
side chain. Stereoselective reduction of ketone 20 with
NaBH4 yielded iodo alcohol 21 as the only product
1
detected by H NMR spectroscopy.24 As in the reduction
of iodo ketone 3, the presence of the iodine atom at the
C-18 position seems to induce the high stereoselectivity.
Iodo alcohol 21 was converted to ether 22 by an intra-
molecular Williamson reaction using silver acetate (80%
yield). An oxymercuration-demercuration protocol al-
lowed the introduction of the C-25 hydroxyl group (23),
which was protected as the MOM ether (24, 76%, two
steps). Removal of the silyl group at C-8 (24 f 25)
followed by oxidation of the resulting alcohol 25 with
PDC gave ketone 26 (85%, two steps).25 A Wittig-Horner
reaction between ketone 26 and the anion derived from
a
Key: (a) LDA, THF/HMPA, -78 °C, then 3,3-dimethylallyl
bromide, THF, -78 °C to rt, 89%. (b) NaBH4, MeOH, 0 °C, 99%;
(c) AgOAc, acetone, ∆, 80%; (d) Hg(OAc)2, THF/H2O, then NaBH4,
NaOH, H2O, 84%; (e) MOMCl, i-Pr2NEt, DMAP, CH2Cl2, 91%; (f)
n-Bu4NF, THF, ∆, 99%; (g) PDC, CH2Cl2, 85%; (h) 8, n-BuLi, THF,
-78 °C, 78%; (i) n-Bu4NF, THF, rt, then AG 50W-X4, MeOH, rt,
75%.
phosphine oxide 8 afforded the protected vitamin D
analogue 27 in 78% yield. Treatment of 27 with n-Bu4NF
and AG 50W-X4 led to the desired calcitriol analogue 28
in nine steps and 27% overall yield (Scheme 5).
In summary, a novel synthetic strategy for the func-
tionalization of the C-18 position, based on the introduc-
tion of an iodine atom into the bicyclic moiety of the
vitamin D structure by means of a photochemical remote
functionalization using DIB, was developed. This new
methodology allowed the efficient synthesis of two new
calcitriol derivatives from iodo ketone 3: analogue 19,
the first containing a hydroxylated alkyl side chain at
C-18, and analogue 28, with restricted mobility in the
side chain. The synthesis of other new C-18 analogues
of calcitriol from cyclobutanol 12 and cyclopropanol 14
as well as analogues derived from ester 13 are now
underway.
(22) Mourin˜o, A.; Torneiro, M.; Vitale, C.; Ferna´ndez, S.; Pe´rez
Sestelo, J .; Anne´, S.; Gregorio, C. Tetrahedron Lett. 1997, 38, 4713-
4716.
(23) Analogues of calcitriol with oxygen atoms in the side chain have
shown interesting biological properties; see: (a) 20-oxa analogues:
Kubodera, N.; Miyamoto, K.; Ochi, K.; Matsunaga, I. Chem. Pharm.
Bull. 1986, 34, 2286-2289. (b) 22-Oxa analogues: Kubodera, N.;
Watanabe, H.; Kawanishi, T.; Matsumoto, M. Chem. Pharm. Bull.
1992, 40, 1494-1499. (c) 23-Oxa analogues: Kubodera, N.; Miyamoto,
K.; Akiyama, M.; Matsumoto, M.; Mori, T. Chem. Pharm. Bull. 1991,
39, 3221-3224. (d) 24-Oxa analogues: Allewaert, K.; Sarandeses, L.
A.; Mourin˜o, A.; Convents, R.; Tan, B.-K.; Zhao, J .; Bouillon, R. Steroids
1995, 60, 484-490.
(24) The stereochemistry of this alcohol was assigned as (20R) on
the basis of literature precedents; see ref 19a and: (a) Mijares, A.;
Cargill, D. I.; Glasel, J . A.; Lieberman, S. J . Org. Chem. 1967, 32, 810-
812. (b) Piatak, D. M.; Wicha, J . Chem. Rev. 1978, 78, 199-241.
(25) At this step, the stereochemistry at C-20 was definitively
confirmed from the X-ray structure of the semicarbazone 30 prepared
from ketone 26. For experimental details see the Supporting Informa-
tion.
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)
was distilled from the sodium ketyl of benzophenone. Di-
chloromethane (CH2Cl2) was distilled from P2O5. Cyclohexane
4710 J . Org. Chem., Vol. 67, No. 14, 2002

Synthesis of 18-Substituted Analogues of Calcitriol
and i-Pr2NH were distilled from CaH2. Absolute MeOH and
EtOH were distilled from Mg turnings. Methyl acrylate and
HMPA were distilled under vacuum prior use. Zinc was
purified as described in the literature.26 Copper iodide was
purified by recrystallization from saturated potassium iodide
solution.27 J ones’ reagent was prepared by slow addition of
concentrated H2SO4 (10.4 mL) to a cold solution of CrO3 (12.1
g) in water (17 mL) and dissolving the resulting red precipitate
by the addition of water (34 mL).28 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. The compound was usually dis-
solved in 80% of the given volume, and the flask was then
rinsed with the remaining 20% of fresh solvent. Thin-layer
chromatography was effected on silica gel 60 F254 (layer
thickness 0.2 mm), and components were located by observa-
tion 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.29 1H NMR
spectra were recorded on a 200 MHz spectrometer, and 13C
NMR spectra were recorded at 50 MHz.
1 H); 13C NMR (CDCl3) δ -5.5, -4.9, 11.7, 17.1, 17.9, 22.1,
23.1, 25.7 (3), 33.7, 33.9, 40.5, 46.5, 53.4, 63.1, 69.0, 208.8; MS
(EI) m/z 437 (M+ + 1, 2), 379 (M+ - C4H9, 39), 309 (M+ - I, 7),
133 (100); HRMS (EI) calcd for C14H24IO2Si 379.0590 (M+
C4H9), found 379.0589.
-
(8â)-(20S )-8-[(t er t -Bu t yld im e t h ylsilyl)oxy]d e s-A,B-
18,20-cyclop r egn a n -20-ol (10). To a cooled solution of 3
(97 mg, 0.22 mmol) in THF (10 mL) at -78 °C was slowly
added a solution of t-BuLi in hexanes (0.16 mL, 1.7 M, 0.25
mmol) during 10 min. The resulting solution was stirred for
15 min, and an electrophile (RI or RCHO, 0.56 mmol) was
added. The mixture was warmed to room temperature and the
reaction quenched by addition of few drops of MeOH. The
resulting mixture was concentrated to small volume, and Et2O
(20 mL) and a saturated solution of NaHCO3 (10 mL) were
added. The organic phase was washed with a saturated
solution of NaCl (10 mL), dried, filtered, and concentrated in
vacuo. The crude was purified by flash chromatography (5%
EtOAc/hexanes) to afford, after concentration and high vacuum-
drying, 51 mg of 10 (75%) as a colorless oil: Rf ) 0.35 (10%
EtOAc/hexanes); IR (neat) 3400 cm-1; 1H NMR (CDCl3) δ 0.01
(s, 3 H), 0.03 (s, 3 H), 0.88 (s, 9 H), 1.36 (s, 3 H), 1.71 and 2.36
(2 d, AB system, J ) 13.5 Hz, 2 H), 4.13 (dd, J ) 4.8, 2.5 Hz,
1 H); 13C NMR (CDCl3) δ -5.0, -4.9, 17.7, 18.0, 24.1, 25.9 (3),
27.2, 30.5, 34.5, 36.5, 39.3, 43.1, 50.9, 52.6, 68.8, 69.3; MS
(FAB) m/z 310 (M+, 1), 309 (M+ - 1, 5), 295 (M+ - CH3, 1),
293 (M+ - H2O, 12), 217 (100); HRMS (EI) calcd for C18H34O2-
Si 310.2328 (M+), found 310.2335.
(8â,20ê)-8-[(ter t-Bu tyld im eth ylsilyl)oxy]d es-A,B-p r eg-
n a n -20-ol (9).12,30 To a cooled solution of 211 (1580 mg, 5.09
mmol) in MeOH (50 mL) at -20 °C was added NaBH4 (570
mg, 15.07 mmol) in portions. After 30 min of stirring, HCl 5%
(30 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 20 mL). The combined organic phase was washed
with a saturated solution of NaHCO3 (70 mL), dried, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography (10% EtOAc/hexanes) affording, after con-
centration and high vacuum-drying, 1145 mg of 9b (72%) as a
colorless oil and 430 mg of its epimer 9a (27%) as a white solid.
(20R)-9 (9b): Rf 0.3 (10% EtOAc/hexanes); 1H NMR (CDCl3) δ
0.00 (s, 3 H), 0.01 (s, 3 H), 0.89 (s, 9 H), 1.00 (s, 3 H), 1.12 (d,
J ) 6.1 Hz, 3 H), 3.74 (br s, 1 H), 4.01 (m, 1 H); 13C NMR
(CDCl3) δ -5.2, -4.8, 14.4, 17.5, 18.0, 23.2, 23.3, 24.7, 25.8
(3), 34.4, 40.9, 42.0, 52.6, 59.1, 69.1, 70.2. (20S)-9 (9a ): Rf 0.2
(8â)-8-[(ter t-Bu tyldim eth ylsilyl)oxy]des-A,B-18-[2-(m eth -
oxyca r bon yl)eth yl]p r egn a n -20-on e (11). A mixture of Zn
(59 mg, 0.90 mmol) and CuI (58 mg, 0.30 mmol) in aqueous
EtOH (3 mL, 70%) was sonicated for 5 min, and to the
resulting black mixture was succesively added a solution of 3
(120 mg, 0.27 mmol) and methyl acrylate (0.5 mL, 5.8 mmol)
in EtOH (0.8 mL). After 3 h, more Zn (29 mg, 0.44 mmol) and
CuI (28 mg, 0.15 mmol) were added, and the sonication was
continued for 1 h. The mixture was diluted with EtOAc (8 mL)
and filtered through a short pad of Celite, washing the solids
with EtOAc (3 × 10 mL). The organic phase was washed with
saturated NH4Cl (30 mL) and NaCl (30 mL), dried, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography (12% EtOAc/hexanes) to afford, after concen-
tration and high vacuum-drying, 44 mg of 11 as a colorless oil
(40%), 34 mg of (1′R,2′S)-5-[2′-[(tert-butyldimethylsilyl)oxy]-
6′-methylenecyclohexyl]-2-pentanone (29, 40%), and 11 mg of
ketone 2 (12%). 11: Rf 0.35 (30% EtOAc/hexanes); IR (neat)
1
(10% EtOAc/hexanes); H NMR (CDCl3) δ 0.01 (s, 3 H), 0.02
(s, 3 H), 0.88 (s, 9 H), 0.91 (s, 3 H), 1.20 (d, J ) 6.2 Hz, 3 H),
3.69 (dd, J ) 8.4, 6.2 Hz, 1 H), 4.01 (m, 1 H); 13C NMR (CDCl3)
δ -5.2, -4.8, 14.4, 17.4, 18.0, 23.0, 23.3, 25.0, 25.8 (3), 34.3,
39.7, 41.4, 52.9, 59.0, 69.2, 70.2.
(8â)-8-[(ter t-Bu t yld im et h ylsilyl)oxy]d es-A,B-18-iod o-
p r egn a n -20-on e (3). A degassed solution of 9 (600 mg, 1.92
mmol), DIB (680 mg, 2.11 mmol), and iodine (487 mg, 1.92
mmol) in dry cyclohexane (250 mL) was irradiated with visible
light (300 W) for 15 h. The solution was washed with saturated
aqueous Na2S2O3 (70 mL), and the organic phase was dried
(Na2SO4), filtered, and concentrated in vacuo. To the crude iodo
alcohol dissolved in acetone (150 mL) and cooled to 0 °C was
added J ones’ reagent (1.40 mL, 1.9 M). The mixture was stirred
for 2 h, and i-PrOH (12 mL) was added, neutralized by addition
of saturated aqueous NaHCO3 (30 mL), and filtered. The
filtrate was concentrated in vacuo, the residue was extracted
with Et2O (3 × 70 mL), and the organic phase was washed
with brine (50 mL), dried (Na2SO4), filtered, and concentrated
in vacuo. The residue was purified by flash chromatography
(3% EtOAc/hexanes) to afford, after concentration and high
vacuum-drying, 702 mg of 3 (84%) as a pale yellow oil: Rf 0.45
1
2931, 1741, 1704 cm-1; H NMR (CDCl3) δ 0.00 (s, 3 H), 0.02
(s, 3 H), 0.87 (s, 9 H), 2.20 (s, 3 H), 3.64 (s, 3 H), 4.05 (br s, 1
H); 13C NMR (CDCl3) δ -5.3, -4.8, 17.6, 18.0, 20.0, 22.3, 22.7,
25.8 (3), 25.9, 32.4, 34.3, 34.7, 35.9, 47.9, 51.3, 54.9, 63.7, 69.2,
174.0, 210.2; MS (EI) m/z 397 (M+ + 1, 9), 339 (M+ - C4H9,
100); HRMS (EI) calcd for C22H40O4Si 396.2696 (M+), found
396.2689. 29: Rf 0.65 (30% EtOAc/hexanes); IR (neat) 3070,
1
2936, 1719, 1092 cm-1; H NMR (CDCl3) δ 0.04 (s, 6 H), 0.88
(s, 9 H), 2.13 (s, 3 H), 3.75 (m, 1 H), 4.64 (br s, 1 H), 4.73 (br
s, 1 H); 13C NMR (CDCl3) δ -4.9, -4.6, 18.1, 21.9, 24.2, 24.7,
25.8 (3), 29.7, 31.0, 31.2, 44.0, 50.8, 73.1, 109.3, 149.3, 209.2;
MS (EI) m/z 311 (M+ + 1, 6), 293 (25), 253 (M+ - C4H9, 22),
161 (100); HRMS (EI) calcd for C18H34O2Si 310.2328 (M+),
found 310.2331.
(10% EtOAc/hexanes); IR (neat) 2951, 1706 cm-1 1H NMR
;
(CDCl3) δ 0.01 (s, 3 H), 0.03 (s, 3 H), 0.87 (s, 9 H), 2.28 (s, 3
H), 3.18 and 4.45 (2 d, AB system, J ) 11.0 Hz, 2 H), 4.06 (m,
(8â)-(17S )-8-[(t er t -Bu t yld im e t h ylsilyl)oxy]d e s-A,B-
17,18-cyclo-17r-p r egn a n -20-on e (12). A mixture of 3 (48
mg, 0.11 mmol) and KO-t-Bu (26 mg, 0.23 mmol) in THF (10
mL) was refluxed for 3.5 h. The solvent was evaporated in
vacuo, and Et2O (20 mL) was added. The organic layer was
washed succesively with saturated solutions of NaHCO3 (10
mL) and NaCl (10 mL), dried, filtered and concentrated in
vacuo. The crude was purified by flash chromatography (5%
EtOAc/hexanes) to afford 31 mg of 12 (91%) as a colorless oil:
Rf ) 0.55 (10% EtOAc/hexanes); 1H NMR (CDCl3) δ 0.00 (s, 3
H), 0.04 (s, 3 H), 0.89 (s, 9 H), 1.25 (br s, 2 H), 2.14 (s, 3 H),
4.06 (br s, 1 H); 13C NMR (CDCl3) δ -5.1, -4.7, 18.0, 20.3,
(26) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis;
Wiley: New York, 1967; Vol. 1, p 1292.
(27) Kauffman, G. B.; Teter, L. A. Inorg. Synth. 1963, 7, 9-12
(28) Meinwald, J .; Crandall, J .; Hymans, W. E. Organic Syntheses;
Wiley & Sons: New York, 1973; Collect. Vol. V, p 866.
(29) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
(30) Wilson, S. R.; Zhao, H.; Dewan, J . Bioorg. Med. Chem. Lett.
1993, 2, 341-344.
J . Org. Chem, Vol. 67, No. 14, 2002 4711

Cornella et al.
21.2, 21.9, 25.8 (3), 28.4, 28.7, 30.5, 34.3, 41.0, 42.5, 47.6, 68.8,
208.7; MS (EI) m/z 308 (M+, 7), 195 (M+ - C6H15OSi, 5), 118
(100); HRMS (EI) calcd for C18H32O2Si 308.2172 (M+), found
308.2176.
drying, 14 mg of 16 (88%) as a colorless oil: Rf 0.2 (20% EtOAc/
1
hexanes); IR (neat) 1716, 1079 cm-1; H NMR (CDCl3) δ 1.86
(s, 3 H), 3.64 (s, 3 H), 4.88 (br s, 2 H); 13C NMR (CDCl3) δ
18.5, 18.8, 23.9, 24.65, 24.70, 26.4, 34.5, 34.6, 41.0, 51.4, 52.3,
57.4, 63.1, 111.9, 144.8, 173.8, 211.5; MS (EI) m/z 278 (M+,
17), 260 (M+ - H2O, 18), 177 (100); HRMS (EI) calcd for
(8â)-(20R)-8-[(ter t-Bu tyldim eth ylsilyl)oxy]des-A,B-18,20-
ep oxyp r egn a n e (13). To a cooled solution of 3 (234 mg, 0.54
mmol) in MeOH (10 mL) at 0 °C was added NaBH4 (80 mg,
2.11 mmol) in portions. After 30 min of stirring, water (30 mL)
was added, and the mixture was extracted with CH2Cl2 (2 ×
15 mL). The combined organic phase was washed with a
saturated solution of NaHCO3 (15 mL), dried, filtered, and
concentrated in vacuo to afford 234 mg of an unstable iodo
alcohol (99%, 20R/20S ≈ 20:1) as a colorless oil. This crude
compound was dissolved in acetone (19 mL), and AgOAc (267
mg, 1.60 mmol) was added. The resulting mixture was refluxed
for 10 h with protection from the light, cooled, and filtered
through Celite, washing the solids with acetone (3 × 15 mL).
The filtrate was concentrated, and the residue was purified
by flash chromatography (10% EtOAc/hexanes) to give 124 mg
of 13 (75%) as a yellowish oil: Rf ) 0.55 (20% EtOAc/hexanes);
1H NMR (CDCl3) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.89 (s, 9 H),
1.24 (d, J ) 6.2 Hz, 3 H), 3.58 (dd, J ) 9.8, 2.0 Hz, 1 H), 3.60
(dq, J ) 6.2, 3.9 Hz, 1 H), 3.78 (d, J ) 9.8 Hz, 1 H), 4.08 (br s,
1 H); 13C NMR (CDCl3) δ -5.1, -4.9, 18.0, 18.7, 22.1, 25.2,
25.8 (3), 30.6, 34.4, 36.5, 51.4, 54.3, 55.9, 68.6, 72.6, 83.3;
HRMS (EI) calcd for C18H34O2Si 310.2328 (M+), found 310.2329.
C
17H26O3 278.1882 (M+), found 278.1893.
(5Z,7E)-(1S,3R)-1,3-Di[(ter t-bu tyld im eth ylsilyl)oxy]-18-
[2-(m eth oxyca r bon yl)eth yl]-20-m eth yl-9,10-secop r egn a -
5,7,10(19),20-tetr a en e (17). To a cooled solution of the
phosphine oxide 8 (69 mg, 0.12 mmol) in THF (3 mL) at -78
°C was added dropwise a solution of n-BuLi in hexanes (0.075
mL, 1.47 M, 0.11 mmol). The red solution was warmed to 0
°C, stirred for 20 min, and cooled again to -78 °C. Then a
solution of 16 (14 mg, 0.05 mmol) in THF (3 mL) was added
by cannula. The mixture was warmed to -50 °C and quenched
by addition of a few drops of MeOH. The resulting mixture
was concentrated to small volume, and Et2O (8 mL) and a
saturated solution of NH4Cl (10 mL) were added. The organic
phase was washed with a saturated solution of NaCl (10 mL),
dried, filtered, and concentrated with protection from the light.
The residue was purified by flash chromatography (30%
EtOAc/hexanes) to afford, after concentration and high vacuum-
drying, 21 mg of 17 (65%) as a colorless oil: Rf 0.75 (50%
1
EtOAc/hexanes); H NMR (CD2Cl2) δ 0.14 (s, 6 H), 0.21 (s, 3
H), 0.22 (s, 3 H), 1.02 (s, 9 H), 1.08 (s, 9 H), 1.78 (s, 3 H), 3.39
(s, 3 H), 4.28 (m, 1 H), 4.56 (m, 1 H), 4.88 (s, 1 H), 4.91 (s, 1
H), 5.20 (br s, 1 H), 5.43 (br s, 1 H), 6.37 and 6.53 (2 d, AB
system, J ) 11.2 Hz, 2 H); 13C NMR (CD2Cl2) δ -4.7 (2), -4.4
(2), 19.6, 22.0, 23.9, 25.0, 25.1, 25.7, 26.0 (6), 26.1, 29.1, 30.2,
30.4, 35.0, 35.9, 45.4, 46.5, 48.7, 50.8, 57.8, 57.9, 68.0, 72.4,
119.3, 123.7, 128.3, 135.8, 140.9, 145.9, 149.0, 173.2; MS (FAB)
m/z 642 (M+, 8), 525 (M+ - C6H17Si, 100); HRMS (EI) calcd
for C38H66O4Si2 642.4500 (M+), found 642.4491.
(8â)-8-[(ter t-Bu tyldim eth ylsilyl)oxy]des-A,B-18-[2-(m eth -
oxyca r bon yl)eth yl]-20-m eth yl-20-p r egn en e (14). To a sus-
pension of methyltriphenylphosphonium bromide (65 mg, 0.18
mmol) in THF (20 mL) at 0 °C was added a solution of n-BuLi
in hexanes (0.11 mL, 1.64 M, 0.18 mmol), and the resulting
yellow mixture was warmed and stirred for 15 min at room
temperature. Then, a solution of ketone 11 (32 mg, 0.08 mmol)
in THF (9 mL) was slowly added by cannula. After being
stirred for 20 h, a saturated solution of NH4Cl (20 mL) was
added, and the mixture was extracted with EtOAc (4 × 8 mL).
The combined organic phase was dried, filtered, concentrated
in vacuo, and purified by flash chromatography (8% EtOAc/
hexanes) to give 57 mg of 14 (80%) as a colorless oil: Rf 0.6
(5Z,7E)-(1S,3R)-1,3-Di[(ter t-bu tyld im eth ylsilyl)oxy]-18-
(3-h yd r oxy-3-m et h ylb u t yl)-20-m et h yl-9,10-secop r egn a -
5,7,10(19),20-tetr a en e (18). To a cooled solution of 17 (19 mg,
0.03 mmol) in THF (3 mL) at -78 °C was slowly added a
solution of MeLi in hexanes (0.18 mL, 1.22 M, 0.22 mmol)
during 10 min. The mixture was warmed to -10 °C, stirred
for 5 h, and quenched with a few drops of MeOH. The resulting
mixture was concentrated to small volume, and the residue
was dissolved in CH2Cl2 (8 mL), washed with saturated NH4Cl
(10 mL), dried, filtered, and concentrated in vacuo. The crude
was purified by flash chromatography (20% EtOAc/hexanes)
to afford, after concentration and high vacuum-drying, 16 mg
of 18 (86%) as a colorless oil: Rf 0.7 (50% EtOAc/hexanes); IR
(neat) 3447, 1642 cm-1; 1H NMR (CDCl3) δ 0.12 (s, 3 H), 0.13
(s, 3 H), 0.21 (s, 3 H), 0.23 (s, 3 H), 1.02 (s, 9 H), 1.09 (s, 9 H),
1.10 (s, 6 H), 1.82 (s, 3 H), 4.29 (m, 1 H), 4.55 (m, 1 H), 4.90
(br s, 1 H), 4.94 (br s, 1 H), 5.23 (d, J ) 2.9 Hz, 1 H), 5.43 (d,
J ) 2.9 Hz, 1 H), 6.43 and 6.57 (2 d, AB system, J ) 11.2 Hz,
2 H); 13C NMR (CDCl3) δ -4.6 (4), 18.3, 18.4, 18.5, 22.1, 24.0,
24.9, 25.1, 26.0 (6), 26.2 (2), 26.5, 28.9, 29.2, 29.9, 36.1, 45.38,
45.42, 46.6, 49.2, 57.88, 57.93, 67.9, 72.5, 110.8, 111.7, 119.2,
123.8, 128.3, 135.7, 146.3; MS (FAB) m/z 643 (M+, 3), 511 (M+
- C6H15OSi, 7), 288 (100); HRMS (EI) calcd for C39H70O3Si2
642.4864 (M+), found 642.4872.
(5Z,7E)-(1S,3R)-18-(3-Hydr oxy-3-m eth ylbu tyl)-20-m eth -
yl-9,10-secop r egn a -5,7,10(19),20-tetr a en e-1,3-d iol (19). To
a solution of 18 (15 mg, 0.02 mmol) in THF (5 mL), with
protection from light, was added n-Bu4NF‚3H2O (30 mg, 0.09
mmol). The solution was stirred for 20 h and poured into a
separatory funnel with EtOAc (8 mL), and the organic layer
was washed with a saturated solution of NH4Cl (10 mL), dried,
filtered, and concentrated in vacuo. The crude was purified
by flash chromatography (20% MeOH/EtOAc) to afford 13 mg
of 19 (99%) as a white solid: Rf 0.2 (EtOAc); 1H NMR (CD3OD)
δ 1.13 (s, 3 H), 1.15 (s, 3 H), 1.88 (s, 3 H), 4.17 (m, 1 H), 4.40
(m, 1 H), 4.83 (s, 1 H), 4.89 (s, 1 H), 4.95 (br s, 1 H), 5.34 (br
s, 1 H), 6.14 and 6.37 (2 d, AB system, J ) 11.2 Hz, 2 H); 13C
NMR (CD3OD) δ 15.5, 20.4, 23.8, 24.7, 26.0, 26.2, 26.9, 28.3,
(20% EtOAc/hexanes); IR (neat) 1742, 1252, 1026 cm-1 1H
;
NMR (CDCl3) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.89 (s, 9 H), 1.82
(s, 3 H), 3.65 (s, 3 H), 4.03 (m, 1H), 4.78 (br s, 1 H), 4.83 (br s,
1 H); 13C NMR (CDCl3) δ -5.2, -4.8, 17.8, 18.0, 19.9, 22.5,
24.5, 25.1, 25.8 (3), 26.1, 34.6, 35.3, 36.1, 45.8, 51.3, 54.4, 57.7,
69.6, 110.3, 146.4, 174.4; MS (EI) m/z 394 (M+, 23), 379 (M+
-
CH3, 47), 337 (M+ - C4H9, 100); HRMS (EI) calcd for C23H42O3-
Si 394.2903 (M+), found 394.2891.
(8â)-Des-A,B-18-[2-(m eth oxyca r bon yl)eth yl]-20-m eth yl-
p r egn -20-en -8-ol (15). To a solution of 14 (40 mg, 0.10 mmol)
in THF (12 mL) was added a solution of n-Bu4NF in THF (0.31
mL, 1 M, 0.31 mmol), and the resulting mixture was heated
to reflux during for 22 h. The reaction mixture was cooled to
room temperature, poured into a separatory funnel with EtOAc
(30 mL), washed succesively with HCl (3%, 12 mL), saturated
solutions of NaHCO3 (20 mL), and NaCl (20 mL), dried,
filtered, and concentrated in vacuo. The crude was purified
by flash chromatography (35% EtOAc/hexanes) to afford 24
mg of 15 (87%) as a colorless oil: Rf 0.15 (20% EtOAc/hexanes);
IR (neat) 3450, 3000, 2925, 1757, 1290 cm-1; 1H NMR (CDCl3)
δ 1.83 (s, 3 H), 3.65 (s, 3 H), 4.12 (m, 1 H), 4.80 (br s, 1 H),
4.84 (br s, 1 H); 13C NMR (CDCl3) δ 17.7, 20.0, 22.0, 24.5, 25.1,
26.3, 33.9, 35.1, 36.0, 45.5, 51.3, 54.0, 57.5, 69.4, 110.5, 146.1,
174.4; MS (EI) m/z 280 (M+, 18), 262 (M+ - H2O, 42), 119 (100);
HRMS (EI) calcd for C17H28O3 280.2038 (M+), found 280.2037.
Des-A,B-18-[2-(m eth oxycar bon yl)eth yl]-20-m eth ylpr egn -
20-en -8-on e (16). A mixture of 15 (16 mg, 0.06 mmol) and
PDC (64 mg, 0.17 mmol) in CH2Cl2 (5 mL) was stirred for 6 h.
Et2O (10 mL) was added, and the resulting mixture was stirred
for 15 min and filtered through Celite, washing the solids with
Et2O (5 × 10 mL). The filtrate was concentrated in vacuo, and
the residue was purified by flash chromatography (18% EtOAc/
hexanes), affording, after concentration and high vacuum-
4712 J . Org. Chem., Vol. 67, No. 14, 2002

Synthesis of 18-Substituted Analogues of Calcitriol
29.4, 30.6, 31.0, 34.1, 38.1, 44.7, 47.0, 47.2, 59.9, 68.4, 72.5,
112.1, 113.2, 120.7, 125.8, 137.0, 143.4, 148.4, 150.8; MS (EI)
m/z 414 (M+, 5), 396 (M+ - H2O, 10), 69 (100); HRMS (EI)
calcd for C27H42O3 414.3134 (M+), found 414.3131.
mmol) were succesively added. After the mixture was stirred
for 15 min, saturated NaCl (15 mL) was added, and the
mixture was extracted with Et2O (3 × 15 mL). The combined
organic phase was dried, filtered, and concentrated in vacuo
to afford a yellow residue that was flash chromatographed
(20% EtOAc/hexanes) to give, after concentration and high
vacuum-drying, 113 mg of 23 (84%) as a colorless oil: Rf 0.6
(8â)-8-[(ter t-Bu t yld im et h ylsilyl)oxy]d es-A,B-18-iod o-
21-n or ch olest-24-en -20-on e (20). To a solution of LDA,
prepared by addition of i-Pr2NH (0.07 mL, 0.55 mmol) to a
solution of n-BuLi in hexanes (0.33 mL, 1.61 M, 0.53 mmol)
at -78 °C and dilution with THF (5 mL),31 was slowly added
a solution of 3 (190 mg, 0.43 mmol) in THF (5 mL) by cannula.
After 45 min, HMPA (0.24 mL, 1.37 mmol) and 3,3-dimethyl-
allyl bromide (0.16 mL, 1.37 mmol) were succesively added.
The solution was warmed to room temperature for 4 h, the
solvents were evaporated in vacuo, and the resulting residue
was dissolved in Et2O (15 mL). The organic phase was
succesively washed with water (15 mL) and brine (15 mL),
dried, filtered, and concentrated in vacuo. The crude was
purified by flash chromatography (7% EtOAc/hexanes) to
afford, after concentration and high vacuum-drying, 193 mg
of 20 (89%) as a colorless oil: Rf 0.55 (10% EtOAc/hexanes);
IR (neat) 3068, 2930, 1705, 1254, 1022 cm-1; 1H NMR (CDCl3)
δ 0.01 (s, 3 H), 0.03 (s, 3 H), 0.87 (s, 9 H), 1.62 (s, 3 H), 1.68
(s, 3 H), 3.15 and 4.46 (2 d, AB system, J ) 10.7 Hz, 2 H),
4.07 (br s, 1 H), 5.12 (t, J ) 7.3 Hz, 1 H); 13C NMR (CDCl3) δ
-5.2, -4.8, 11.6, 17.1, 17.7, 17.9, 22.3, 22.9, 23.3, 25.66, 25.72
(3), 33.8, 40.7, 46.3, 46.7, 53.5, 61.9, 69.1, 123.1, 132.4, 210.1;
MS (FAB) m/z 503 (M+ - 1, 5), 447 (M+ - C4H9, 6), 377 (M+
- I, 29); HRMS (EI) calcd for C23H41O2SiI 504.1921 (M+), found
504.1929.
(50% EtOAc/hexanes); IR (neat) 3490, 1254, 1021 cm-1 1H
;
NMR (CDCl3) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.88 (s, 9 H), 1.21
(s, 6 H), 3.45 (m, 1 H), 3.58 (dd, J ) 9.8, 2.0 Hz, 1 H), 3.79 (d,
J ) 9.8 Hz, 1 H), 4.08 (br s, 1 H); 13C NMR (CDCl3) δ -5.1,
-4.9, 18.0, 18.7, 21.4, 25.2, 25.8 (3), 29.0, 29.3, 30.8, 34.4, 36.4,
37.1, 43.9, 51.4, 53.9, 54.5, 68.6, 71.0, 72.3, 87.6; MS (EI) m/z
396 (M+, 10), 381 (M+ - CH3, 19), 378 (M+ - H2O, 19), 295
(100); HRMS (EI) calcd for C23H44O3Si 396.3059 (M+), found
396.3047.
(8â)-(20R)-8-[(ter t-Bu tyldim eth ylsilyl)oxy]des-A,B-18,20-
ep oxy-25-[(m eth oxym eth yl)oxy]-21-n or ch olesta n e (24).
To a cooled solution of 23 (42 mg, 0.11 mmol) and DMAP (5
mg, 0.04 mmol) in CH2Cl2 (5 mL) at 0 °C were succesively
added i-Pr2NEt (0.08 mL, 0.44 mmol) and MOMCl (0.04 mL,
0.50 mmol). After the mixture was stirred at room temperature
for 30 h, water (5 mL) was added, and the organic phase was
washed with HCl (3%, 15 mL) and saturated NaHCO3 (15 mL),
dried, filtered, and concentrated in vacuo. The residue was
flash chromatographed (20% EtOAc/hexanes) to give 44 mg
of 24 (91%) as a colorless oil: Rf 0.75 (50% EtOAc/hexanes);
1H NMR (CDCl3) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.88 (s, 9 H),
1.21 (s, 6 H), 3.36 (s, 3 H), 3.43 (m, 1 H), 3.57 (dd, J ) 9.8, 2.0,
1 H), 3.79 (d, J ) 9.8 Hz, 1 H), 4.07 (br s, 1 H), 4.70 (s, 2 H);
13C NMR (CDCl3) δ -5.1 (2), 18.0, 18.7, 21.1, 25.2, 25.8 (2),
26.1, 26.3, 30.8, 34.4, 36.4, 37.2, 42.0, 51.4, 53.9, 54.4, 55.1,
(8â)-(20R)-8-[(ter t-Bu tyld im eth ylsilyl)oxy]d es-A,B-18-
iod o-21-n or ch olest-24-en -20-ol (21). To a cooled solution of
20 (94 mg, 0.19 mmol) in MeOH (10 mL) at 0 °C was added
NaBH4 (25 mg, 0.66 mmol) in portions. After 30 min of stirring,
water (30 mL) was added, and the mixture was extracted with
CH2Cl2 (2 × 15 mL). The combined organic phase was washed
with a saturated solution of NaHCO3 (15 mL), dried, filtered,
and concentrated in vacuo to afford 94 mg of 21 (99%) as a
68.6, 72.3, 87.7, 91.0; MS (EI) m/z 439 (M+ - 1, 6), 425 (M+
-
CH3, 10), 321 (100); HRMS (EI) calcd for C25H48O4Si 440.3322,
found 440.3308.
(8â)-(20R)-Des-A,B-18,20-ep oxy-25-[(m et h oxym et h yl)-
oxy]-21-n or ch olesta n -8-ol (25). Following the same experi-
mental procedure as for 15, reaction of 24 (40 mg, 0.07 mmol)
with n-Bu4NF‚3H2O (100 mg, 0.30 mmol) afforded, after
purification by flash chromatography (25% EtOAc/hexanes),
33 mg of 25 (99%) as a colorless oil: Rf 0.3 (50% EtOAc/
1
colorless oil: Rf 0.3 (5% EtOAc/hexanes); H NMR (CDCl3) δ
0.01 (s, 3 H), 0.04 (s, 3 H), 0.89 (s, 9 H), 1.64 (s, 3 H), 1.70 (s,
3 H), 3.11 and 4.61 (2 d, AB system, J ) 11.0 Hz, 2 H), 3.90
(m, 1 H), 4.04 (br s, 1 H), 5.12 (t, J ) 7,3 Hz, 1 H); 13C NMR
(CDCl3) δ -5.2, -4.8, 12.7, 16.7, 17.7, 17.9, 23.0, 23.9, 24.3,
25.8 (3), 29.7, 33.9, 35.3, 41.2, 44.7, 52.8, 57.4, 69.2, 71.0, 124.4,
131.8; MS (EI) m/z 505 (M+ - 1, 4), 488 (M+ - H2O, 7), 379
(M+ - I, 29), 229 (100); HRMS (EI) calcd for C23H43IO2Si
506.2077 (M+), found 506.2064.
1
hexanes); H NMR (CDCl3) δ 1.21 (s, 6 H), 3.36 (s, 3 H), 3.45
(m, 1 H), 3.56 (dd, J ) 9.8, 2.0 Hz, 1 H), 3.83 (d, J ) 9.8 Hz,
1 H), 4.17 (br s, 1 H), 4.70 (s, 2 H); 13C NMR (CDCl3) δ 18.6,
21.0, 24.8, 26.1, 26.3, 30.8, 33.9, 36.3, 37.0, 42.0, 51.0, 53.7,
54.3, 55.1, 68.1, 71.9, 76.3, 87.7, 91.0; MS (EI) m/z 311 (M+
-
CH3, 1), 265 (M+ - C2H5O2, 16), 181 (100); HRMS (EI) calcd
(8â)-(20R)-8-[(ter t-Bu tyldim eth ylsilyl)oxy]des-A,B-18,20-
ep oxy-21-n or ch olest-24-en e (22). A mixture of 21 (230 mg,
0.45 mmol) and AgOAc (227 mg, 1.36 mmol) in acetone (19
mL) was refluxed during 5 h with protection from light. The
resulting mixture was filtered through Celite, washing the
solids with acetone (3 × 15 mL), the filtrate was concentrated,
and the residue was purified by flash chromatography (10%
EtOAc/hexanes) to give 136 mg of 22 (80%) as a yellowish oil:
for C19H34O4 326.2457 (M+), found 326.2462.
(20R)-Des-A,B-18,20-ep oxy-25-[(m et h oxym et h yl)oxy]-
21-n or ch olesta n -8-on e (26). Following the same experimen-
tal procedure as for 16, alcohol 25 (33 mg, 0.10 mmol) was
oxidized with PDC (115 mg, 0.31 mmol) to give 28 mg of ketone
26 (85%) as a colorless oil: Rf 0.4 (50% EtOAc/hexanes); IR
(neat) 1707, 1040 cm-1; 1H NMR (CD2Cl2) δ 1.17 (s, 6 H), 2.60
(m, 1 H), 3.19 (dd, J ) 9.8, 2.0 Hz, 1 H), 3.51 (d, J ) 9.8 Hz,
1 H), 3.30 (s, 3 H), 3.57 (m, 1 H), 4.64 (s, 2 H); 13C NMR
(CD2Cl2) δ 21.1, 22.8, 25.7, 26.36, 26.39, 31.7, 35.8, 36.2, 41.1,
42.2, 54.1, 55.1, 60.6, 60.8, 71.3, 76.2, 88.8, 91.3, 210.4; MS
Rf 0.65 (10% EtOAc/hexanes); IR (neat) 2930, 1253, 1021 cm-1
;
1H NMR (CDCl3) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.89 (s, 9 H),
1.61 (s, 3 H), 1.69 (d, J ) 1.1 Hz, 3 H), 3.44 (dt, J ) 6.6, 3.7
Hz, 1 H), 3.57 (dd, J ) 9.8, 2.0 Hz, 1 H), 3.79 (d, J ) 9.8 Hz,
1 H), 4.08 (br s, 1 H), 5.13 (br t, J ) 7.0 Hz, 1 H); 13C NMR
(CDCl3) δ -5.1, -4.8, 17.7, 18.0, 18.7, 25.0, 25.2, 25.7, 25.8
(3), 30.8, 34.4, 36.4, 36.8, 51.4, 53.9, 54.4, 68.6, 72.3, 87.3,
124.2, 131.5; MS (EI) m/z 378 (M+, 12), 321 (M+ - C4H9, 46),
75 (100); HRMS (EI) calcd for C23H42O2Si 378.2954 (M+), found
378.2957.
(EI) m/z 323 (M+ - 1, 12), 309 (M+ - CH3, 6), 263 (M+
-
C2H5O2, 53), 83 (100); HRMS (EI) calcd for C19H32O4 324.2301
(M+), found 324.2308.
(5Z,7E)-(1S,3R,20R)-1,3-Di[(ter t-b u t yld im et h ylsilyl)-
oxy]-18,20-ep oxy-25-[(m et h oxym et h yl)oxy]-21-n or -9,10-
secoch olesta -5,7,10(19)-tr ien e (27). Following the same
experimental procedure as for 17, reaction of ketone 26 (17
mg, 0.05 mmol) with the anion formed from phosphine oxide
8 (78 mg, 0.13 mmol) generated by addition of n-BuLi in
hexanes (0.06 mL, 2.17 M, 0.13 mmol) afforded, after purifica-
tion by flash chromatography (35% EtOAc/hexanes), 28 mg of
27 (78%) as a colorless oil: Rf 0.7 (50% EtOAc/hexanes); 1H
NMR (CD2Cl2) δ 0.05 (s, 6 H), 0.07 (s, 6 H), 0.86 (s, 9 H), 0.89
(s, 9 H), 1.17 (s, 6 H), 3.20 (dd, J ) 9.8, 2.0 Hz, 1 H), 3.42 (d,
(8â)-(20R)-8-[(ter t-Bu tyldim eth ylsilyl)oxy]des-A,B-18,20-
ep oxy-21-n or ch olesta n -25-ol (23). A mixture of 22 (130 mg,
0.34 mmol) and Hg(OAc)2 (120 mg, 0.37 mmol) in THF/H2O
(20 mL, 1:1) was stirred for 7 days. Then, NaOH (8 mL, 3 M)
and a solution of NaBH4 in 3 M NaOH (3.4 mL, 0.5 M, 1.7
(31) Vedejs, E.; Engler, D. A.; Telschow, J . E. J . Org. Chem. 1978,
43, 188-196.
J . Org. Chem, Vol. 67, No. 14, 2002 4713

Cornella et al.
J ) 9.8 Hz, 1 H), 3.30 (s, 3 H), 3.55 (m, 1 H), 4.20 (m, 1 H),
4.39 (m, 1 H), 4.64 (s, 2 H), 4.85 (d, J ) 2.4 Hz, 1 H), 5.21 (d,
J ) 2.4 Hz, 1 H), 6.07 and 6.18 (2 d, AB system, J ) 11.2 Hz,
2 H); 13C NMR (CD2Cl2) δ -5.0, -4.9, -4.72, -4.68, 21.1, 25.4,
25.9 (3), 26.0 (3), 26.37, 26.42, 28.8, 28.9, 32.3, 36.1, 37.7, 42.2,
44.3, 46.1, 54.1, 55.1, 55.4, 55.5, 57.9, 67.5, 67.9, 70.8, 71.8,
76.3, 89.2, 91.3, 115.7, 117.2, 121.8, 123.1, 143.4, 153.9; MS
H), 3.42 (d, J ) 9.3 Hz, 1 H), 3.56 (m, 1 H), 4.16 (m, 1 H), 4.37
(m, 1 H), 4.95 (br s, 1 H), 5.30 (br s, 1 H), 6.08 and 6.28 (2 d,
AB system, J ) 11.2 Hz, 2 H); 13C NMR (CD2Cl2) δ 21.4, 25.4,
26.1, 29.0, 29.3, 29.5, 32.3, 35.9, 37.7, 43.4, 44.2, 45.6, 53.8,
55.5, 57.9, 67.1, 70.9 (2), 71.9, 89.2, 111.7, 116.5, 124.4, 134.7,
142.7, 148.5; MS (FAB) m/z 417 (M+ + 1, 8), 416 (M+, 4), 307
(100). HRMS (EI) calcd for C26H40O4 416.2927 (M+), found
416.2921.
(EI) m/z 688 (M+, 28), 627 (M+ - C2H5O2, 6), 556 (M+
-
C6H15OSi, 85), 248 (100); HRMS (EI) calcd for C40H72O5Si2
688.4918 (M+), found 688.4921.
Ack n ow led gm en t. We are grateful to the Xunta de
Galicia (XUGA 10305A98), DGES (Spain, PM97-0166),
and the University of A Corun˜a for financial support.
I.C. acknowledges a predoctoral fellowship from the
University of A Corun˜a. We also thank RIAIDT-AÄ rea
de Estudio Estructural/Unidade de Rayos X (Univer-
sidade de Santiago de Compostela, Spain) for the X-ray
structure determination.
(5Z,7E)-(1S,3R,20R)-18,20-Epoxy-21-n or -9,10-secoch oles-
ta -5,7,10(19)-tr ien -1,3,25-tr iol (28). To a solution of 27 (22
mg, 0.03 mmol) in THF (5 mL) protected from the light was
added n-Bu4NF‚3H2O (40 mg, 0.13 mmol). The solution was
stirred for 22 h and poured into a separatory funnel with
EtOAc (10 mL), and the organic layer was washed with a
saturated solution of NH4Cl (10 mL), dried, filtered, and
concentrated in vacuo. The residue was dissolved in deoxy-
genated MeOH (5 mL), and resin AG 50W-X4 (150 mg) was
added. The mixture was stirred for 22 h and filtered, the solids
were washed with MeOH (4 × 5 mL) and concentrated in
vacuo. The residue was purified by flash chromatography (3%
MeOH/EtOAc) to afford, after concentration and high vacuum-
drying, 10 mg of 28 (75%) as a colorless oil: Rf 0.2 (EtOAc);
1H NMR (CD2Cl2) δ 1.16 (s, 6 H), 3.22 (dd, J ) 9.3, 1.5 Hz, 1
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds. Experimental procedure for
the preparation of 30 and X-ray data. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O020022Z
4714 J . Org. Chem., Vol. 67, No. 14, 2002