Synthesis of novel analogues of 1α,25-dihydroxyvitamin D3 with side chains at C-18

Article abstract of DOI:10.1021/jo0498664

Novel analogues of the hormone 1α,25-(OH)₂-D₃ with side chains attached to C-18 were synthesized by a versatile route in which key steps were the remote radical-induced functionalization of the 18-methyl by the C-8β-hydroxyl group an

Full text of DOI:10.1021/jo0498664

Syn th esis of Novel An a logu es of 1r,25-Dih yd r oxyvita m in D3 w ith
Sid e Ch a in s a t C-18
Edelmiro Moma´n, Daniel Nicoletti, and Antonio Mourin˜o*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC,
Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
qomourin@usc.es
Received J anuary 23, 2004
Novel analogues of the hormone 1R,25-(OH)2-D3 with side chains attached to C-18 were synthesized
by a versatile route in which key steps were the remote radical-induced functionalization of the
18-methyl by the C-8â-hydroxyl group and the introduction of the side chains by Wittig reactions
on a C-18-aldehyde. The triene system of the novel analogues was constructed by the convergent
Lythgoe-Hoffmann la Roche approach, which involves reaction of a phosphine oxide (the ring A
fragment) with a ketone (the upper fragment).
In tr od u ction
1R,25-Dihydroxyvitamin D3 [1R,25-(OH)2-D3, calcitriol,
1a , Figure 1], which is the hormonally active form of
vitamin D3 (cholecalciferol, 1b), not only plays an impor-
tant role in calcium homeostasis but also promotes cell
differentiation and inhibits the proliferation of various
tumor cells. Unfortunately, the therapeutic value of 1R,-
25-(OH)2-D3 as an antitumor agent is severely limited
by its potent calcemic effects.1,2 Attempts are therefore
being made to develop an analogue of 1R,25-(OH)2-D3 that
acts against cancer and related skin diseases without
causing calcium unbalance. To date, more than 3000
analogues have been synthesized, although only a few
have reached the pharmaceutical market or advanced
clinical trials.3,4
F IGURE 1. 1R,25-(OH)2-D3 and 20(17f18)-abeo-analogues.
was rather limited and the design of new compounds was
essentially intuitive. However, it is now known that
calcitriol acts in the cell nucleus through a multistep
mechanism that includes its binding to the nuclear
vitamin D receptor (VDR),5 heterodimerization of the
VDR with retinoid X receptor (RXR), and binding of the
resulting complex to specific DNA sequences named
vitamin D-responsive elements (VDRE).1,6 The recent
elucidation of the crystalline structure of a complex
formed by 1R,25-(OH)2-D3 and a mutant VDR opens new
possibilities for rational design of new vitamin D ana-
logues with therapeutic potential.7
Until recently, the available information on the struc-
ture-activity relationships of 1R,25-(OH)2-D3 analogues
(1) For details on the biochemistry of vitamin D, see: (a) Bouillon,
R.; Okamura, W. H.; Norman, A. W. Endocr. Rev. 1995, 16, 200-257.
(b) Vitamin D; Feldman, D., Glorieux, F. H., Pike, J . W., Eds.; Academic
Press: New York, 1997. (c) J ones, G.; Strugnell, S. A.; DeLuca, H. F.
Physiol. Rev. 1998, 78, 1193-1231. (d) Brown, A. J . Dusso, A.;
Slatoplosky, E. Am. J . Physiol. 1999, 2777, F157-F175. (e) Vitamin
D; Holick, M. F., Ed.; Humana: Totowa, NJ , 1999. (f) Carlberg, C.;
Mourin˜o, A. Expert Opin. Ther. Patents 2003, 13, 761-772.
(2) Vitamin D Endocrine System: Structural, Biological, Genetic,
and Clinical Aspects; Norman, A. W., Bouillon, R., Thomasset, M., Eds.;
Vitamin D Workshop, Inc.: University of CaliforniasRiverside, 2000.
(3) (a) Hansen, C. M.; Hamberg, K. J .; Binderup, E.; Binderup, L.
Curr. Pharm. Des. 2000, 6, 803-828. (b) Verstuyf, A.; Segaert, S.;
Verlinden, L.; Bouillon, R.; Mathieu, C. Exp. Opin. Invest. Drugs 2000,
9, 443-455. (c) Kabat, M. M.; Radinov, R. Curr. Opin. Drug Discov.
Devel. 2001, 4, 808-833. (d) Hansen, C. M.; Binderup, L.; Hamberg,
K. J .; Carlberg, C. Front. Biosci. 2001, 6, D820-D848. (e) Guyton, K.
Z.; Kensler, T. W.; Posner, G. H. Annu. Rev. Pharmacol. Toxicol. 2001,
41, 421-442. (f) Van den Bemd, G. J . C. M.; Chang, G. T. G. Curr.
Drug Targets 2002, 3, 85-94. (g) Evans, T. R. J .; Colston, K. W.; Lofts,
F. J .; Cunningham, D.; Anthoney, D. A.; Gogas, H.; de Bono, J . S.;
Hamberg, K. J .; Skov, T.; Mansi, J . L. Br. J . Cancer 2002, 86, 680-
685.
During the past decade, we have systematically syn-
thesized a number of 1R,25-(OH)2-D3 analogues to study
their structure-activity relationships.8 One of our re-
(5) Chawla, A.; Repa, J . J .; Evans, R. M.; Mangelsdorf, D. J . Science
2001, 294, 1866-1870.
(6) Calberg, C. J . Cell Biochem. 2003, 88, 274.
(7) (a) Rochel, N.; Wurtz, J . M.; Mitschler, B. K.; Moras, D. Mol.
Cell 2000, 5, 173-179. (b) Yamada, S.; Yamamoto, K.; Masuno, H.
Curr. Pharm. Design 2000, 6, 733-748. (c) Tocchini-Valentini, G.;
Rochel, N.; Wurtz, J . M.; Mitschler, A.; Moras, D. Proc. Natl. Acad.
Sci. U.S.A. 2001, 98, 5491-5496. (d) Carlberg, C.; Quack, M.; Herdick,
M.; Bury, Y.; Polly, P.; Toell, A. Steroids 2001, 66, 213-221. (e)
Rotkiewicz, P.; Sicinska, W.; Kolinski, A.; DeLuca, H. F. Proteins
Struct. Funct. Genet. 2001, 44, 188-199. (f) Masuno, H.; Yamamoto,
K.; Xinxiang, W.; Mihwa, C.; Hiroshi, O.; Toshimasa, S.; Yamada, S.
J . Med. Chem. 2002, 45, 1825-1834.
(4) For syntheses of vitamin D metabolites and analogues, see: (a)
Dai, H.; Posner, G. H. Synthesis 1994, 1383-1398 (b) Zhu, G.-D.;
Okamura, W. H. Chem. Rev. 1995, 95, 1877-1952. (c) Krause, S.;
Schmalz, H.-G. In Organic Synthesis Highliths IV; Schmalz, H.-G., Ed.;
Wiley-VCH: Weinheim, Germany, 2000; pp 212-217. (d) Reference
3c. (e) Reference 1f.
10.1021/jo0498664 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/12/2004
J . Org. Chem. 2004, 69, 4615-4625
4615

Moma´n et al.
SCHEME 1. Retr osyn th etic An a lysis
search programs was directed to the synthesis of 1R,25-
(OH)2-D3 analogues with side chains attached to selected
positions of the molecule, such as the angular C18 methyl
group. A number of analogues modified at C-18 have
already been reported by us9 and others10 including a
series of analogues with side chains linked to C-18
through an oxygen atom.11 Despite the fact that some of
these compounds have promising therapeutic profiles,11,12
only one analogue with a side chain linked to C-18
through a carbon-carbon bond has been reported to
date.13
SCHEME 2. Ir r a d ia tion of Keton es 7 a n d 10a
We describe here new synthetic approaches to 1R,25-
(OH)2-D3 analogues with side chains at C-18 and the use
of one of these strategies for the preparation of three
novel 1R,25-(OH)2-D3 analogues in which side chains
homologous to that of the natural hormone are linked to
C-18 through a C-C bond (2a -c, Figure 1). The new
analogues, unlike previously reported analogues with
C-18 modifications, have no substituents on C-17.
Retr osyn th esis. The mild, convergent Lythgoe-Hoff-
mann la Roche approach1f,3c was chosen for the introduc-
tion of the triene system of the target 1R,25-(OH)2-D3
analogues 2 (Scheme 1). Key elements of the synthetic
plan involve the construction of the upper ketones 3 from
alcohol 5, which in turn might be prepared from ketone
6 using as key reaction the C-8-OH-induced14 radical
functionalization15 of the C-18-methyl group. We consid-
ered that degradation of commercially available vitamin
D2 might provide convenient entry to alcohol 5.
a
Key: (a) hν, EtOH (8/9 ) 2:1), 73%; (b) (i) LDA, THF, -78 °C,
then TMSCl, (ii) m-CPBA, hexanes, -20 °C, (iii) TBAF, THF, (iv)
HF, H2O, CH3CN; (c) hν, EtOH, 28% (from 7).
Syn th esis of Alcoh ol 5. We envisaged the prepara-
tion of alcohol 5 by type I Norrish fragmentation of ketone
7 (Scheme 2). This compound was prepared by degrada-
tion of commercially available vitamin D2 according to
procedures optimized in these laboratories.16 Unfortu-
nately, irradiation of 7 in ethanol provided a 2:1 mixture
of cyclic compounds 8 and 9 accordingly with previous
results reported by Corey et al. on Quabain derivatives.17
It was possible to induce the Norrish fragmentation of
the hydroxy ketone 10, but this alternative pathway
furnished the desired alcohol 5 only in poor yield. We
therefore decided to explore the preparation of alcohol 5
from protected methyl ketone 6 (Scheme 3).
Ketone 6 was converted to ketone 13 by Baeyer-
Villiger oxidation using m-CPBA in phosphate buffer and
CH2Cl2 followed by hydrolysis of the resulting acetate 11
and oxidation of the resulting alcohol 12, as previously
described.16 Use of freshly purified m-CPBA in cyclohex-
ane or CH2Cl2 instead of the biphasic mixture led to a
significant improvement of the Baeyer-Villiger step.
Attempts to deoxygenate C-17 by reduction of the tosylate
of alcohol 12 gave only starting alcohol 12, even though
a wide variety of hydride reagents were tried. Treatment
of the methylxanthate derivative of 12 with HSnBu3-
AIBN under conventional thermal or photochemical
reaction conditions gave an intractable mixture of prod-
(8) (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 . R.; Mourin˜o, A. J . Org. Chem. 1999, 64, 3196-3206 and
references therein. (c) Ferna´ndez-Gacio, A.; Vitale, C.; Mourin˜o, A. J .
Org. Chem. 2000, 65, 6978-6983 (d) Gonza´lez-Avio´n, X.-C.; Mourin˜o,
A. Org. Lett. 2003, 5, 2291-2293. (e) Pe´rez-Garc´ıa, X.; Rumbo, A.;
Larriba, M. J .; Ordon˜ez, P.; Mun˜oz, A.; Mourin˜o, A. Org. Lett. 2003, 5,
4033-4036.
(9) (a) Valle´s, M. J .; Castedo, L.; Mourin˜o, A. Tetrahedron Lett. 1992,
33, 1503-1506. (b) Varela, C.; Nilsson, K.; Torneiro, M.; Mourin˜o, A.
Helv. Chim. Acta 2002, 85, 3251-3261.
(10) Maynard, D. F.; Norman, A. W.; Okamura, W. H. J . Org. Chem.
1992, 57, 3214-3217.
(11) Grue-Sørensen, G.; Hansen, C. M. Bioorg. Med. Chem. 1998,
6, 2029-2039.
(12) Nilsson, K.; Valle´s, M. J .; Castedo, L.; Mourin˜o, A.; Halkes, J .
P.; van de Velde, J . P. Bioorg. Med. Chem. Lett. 1993, 3, 1855-1858.
(13) Cornella, I.; Pe´rez, J .; Mourin˜o, A.; Sarandeses, L. A. J . Org.
Chem. 2002, 67, 4707-4714.
(14) To facilitate understanding, steroid numbering is used for all
compounds
(15) For reviews on remote functionalization, see: (a) Majetich, G.;
Wheless, K. Tetrahedron 1995, 51, 7095-7129. (b) Reese, P. B. Steroids
2001, 66, 481-497. (c) Pellissier, H.; Santelli, M. Org. Prep. Proced.
Int. 2001, 33, 455-476.
(16) Ferna´ndez, B.; Mart´ınez-Pe´rez, J . A.; Granja, J . R.; Castedo,
L.; Mourin˜o, A. J . Org. Chem. 1992, 57, 3173-3178.
(17) Corey, E. J .; Stoltz, B. M. Tetrahedron Lett. 1999, 40, 2061-
2064.
4616 J . Org. Chem., Vol. 69, No. 14, 2004

Synthesis of Analogues of 1R,25-Dihydroxyvitamin D3
SCHEME 3. Syn th esis of Alcoh ol 5a
SCHEME 5. Rea ctivity of La ctol 18a
a
Key: (a) m-CPBA, cyclohexane, 95%; (b) K2CO3, MeOH, 99%;
(c) PDC, CH2Cl2, 96%; (d) LDA, THF, -78 °C, then N,N-bis(trif-
luoromethanesulfonyl)-2-amino-5-chloropyridine, 93%; (e) (i) H2,
PtO2, EtOH, (ii) HF, CH3CN, 99%.
a
Key: (a) DIBAL-H, toluene, -80 °C, 88%; (b) CH3PPh3Br, KO-
t-Bu, THF, ∆, 86%; (c) (EtO)2P(O)CH2CO2Et, NaOEt, EtOH, ∆,
30%; (d) 21, KO-t-Bu, benzene, ∆, no reaction; (e) 22, n-BuLi, Et2O,
∆, no reaction; (f) 23, K2CO3, MeOH, no reaction; (g) 24, n-BuLi,
THF, Et2O, no reaction.
SCHEME 4. Ir r a d ia tion of 5a
iodine 17 were also isolated (Scheme 4, b). Ether 15 can
be converted to lactone 16 using catalytic RuO2 and
NaIO4 (Scheme 4, c).
We next turned our attention to reactions known to
provide cyclic ethers as the major products. Irradiation
of alcohol 5 in benzene in the presence of Pb(OAc)4
proceeded efficiently to deliver the cyclic ether 15 in
excellent yield. To circumvent the toxicity of lead re-
agents and high dilution in benzene we explored the
variant of the hypoiodite reaction developed by Sua´rez
et al.19 Thus, reaction of 5 with diacetoxyiodobenzene
(DIB) and iodine under photochemical or sonochemical
conditions in cyclohexane gave the desired ether 15 in
excellent yield (Scheme 4, e,f). Ultrasounds allowed
higher concentrations to be used.
a
Key: (a) (i) Pb(OAc)4, I2, CaCO3, cyclohexane, hν, (ii) CrO3,
H2SO4, pyridine, acetone; (b) (i) Pb(OAc)4, I2, CaCO3, cyclohexane,
sonication, (ii) CrO3, H2SO4, pyridine, acetone; (c) (i) Pb(OAc)4, I2,
CaCO3, cyclohexane, sonication, (ii) CrO3, H2SO4, silica gel, THF,
-10 °C; (iii) RuO2‚H2O, NaIO4, CCl4, CH3CN, buffer; (d) Pb(OAc)4,
benzene, hν; (e) DIB, I2, cyclohexane, hν; (f) DIB, I2, cyclohexane,
sonication.
In sta lla tion of th e Sid e Ch a in . We initially at-
tempted to introduce side chains at C18 by reaction of
ylides with lactol 18, which was prepared in 88% yield
by reduction of 16 with DIBAL-H (Scheme 5). Unfortu-
nately, most of these attempts failed, probably as the
result of steric congestion at C-18. Only the simplest ylide
(Ph3PdCH2) reacted efficiently with lactol 18, providing
olefin 19 in 86% yield. The simple phosphonate carbanion
(EtO)2P(O)CHNaCO2Et formed ester 20 by Horner-
Wadsworth-Emmons reaction followed by hetero-Micha-
el cyclization, but only in low yield (30%), while no
reaction took place with the anions derived from 21-24
(Scheme 5).
In view of the above results, we investigated a different
approach to the introduction of the side chain. Logan et
al.21 have reported that reaction of alkyl Grignard
reagents with certain ester moieties adjacent to quater-
nary carbons can give rise to alkynes in moderate-to-good
yields. Reaction of lactone 16 under Logan’s conditions
(MeMgCl, anisole, reflux) provided alkyne 25 (73%),
tertiary alcohol 26 (15%), and lactol 27 (3%) (Scheme 6).
ucts. Wolff-Kishner reduction of ketone 13 also failed,
as did related procedures. Eventually, we found that
formation of enol triflate 14 from 13, treatment of 14 with
hydrogen in the presence of catalytic PtO2, and final
desilylation provided the desired alcohol 5 in 92% from
13.
F u n ction a liza tion of C-18. Our experiments on the
functionalization of C18 started with irradiation of
alcohol 5 in the presence of Pb(OAc)4 and I2 and oxidation
of the resulting mixture with J ones’ reagent, which
furnished a mixture of the desired lactone 16 and, as the
major product, cyclic ether 15 (Scheme 4, a). This trend
is in contrast with previous observations where the
irradiation of similar substrates with bulky substituents
at C-17 afford the lactone as the major product.9b These
results can be rationalized on a mechanistic basis. The
presence of bulky substituents at C-17 prevents the
C18-I bond orientation required for SNi cyclization with
C-8-OH (Scheme 4).18 The reaction pursues an alternative
radical chain pathway that ends up with the formation
of an R-iodoether and its oxidation to the lactone by
J one’s reagent. Irradiation with light was advantageously
replaced by sonication. Under these conditions, traces of
(19) 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.
(20) Costa, S. C. P.; Miranda, M. J . S.; Sa´ e Melo, M. L.; Campos,
A. S. Tetrahedron Lett. 1999, 40, 8711-8714.
(21) Logan, R. T.; Roy, R. G.; Woods, G. F. J . Chem. Soc., Perkin
Trans. 1 1981, 1079-1080.
(18) Heusler, K.: Kalvoda, J . Angew. Chem., Int. Ed. Engl. 1964,
3, 525-538. (b) Kalvoda, J ,; Heusler, K. Synthesis 1971, 501-526.
J . Org. Chem, Vol. 69, No. 14, 2004 4617

Moma´n et al.
SCHEME 6. Syn th esis of Alk yn e 25a
SCHEME 7. Syn th esis a n d Alk yla tion of Alk yn e
32a
a
Key: (a) MeMgCl, anisole, ∆, 25 (73%), 26 (25%), 27 (3%).
However, attempts to introduce alkynes with longer
chains using Grignard reagents were unsuccessful. Un-
expectedly, attempts of alkylation of 25 or its C-8-OTBS-
protected derivative also failed.
The above failures to install the desired side chains
led us to eliminate the steric hindrance at C-18 by
inverting the configuration of the C-8-OH group. Cleav-
age of ether 15 in the presence of BF3‚OEt2 and Ac2O
using conditions reported by Okamura,10 hydrolysis of the
resulting diacetate 28 to diol 29,22 and selective oxidation
of the latter with catalytic TEMPO and DIB as co-
oxidant23 afforded the key aldehyde 30 in 60% yield from
15 (Scheme 7). Disappointingly, it was not possible to
convert the protected aldehyde 31 to the corresponding
vinylic dibromide using Corey-Fuchs reaction conditions.
Even more surprising was our inability to convert the
tosylate or mesylate of the corresponding protected
alcohol to its iodide by SN2 displacement with NaI. To
our delight, however, treatment of aldehyde 31 with
diazophosphonate 2324 in the presence of K2CO3 afforded
the desired alkyne 32 in 94% yield. The reaction of the
organolithium reagent derived from alkyne 32 (n-BuLi)
with 1,1-dimethyldioxirane (35) in the presence of BF3‚
OEt2 provided the tertiary alcohol 33 in 87% yield. The
lithium species derived from 32 also reacted with 36 to
give alkyne 34 in 63% yield. Unfortunately, efforts to
hydrogenate the triple bonds of 33 or 34 to the corre-
sponding saturated derivatives were unsuccessful. Cata-
lytic hydrogenation using PtO2 (33) or Ni-Raney (34)
furnished almost exclusively the corresponding alkenes,
with only traces of the desired saturated compounds.
These results further illustrate the low C-18 reactivity
of trans-hydrindan systems due to the the severe steric
congestion at this position.
a
Key: (a) BF3‚OEt2, Ac2O, -20 °C, 62%; (b) K2CO3, MeOH, 99%;
(c) TEMPO, DIB, CH2Cl2, CH3CN, 97%; (d) TBSCl, imidazole,
DMF, 98%; (e) 23, K2CO3, MeOH, 94%; (f) n-BuLi, THF, then 35,
BF3‚OEt2, -50 °C, 87%; (g) n-BuLi, HMPA, THF, -30 °C, then
36, 63%.
SCHEME 8. Cou p lin g of Sid e Ch a in s on
Ald eh yd es 31 a n d 39a
At this point, we back-tracked in our efforts to intro-
duce side chains and took as the starting point aldehyde
31, which upon Horner-Wadsworth-Emmons reaction
with (EtO)2P(O)CHdCHCO2Et provides the R,â-unsatur-
ated ester 37 (Scheme 8). After catalytic hydrogenation
of 37 to 38, the latter was reduced with DIBAL-H, giving
aldehyde 39 in 73% yield from 31. Aldehydes 31 and 39
were then successfully coupled with the anions derived
a
Key: (a) (EtO)2P(O)CH2CO2Et, NaH, THF, 93%; (b) H2, Pd/
C, EtOAc, 98%; (c) DIBAL-H, toluene, -80 °C, 81%; (d) 21a or
21b, KO-t-Bu, benzene, 40a (79%) or 40b (76%); (e) 21a , KO-t-
Bu, benzene, 40c (71%).
(22) Attempts of selective deprotection of 28 or protection of 29 did
not provide the selectivity reported for similar substrates.10,11
(23) De Mico, A.; Matgarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J . Org. Chem. 1997, 62, 6974-6977.
(24) (a) Callant, P.; D’Haenens, L.; Vandewalle, M. Synth. Commun.
1984, 14, 155-161. (b) Mu¨ller, S.; Bernd, L.; Roth, G. J .; Bestmann,
H. J . Synlett 1996, 521-522.
from phosphonium salts 21a and/or 21b, affording the
olefinic upper fragments 40a (79%), 40b (76%), and 40c
(71%).
4618 J . Org. Chem., Vol. 69, No. 14, 2004

Synthesis of Analogues of 1R,25-Dihydroxyvitamin D3
aqueous layer was extracted with hexanes (3 × 150 mL). The
combined organic fractions were dried, filtered, and concen-
trated. The residue was purified by flash chromatography (18
× 5 cm, 1% EtOAc/hexanes) to give 11 [13 g, 95%, Rf ) 0.7
(5% EtOAc/hexanes), white solid, mp 47-49 °C]. 1H NMR
(CDCl3, 250 MHz): δ 4.54 (1H, dd, J ) 7.7 Hz, 9.0 Hz, H-17),
4.01 (1H, m, H-8), 2.03 (3H, s, H-21), 1.01 (3H, s, H-18), 0.89
(9H, s, t-BuSi), 0.002 (3H, s, Me2Si), 0.003 (3H, s, Me2Si). 13C
NMR (CDCl3, 62.89 MHz): δ 171.2 (CO), 82.7 (CH), 68.9 (CH),
47.6 (CH), 41.8 (C), 37.5 (CH2), 34.2 (CH2), 26.5 (CH2), 25.6
(t-BuSi), 22.1 (CH2), 21.0 (CH3), 17.9 (C), 17.0 (CH2), 13.6 (Me-
18), -4.9 (Me2Si), -5.3 (Me2Si).
SCHEME 9. Syn th esis of Ca lcitr iol An a logu es
2a -ca
8â-[(ter t-Bu tyldim eth ylsilyl)oxy]de-A,B-an dr ostan -17â-
ol (12).16 K2CO3 (6.9 g, 49.9 mmol) was added to a solution of
11 (13 g, 39.8 mmol) in MeOH (200 mL). The reaction mixture
was stirred for 16 h. The solution was concentrated. Hexanes
were added to the residue, and the resulting suspension was
filtered and concentrated. The residue was purified by flash
chromatography (16 × 5 cm, 5% EtOAc/hexanes) to give 12
[11.3 g, 99%, Rf ) 0.3 (15% EtOAc/hexanes), white solid, pf
1
69-71 °C]. H NMR (CDCl3, 250 MHz): δ 3.93 (1H, m, H-8),
3.50 (1H, t, J ) 8.3 Hz, H-17), 1.97 (1H, m, H-14), 0.91 (3H, s,
H-18), 0.85 (9H, s, t-BuSi), 0.02 (3H, s, Me2Si), 0.04 (3H, s,
Me2Si). 13C NMR (CDCl3, 62.89 MHz): δ 81.8 (CH), 69.1 (CH),
47.9 (CH), 42.0 (C), 37.3 (CH2), 34.3 (CH2), 29.5 (CH2), 25.7
(t-BuSi), 22.1 (CH2), 17.9 (C), 17.2 (CH2), 12.5 (Me-18), -4.9
(Me2Si), -5.3 (Me2Si).
8â-[(ter t-Bu tyld im eth ylsilyl)oxy]d e-A,B-a n d r osta n -17-
on e (13).14 Pyridinium dichromate (48 g, 127.6 mmol) was
added to a solution of 12 (11 g, 38.7 mmol) in CH2Cl2 (300
mL). After 16 h, Et2O (500 mL) was added. The reaction
mixture was stirred for an additional 15 min and filtered
through a silica gel layer. The residue obtained after concen-
tration was purified by flash chromatography (18 × 5 cm, 2%
EtOAc/hexanes) to give 13 [10.5 g, 96%, Rf ) 0.4 (15% EtOAc/
hexanes), colorless oil]. 1H NMR (CDCl3, 250 MHz): δ 4.15 (1H,
m, H-8), 2.42 (1H, m, H-16), 2.04-1.68 (2H, m, H-16, H-14),
1.10 (3H, s, H-18), 0.90 (9H, s, t-BuSi), 0.05 (6H, s, Me2Si).
13C NMR (CDCl3, 62.89 MHz): δ 221.9 (C-17), 69.8 (CH), 48.6
(CH), 47.4 (C), 35.2 (CH2), 34.2 (CH2), 32.1 (CH2), 25.7 (t-BuSi),
21.2 (CH2), 17.9 (C), 16.9 (CH2), 16.4 (Me-18), -4.9 (Me2Si),
-5.2 (Me2Si).
8â-[(ter t-Bu tyldim eth ylsilyl)oxy]de-A,B-an dr ost-16-en e-
17-yl Tr iflu or om eth a n esu lfon a te (14). n-BuLi in hexanes
(27.5 mL, 2.32 M) was added dropwise (20 min) to i-Pr2NH
(9.7 mL, 69.2 mmol) at -78 °C. Dry THF (10 mL) was added
to the reaction mixture at 0 °C. The white precipitate formed
was dissolved with THF (40 mL). The solution was stirred for
30 min and then cooled to -78 °C. A solution of 13 (14 g, 49.6
mmol) in THF (120 mL) was added dropwise to the LDA
solution. After 45 min, a solution of N,N-bis(trifluoromethane-
sulfonyl)-2-amine-5-chloropyridine (29 g, 74.5 mmol) in THF
(60 mL) was added. The reaction mixture was stirred at rt for
6 h and then filtered two times through silica gel (5 × 4 cm)
eluting with 3% Et2O/hexanes. The residue obtained after
concentration was purified by flash chromatography (15 × 5
cm, 1% Et2O/hexanes) to give 14 [19.2 g, 93%, Rf ) 0.6
(hexanes), colorless oil]. 1H NMR (CDCl3, 250 MHz): δ 5.54
(1H, dd, J ) 3.3, 1.7 Hz, H-16), 4.08 (1H, m, H-8), 2.37 (1H,
ddd, J ) 14.6, 11.5, 1.7 Hz, H-15â), 2.06 (1H, ddd, J ) 14.6,
6.0, 3.3 Hz, H-15R), 1.22 (3H, s, H-18), 0.89 (9H, s, t-BuSi),
0.04, 0.03 (3H, s, Me2Si). 13C NMR (CDCl3, 63 MHz): δ 159.1
(C-17), 118.6 (CF3, q, J ) 320 Hz), 113.7 (C-16), 68.5 (C-8),
52.1 (C-14), 44.5 (C-13), 34.2 (CH2), 33.3 (CH2), 28.4 (CH2),
25.7 (CH3, t-BuSi), 18.3 (C-18), 18.0 (C, t-BuSi), 17.4 (CH2),-
4.9 (Me2Si), -5.2 (Me2Si). MS [CI+, m/z]: 415 (M+ + H, 25),
414 (M+, 15), 413 (M+ - H, 37), 399 (M+ - Me, 20), 357 (M+
- t-Bu, 62), 283 (M+ - OTBS, 59), 265 (M+ - OTf, 73), 151
(27), 133 (100). HRMS (CI+): calcd for C17H28O4F3SiS 413.1430,
found 413.1424.
a
Key: (a) (i) MeLi, THF, -30 °C, (ii) MeLi, THF, -30 °C, 41a
(82%) or 41b (80%) or 41c (79%); (b) HF, H2O, CH3CN, 42a (69%)
or 42b (63%) or 42c (60%); (c) H2, Pd/C, EtOAc, 43a (98%) or 43b
(96%) or 43c (98%); (d) PDC, CH2Cl2, 3a (92%) or 3b (90%) or 3c
(90%); (e) 4, n-HexLi, THF, -30 °C, 44a (87%) or 44b (93%) or
44c (96%); (f) TBAF, THF, 2a (88%)or 2b (81%) or 2c (80%).
Syn th esis of 1r,25-(OH)2-D3 An a logu es. The upper
ketones 3a -c (Scheme 9) required for the preparation
of the desired vitamin D analogues 2a -c by the conver-
gent Lythgoe-Hoffmann la Roche approach were syn-
thesized in a straightforward manner from carboxylic
acids 40a -c. After reaction with MeLi, alcohols 41a -c
were desilylated (HF) and hydrogenated to provide diols
43a -c, which upon oxidation (PDC) furnished the key
ketones 3a -c in 50% average yield from 40a -c. Coupling
3a -c with the anion of phosphine oxide 425 provided,
after desilylation (n-Bu4NF, THF), the desired 1R,25-
(OH)2-D3 analogues 2a (76%), 2b (75%), and 2c (77%)
(Scheme 9).
In summary, we have developed a versatile synthetic
route to novel analogues of the hormone 1R,25-(OH)2-D3
in which side chains are attached to C-18 rather than
C-17. The results of biological assays currently in progress
will be published elsewhere.
Exp er im en ta l Section
8â-[(ter t-Bu tyldim eth ylsilyl)oxy]de-A,B-an dr ostan -17â-
yl Aceta te (11).16 m-CPBA (16 g, 92.7 mmol) was added to a
solution of 6 (13 g, 41.9 mmol) in cyclohexane (260 mL). The
reaction mixture, protected from direct light, was stirred for
168 h, supplementing 3 g per day of m-CPBA. The reaction
was quenched with saturated aqueous Na2S2O3 (200 mL). The
(25) Mourin˜o, A.; Torneiro, M.; Vitale, C.; Ferna´ndez, S.; Pe´rez-
Sestelo, J .; Anne´, S.; Gregorio, C. Tetrahedron Lett. 1997, 38, 4713-
4716.
(26) Meinwald, J .; Crandall, J .; Hymans, W. E. Organic Syntheses;
Wiley & Sons: New York, 1973; Collect. Vol. V, p 866.
(27) Perrin, D. D.; Amarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon Press: Oxford, 1988.
De-A,B-a n d r osta n -8â-ol (5). PtO2 (0.3 g, 0.03 equiv) was
added to a solution of 14 (17 g, 41.1 mmol) in EtOH (300 mL).
J . Org. Chem, Vol. 69, No. 14, 2004 4619

Moma´n et al.
The resulting suspension was deoxygenated by alternating
vacuum with H2 bubbling and then stirred for 16 h under H2
atmosphere (balloon pressure). H2 was removed by Ar bub-
bling. The mixture was filtered through silica gel and concen-
trated. The residue was dissolved in CH3CN (200 mL) and
aqueous HF (2 mL, 48%) was carefully added. After 12 h, the
reaction was quenched by addition of a saturated solution of
NaHCO3 (200 mL). CH3CN was removed at the rotatory
evaporator, and the aqueous layer was extracted with Et2O
(3 × 100 mL). The combined organic fractions were concen-
trated. The residue was purified by flash chromatography (12
× 5 cm, 5% EtOAc/hexanes) to give 5 [6.3 g, 99%, Rf ) 0.3 (5%
EtOAc/hexanes), volatile colorless oil]. 1H NMR (CDCl3, 250
MHz): δ 4.08 (1H, m, H-8), 0.92 (3H, s, Me-18). 13C NMR
(CDCl3, 63 MHz): δ 68.6 (C-8), 50.6 (C-14), 41.4 (CH2), 39.7
(C-13), 39.2 (CH2), 33.7 (CH2), 23.4 (CH2), 19.6 (C18), 19.3
(CH2), 17.4 (CH2). MS [CI+, m/z]: 155 (M+ + H, 5), 154 (M+,
2), 153 (M+ - H, 12), 139 (M+ - Me, 9), 137 (M+ - OH, 100),
121 (10). HRMS (CI+): calcd for C10H17O 153.1279, found
153.1287.
The combined organic fraction was concentrated. Pyridine (3
drops, Pasteur pipet) was added to a solution of the obtained
residue in acetone (10 mL). A solution of J ones’ reagent (4 mL)
was added to the mixture at 0 °C. The reaction mixture was
stirred, protected from direct light, for 16 h. The reaction was
quenched by pouring the reaction mixture, in small portions,
on cooled saturated aqueous NaOAc (20 mL). The acetone was
removed in vaccum, and the aqueous layer was extracted with
Et2O (2 × 50 mL). The combined organic fraction was washed
with saturated aqueous NaHCO3 (50 mL), dried, and concen-
trated. The residue was purified by flash chromatography (8
× 0.5 cm, 6% EtOAc/hexanes) to give 15 [0.07 g, 46%, Rf ) 0.4
(5% EtOAc/hexanes), volatile colorless oil] and 16 [0.07 g, 41%,
Rf ) 0.3 (5% EtOAc/hexanes), colorless oil].
De-A,B-8â-h yd r oxya n d r osta n -18-oic Acid La cton e (16).
A stirred suspension of CaCO3 (6 g, 60.0 mmol) and Pb(OAc)4
(31.6 g, 71.3 mmol) in cyclohexane (130 mL) was heated to 80
°C, and the heating bath was removed. I2 (5 g, 19.7 mmol) and
a solution of 5 (2 g, 13.0 mmol) in cyclohexane (20 mL) were
successively added. The reaction mixture was sonicated for 4
h with vigorous mechanical stirring. The mixture was filtered
through a silica gel layer eluting with Et2O and then washed
successively with saturated aqueous Na2S2O3 (100 mL) and
AgOAc (100 mL) and with H2O (50 mL). The combined organic
fraction was concentrated. The residue was dissolved (60 mL)
and cooled at -10 °C. Silica gel (13 g) and J ones’ reagent (40
mL) were added. The reaction mixture was stirred, protected
from direct light, for 20 h. After filtering, the solution was
poured carefully on saturated aqueous NaHCO3 (250 mL) at
0 °C. The aqueous fraction was extracted with Et2O (2 × 100
mL). The combined organic fraction was dried, filtered and
concentrated. The residue was dissolved in a mixture of CH3-
CN and CCl4 (160 mL, 1:1). A pH 7 buffer solution (120 mL of
H2O, 1.037 g of KH2PO4, and 0.182 g of NaOH) was added.
NaIO4 (14.4 g, 67.3 mmol)] and RuO2‚H2O (0.22 g, 1.5 mmol)
were consecutively added to the biphasic mixture. The result-
ing yellow mixture was vigorously stirred for 172 h. The
organic solvents were removed at the rotatory evaporator. The
aqueous fraction was extracted with Et2O (3 × 100 mL). The
combined organic fraction was washed successively with
saturated aqueous Na2S2O3 (100 mL) and H2O (100 mL) and
then dried, filtered, and concentrated. The residue was purified
by flash chromatography (18 × 2 cm, 6% EtOAc/hexanes) to
give 16 [1.76 g, 82%, Rf ) 0.3 (5% EtOAc/hexanes), colorless
De-A,B-(8â)-8,18-ep oxya n d r osta n e (15). Pyridine (7 mL)
and Pb(OAc)4 (32 g, 72.2 mmol) were successively added to a
solution of 5 (2.3 g, 14.9 mmol) in benzene (1 L) placed in a
1.5 L photochemical Pyrex glass reactor. The cooled suspension
was irradiated for 150 min with a 450 W medium-pressure
Hg lamp. The reaction mixture was filtered through a silica
gel layer and concentrated. The residue was purified by flash
chromatography (12 × 2 cm, 10% Et2O/hexanes) to give 15
[2.1 g, 92%, Rf ) 0.4 (5% EtOAc/hexanes), volatile colorless
1
oil]. H NMR (CDCl3, 250 MHz): δ 4.21 (1H, dm, J ) 4.3 Hz,
H-8), 3.68 (1H, d, J ) 8.0 Hz, H-18), 3.43 (1H, d, J ) 8.0 Hz,
H-18). 13C NMR (CDCl3, 63 MHz): δ 79.8 (C-8), 75.2 (C-18),
56.1 (C-14), 52.1 (C-13), 35.9 (CH2), 32.6 (CH2), 32.4 (CH2),
27.0 (CH2), 22.5 (CH2), 19.0 (CH2). MS [CI+, m/z]: 153 (M+
+
H, 36), 152 (M+, 31), 151 (M+ - H, 52), 135 (M+ - OH, 100),
121 (36). HRMS (CI+): calcd for C10H16O 152.1201, found
152.1197.
De-A,B-(8â)-8,18-ep oxya n d r osta n e (15) a n d De-A,B-8â-
h yd r oxya n d r osta n -18-oic Acid La cton e (16) (by Ir r a d ia -
tion of 5). A stirred suspension of CaCO3 (8 g, 79.9 mmol)
and Pb(OAc)4 (40 g, 90.2 mmol) in cyclohexane (400 mL) was
heated to 80 °C, and the heating bath was removed. I2 (6 g,
23.6 mmol) and a solution of 5 (2.6 g, 16.9 mmol) in cyclohex-
ane (10 mL) were successively added. The cooled reaction
mixture was irradiated with a 300 W tungsten lamp for 3 h.
The mixture was filtered through a silica gel layer eluting with
Et2O and then washed successively with saturated aqueous
Na2S2O3 (200 mL) and H2O (200 mL). The combined organic
fraction was concentrated. Pyridine (2 mL) was added to a
solution of the obtained residue in acetone (60 mL). A solution
of J ones’ reagent (22 mL) was added to the mixture at 0 °C.
The reaction mixture was stirred, protected from direct light,
for 20 h. The reaction was quenched by pouring the reaction
mixture, in small portions, on cooled saturated aqueous NaOAc
(200 mL). The acetone was removed at the rotatory evaporator,
and the aqueous layer was extracted with Et2O (2 × 100 mL).
The combined organic fraction was washed with saturated
aqueous NaHCO3 (200 mL), dried, and concentrated. The
residue was purified by flash chromatography (12 × 2 cm, 6%
EtOAc/hexanes) to give 15 [1.63 g, 63%, Rf ) 0.4 (5% EtOAc/
hexanes), volatile colorless oil] and 16 [0.7 g, 26%, Rf ) 0.3
(5% EtOAc/hexanes), colorless oil].
1
oil]. H NMR (CDCl3, 250 MHz): δ 4.54 (1H, dm, J ) 4.4 Hz,
H-8). 13C NMR (CDCl3, 63 MHz): δ 181.4 (C-18), 78.4 (C-8),
55.0 (C-13), 53.6 (C-14), 30.9 (CH2), 30.8 (CH2), 28.4 (CH2),
26.8 (CH2), 22.9 (CH2), 18.2 (CH2). MS [CI+, m/z]: 167 (M+
+
H, 33), 166 (M+, 60), 150 (46), 138 (45), 121 (M+ - CO2, 100).
HRMS (CI+): calcd for C10H14O2 166.0994, found 166.0997.
De-A,B-(8â)-8,18-ep oxya n d r osta n e (15) (by Ir r a d ia tion
of 5). (Diacetoxyiodo)benzene (8 g, 24.8 mmol) and I2 (5.4 g,
21.3 mmol) were added to a mixture of cyclohexane (110 mL)
and benzene (10 mL) placed in a 250 mL reaction tube. The
resulting suspension was deoxygenated by Ar bubbling. A
solution of 5 (2.5 g, 16.2 mmol) in cyclohexane (20 mL) was
added. The cooled reaction mixture was irradiated with a
medium-pressure Hg 450 W lamp for 40 min. The reaction was
quenched with saturated aqueous Na2S2O3 (150 mL). The
aqueous layer was extracted with Et2O (100 mL). The com-
bined organic fraction was washed with H2O (100 mL), dried,
filtered, and concentrated. The residue was purified by flash
chromatography (15 × 2 cm, 6% Et2O/hexanes) to give 15 [2.3
g, 93%, Rf ) 0.4 (5% EtOAc/hexanes), volatile colorless oil].
De-A,B-(8â)-8,18-ep oxya n d r osta n e (15) (by Son ica tion
of 5). (Diacetoxyiodo)benzene (0.97 g, 3.0 mmol) and I2 (0.65
g, 2.6 mmol) were added to a mixture of cyclohexane (50 mL)
and benzene (5 mL) placed in a 250 mL reaction tube. The
resulting suspension was deoxygenated by simultaneous Ar
bubbling and sonication. A solution of 5 (0.30 g, 2 mmol) in
cyclohexane (10 mL) was added. The reaction mixture was
sonicated for 80 min. The reaction was quenched with satu-
De-A,B-(8â)-8,18-ep oxya n d r osta n e (15) a n d De-A,B-8â-
h yd r oxya n d r osta n -18-oic Acid La cton e (16) (by Son ica -
tion of 5). A stirred suspension of CaCO3 (0.42 g, 4.2 mmol)
and Pb(OAc)4 (2.22 g, 5.0 mmol) in cyclohexane (40 mL) was
heated to 80 °C and the heating bath was removed. I2 (0.33 g,
1.3 mmol) and a solution of 5 (0.15 g, 1.0 mmol) in cyclohexane
(2 mL) were successively added. The reaction mixture was
sonicated for 1 h. The mixture was filtered through a silica
gel layer eluting with Et2O and then washed successively with
saturated aqueous Na2S2O3 (50 mL) and H2O (50 mL).
4620 J . Org. Chem., Vol. 69, No. 14, 2004

Synthesis of Analogues of 1R,25-Dihydroxyvitamin D3
rated aqueous Na2S2O3 (100 mL). The aqueous layer was
extracted with Et2O (100 mL). The combined organic fraction
was washed with H2O (100 mL), dried, filtered, and concen-
trated. The residue was purified by flash chromatography (12
× 1 cm, 6% Et2O/hexanes) to give 15 [0.28 g, 96%, Rf ) 0.4
(5% EtOAc/hexanes), volatile colorless oil].
hexanes), colorless oil]. 1H NMR (CD2Cl2, 250 MHz): δ 9.54
(1H, s, H-18), 3.96 (1H, dt, J ) 9.9, 4.6 Hz, H-8), 0.88 (9H, s,
t-BuSi), 0.06, 0.05 (3H, s, Me2Si). 13C NMR (CD2Cl2, 63 MHz):
δ 205.3 (C-18), 70.9 (C-8), 59.1 (C-13), 55.3 (C-14), 36.5 (CH2),
34.0 (CH2), 31.8 (CH2), 26.1 (CH2), 25.7 (CH3, t-BuSi), 22.6
(CH2), 20.5 (CH2), 18.0 (C, t-BuSi), -4.5, -4.9 (Me2Si). MS [CI+,
m/z]: 283 (M+ + H, 14), 282 (M+, 22), 281 (M+ - H, 100), 267
(37), 253 (83), 151 (15), 121 (15). HRMS (CI+): calcd for
De-A,B-8r,18-d ia cet oxya n d r ost a n e (28). BF3‚OEt2 (22
mL, 174.8 mmol) was added dropwise (10 min) to a solution
of 15 (2 g, 13.1 mmol) in Ac2O (130 mL) at -30 °C. After 10
min, the cooling bath was removed and the reaction mixture
was stirred for an additional 40 min. The reaction was
quenched by carefully carefully the mixture on saturated
aqueous NaHCO3 (250 mL) at 0 °C. NaHCO3 was poured in
small portions, over 6 h, on the vigorously stirred mixture until
CO2 release ceased. The aqueous fraction was extracted with
EtOAc (5 × 100 mL). The combined organic fraction was dried,
filtered, and concentrated. The residue was purified by flash
chromatography (16 × 2 cm, 10% EtOAc/hexanes) to give 28
[2.1 g, 62%, Rf ) 0.3 (20% EtOAc/hexanes), white solid]. 1H
NMR (CDCl3, 250 MHz): δ 4.79 (1H, dt, J ) 11.0, 4.7 Hz, H-8),
4.12 (1H, dd, J ) 11.2, 2.0 Hz, H-18), 3.80 (1H, d, J ) 11.2
Hz, H-18), 2.04 (3H, s, OAc), 1.99 (3H, s, OAc). 13C NMR
(CDCl3, 63 MHz): δ 171.3, 170.6 (C, C(O)CH3), 72.8 (C-8), 62.1
(C-18), 52.7 (C-14), 46.7 (C-13), 35.0 (CH2), 32.5 (CH2), 32.1
(CH2), 25.0 (CH2), 21.2 (CH2), 21.0 (CH3, C(O)CH3), 20.9 (CH3,
C(O)CH3), 19.7 (CH2). MS [CI+, m/z]: 255 (M+ + H, 3), 253
(M+, 1), 211 (M+ - Ac, 4), 195 (M+ - OAc, 40), 135 (100), 121
(22). HRMS (CI+): calcd for C14H23O4 255.1596, found 255.1588.
De-A,B-8r,18-d ih yd r oxya n d r osta n e (29). K2CO3 (2.2 g,
15.9 mmol) was added to a solution of 28 (1.8 g, 7.0 mmol) in
MeOH (100 mL). The suspension was stirred for 2 h, filtered,
and concentrated. The residue was dissolved in EtOAc (20 mL),
and silica gel (2 g) was added. The suspension was filtrated
and concentrated. The residue was purified by flash chroma-
tography (12 × 2 cm, 60% EtOAc/hexanes) to give 29 [1.29 g,
99%, Rf ) 0.3 (60% EtOAc/hexanes), white solid]. 1H NMR
(CDCl3, 250 MHz): δ 3.60 (1H, dd, J ) 10.9, 1.7 Hz, H-18),
3.59 (1H, dt, J ) 10.2, 4.7 Hz, H-8), 3.30 (1H, d, J ) 10.9 Hz,
H-18). 13C NMR (CDCl3, 63 MHz): δ 70.3 (C-8), 60.0 (C-18),
55.8 (C-14), 48.2 (C-13), 36.0 (CH2), 34.4 (CH2), 32.0 (CH2),
24.9 (CH2), 21.3 (CH2), 20.1 (CH2). MS [CI+, m/z]: 170 (M+,
1), 169 (M+ - H, 8), 153 (M+ - OH, 37), 152 (M+ - H2O, 10),
136 (12), 135 (100), 133 (36), 121 (32). HRMS (CI+): calcd for
C
16H30O2Si 282.2015, found 282.2004.
(18Z)-20(17f18)-a beo-8r-[(ter t-Bu tyldim eth ylsilyl)oxy]-
24-ca r boxyd e-A,B-21-n or ch ol-18-en e (40a ). KO-t-Bu (1.00
g, 8.9 mmol) was added to a suspension of (4-carboxybutyl)-
triphenylphosphonium bromide (1.30 g, 2.9 mmol) in dry
benzene (50 mL). The resulting white suspension was refluxed
for 2 h to give rise to a red mixture. A solution of 31 (0.25 g,
0.9 mmol) in benzene (12 mL) was added dropwise. The
reaction mixture was stirred at rt for 12 h. The reaction was
quenched with H2O (50 mL) and acidified with HCl 5% until
pH 3-4. The aqueous fraction was extracted with EtOAc (8 ×
50 mL). The combined organic fraction was washed with
saturated aqueous NaCl (200 mL), dried, filtered, and con-
centrated. The residue was purified by flash chromatography
(16 × 2 cm, 35% EtOAc/hexanes) to give 40a [0.26 g, 79%, Rf
) 0.2 (30% EtOAc/hexanes), white solid]. 1H NMR (CDCl3, 300
MHz): δ 5.34 (1H, d, J ) 12.7 Hz, H-18), 5.27 (1H, ddd, J )
12.7, 11.8, 7.0 Hz, H-20), 3.66 (1H, dt, J ) 10.1, 4.7 Hz, H-8),
2.37 (2H, t, J ) 7.5 Hz), 2.19 (2H, q, J ) 7.2 Hz), 2.08 (2H, dt,
J ) 12.4, 2.8 Hz), 1.92-1.82 (2H, m), 1.69 (2H, qm, J ) 7.5),
0.88 (9H, s, t-BuSi), 0.054, 0.052 (3H, s, Me2Si). 13C NMR
(CDCl3, 75.5 MHz): δ 179.9 (C-25), 133.8 (C-18), 130,2 (C-20),
72.1 (C-8), 57.5 (C-14), 48.4 (C-13), 39.5 (CH2), 37.2 (CH2), 36.4
(CH2), 33.5 (CH2), 28.4 (CH2), 25.9 (CH3, t-BuSi), 25.7 (CH2),
24.5 (CH2), 22.6 (CH2), 20.5 (CH2), 18.1 (C, t-BuSi), -4.2, -4.6
(Me2Si). MS [CI+, m/z]: 367 (M+ + H, 34), 366 (M+, 11), 365
(M+ - H, 22), 349 (M+ - OH, 17), 309 (M+ - t-Bu, 88), 235
(M+ - OTBS, 100). HRMS (CI+): calcd for C21H39O3Si 367.2669,
found 367.2674.
(18Z)-20(17f18)-a beo-8r-[(ter t-Bu tyld im eth ylsilyl)oxy]-
d e-A,B-21-n or ch olest-18-en -25-ol (41a ). MeLi in Et2O (2
mL, 1.25 M) was rapidly added to a cooled solution of 40a (0.17
g, 0.46 mmol) in THF (6 mL) at 0 °C. The mixture was stirred
at rt for 4 h. The reaction was quenched with H2O (10 mL)
and acidified with HCl 5% until pH 3-4. The aqueous fraction
was extracted with EtOAc (5 × 15 mL). The combined organic
fraction was washed with saturated aqueous NaCl (50 mL),
dried, filtered, concentrated, and dried at high vacuum. The
residue was dissolved in THF (6 mL), and MeLi in Et2O (2
mL, 1.25 M) was added to the cooled solution at -20 °C. The
mixture was stirred for 12 h. The reaction was quenched with
H2O (20 mL). The aqueous fraction was extracted with EtOAc
(3 × 15 mL). The organic fraction was washed with saturated
aqueous NaCl (30 mL), dried, filtered, and concentrated. The
residue was purified by flash chromatography (12 × 0.5 cm,
6% EtOAc/hexanes) to give 41a [0.15 g, 82%, Rf ) 0.6 (20%
C
10H17O2 169.1229, found 169.1229.
De-A,B-8r-h yd r oxya n d r ost a n -18-a l (30). (Diacetoxy-
iodo)benzene (0.50 g, 1.6 mmol) and 2,2,6,6-tetramethyl-
piperidinooxyl free radical (0.03 g, 0.2 mmol) were added to a
solution of 29 (0.28 g, 1.6 mmol) in CH2Cl2/CH3CN (16 mL,
1:1). The mixture, protected from direct light, was stirred for
5 h. The reaction was quenched with saturated aqueous
Na2S2O3 (50 mL). The aqueous fraction was extracted with
CH2Cl2 (2 × 50 mL). The combined organic fraction was dried,
filtered, and concentrated. The residue was purified by flash
chromatography (12 × 1 cm, 35% EtOAc/hexanes) to give 30
1
1
EtOAc/hexanes), colorless oil]. H NMR (CDCl3, 300 MHz): δ
[0.27 g, 97%, Rf ) 0.5 (60% EtOAc/hexanes), colorless oil]. H
5.34-5.23 (2H, m, H-18, H-20), 3.65 (1H, dt, J ) 10.1, 4.7 Hz,
H-8), 2.12 (2H, m), 1.94-1.78 (2H, m), 1.19 (6H, s, H-26, H-27),
0.87 (9H, s, t-BuSi), 0.04 (6H, s, Me2Si). 13C NMR (CDCl3, 75.5
MHz): δ 132.8 (CH), 131,4 (CH), 72.0 (C-8), 70,9 (C-25), 57.5
(C-14), 48.3 (C-13), 43.5 (CH2), 39.5 (CH2), 37.2 (CH2), 36.5
(CH2), 29.4 (CH2), 29.2 (C-26, C-27), 25.8 (CH3, t-BuSi), 25.7
(CH2), 24.3 (CH2), 22.6 (CH2), 20.5 (CH2), 18.1 (C, t-BuSi), -4.2,
-4.6 (Me2Si). MS [CI-, m/z]: 381 (M+ + H, 5), 380 (M+, 10),
379 (M+ - H, 36), 378 (M+ - 2H, 13), 265 (M+ - TBS, 10).
HRMS (CI-): calcd for C23H43O2Si 379.3032, found 379.3022.
(18Z)-20(17f18)-a beo-De-A,B-8r,25-d ih yd r oxy-21-n or -
ch olest-18-en e (42a ). Aqueous HF (12 drops, Pasteur pipet,
48%) was slowly added to a solution of 41a (0.14 g, 0.37 mmol)
in CH3CN (10 mL). The reaction mixture was stirred for 3 h.
The reaction was quenched with saturated aqueous NaHCO3
(10 mL). The CH3CN was removed in the rotatory evaporator.
The aqueous fraction was extracted with EtOAc (5 × 10 mL).
NMR (CDCl3, 250 MHz): δ 9.52 (1H, d, J ) 1.8, H-18), 3.97
(1H, dt, J ) 10.5, 4.7 Hz, H-8). 13C NMR (CDCl3, 63 MHz): δ
205.1 (C-18), 70.2 (C-8), 59.2 (C-13), 54.9 (C-14), 35.5 (CH2),
33.7 (CH2), 31.6 (CH2), 25.1 (CH2), 22.5 (CH2), 20.6 (CH2). MS
[CI+, m/z]: 169 (M+ + H, 2), 168 (M+, 5), 167 (M+ - H, 54),
139 (31), 121 (100). HRMS (CI+): calcd for C10H15O2 167.1072,
found 167.1065.
8r-[(ter t-Bu tyld im eth ylsilyl)oxy]-d e-A,B-a n d r osta n -18-
a l (31). Imidazole (1.84 g, 27 mmol) and TBSCl (1.36 g, 9.0
mmol) were consecutively added to a solution of 30 (0.57 g,
3.4 mmol) in DMF (10 mL). The reaction mixture was stirred
for 30 h. The reaction was quenched with H2O (200 mL). The
aqueous fraction was extracted with an Et2O/hexanes mixture
(3 × 60 mL, 10%). The combined organic fraction was washed
with H2O (3 × 50 mL), dried, filtered, and concentrated. The
residue was purified by flash chromatography (12 × 2 cm, 7%
EtOAc/hexanes) to give 31 [0.94 g, 98%, Rf ) 0.7 (20% EtOAc/
J . Org. Chem, Vol. 69, No. 14, 2004 4621

Moma´n et al.
The combined organic fraction was dried, filtered, and con-
centrated. The residue was purified by flash chromatography
(12 × 0.5 cm, 35% EtOAc/hexanes) to give 42a [0.07 g, 69%,
Rf ) 0.4 (50% EtOAc/hexanes), colorless oil]. 1H NMR (CDCl3,
300 MHz): δ 5.28-5.25 (2H, m, H-18, H-20), 3.66 (1H, dt, J )
10.5, 4.7 Hz, H-8), 2.15-2.08 (2H, m), 1.97-1.82 (2H, m), 1.18
(6H, s, H-26, H-27). 13C NMR (CDCl3, 75.5 MHz): δ 132.3 (CH),
131,5 (CH), 71.3 (C-8), 70,8 (C-25), 57.4 (C-14), 48.5 (C-13),
43.5 (CH2), 39.3 (CH2), 37.1 (CH2), 35.8 (CH2), 29.4 (CH2), 29.1
(C-26, C-27), 24.7 (CH2), 24.3 (CH2), 22.5 (CH2), 20.7 (CH2).
MS [CI+, m/z]: 267 (M+ + H, 7), 266 (M+, 9), 265 (M+ - H, 7).
(CH2), 18.2, 18.1 (C, t-BuSi), -4.8, -4.9, -5.0, -5.2 (SiMe2).
MS [FAB+, m/z]: 631 (M+ + H, 1), 630 (M+, 1), 629 (M+ - H,
1), 615 (M+ - Me, 1), 613 (M+ - OH, 1), 573 (M+ - t-Bu, 1),
515 (M+ - TBS, 1), 499 (M+ - OTBS, 1), 498 (1), 400 (M+
-
2TBS, 3), 399 (3), 369 (4), 367 (2), 263 (4), 147 (100). HRMS
(FAB+): calcd for C38H70O3Si2 630.4864, found 630.4875.
20(17f18)-a beo-1r,25-Dih ydr oxy-21-n or vitam in D3 (2a).
A solution of tetrabutylammonium fluoride in THF (1 mL, 1
M) was added to a solution of 44a (0.060 mg, 0.095 mmol) in
THF (2 mL). The mixture, protected from direct light, was
stirred for 16 h. H2O (10 mL) was added, and the aqueous
fraction was extracted with Et2O (7 × 10 mL). The combined
organic fraction was washed with aqueous saturated NaCl (20
mL), dried, filtered, and concentrated. The residue was purified
by flash chromatography (6 × 0.4 cm, 12% i-PrOH/hexanes),
to give the analogue 2a [0.033 g, 88%, Rf ) 0.2 (90% EtOAc/
hexanes), white solid]. 1H NMR(CD2Cl2, 250 MHz): δ 6.34, 6.12
(2H, AB, J ) 11.2, H-6, H-7), 5.30 (1H, bs, H-19E), 4.97 (1H,
bs, H-19Z), 4.37 (1H, m, H-1), 4.16 (1H, m, H-3), 1.18 (6H, s,
H-26, H-27). 13C NMR (CD2Cl2, 63 MHz): δ 148.1 (C), 142.8
(C), 133.6 (C), 124.7 (CH), 117.2 (CH), 111.9 (C-19), 70.85 (C-
25), 70.8 (C-1), 66.6 (C-3), 56.0 (C-14), 46.9 (C-13), 45.9 (CH2),
44.5 (CH2), 43.3 (CH2), 37.6 (CH2), 35.7 (CH2), 31.7 (CH2), 29.6
(C-26, C-27), 29.6 (CH2), 27.8 (CH2), 25.1 (CH2), 24.0 (CH2),
20(17f18)-a beo-De-A,B-8r,25-d ih yd r oxy-21-n or ch oles-
ta n e (43a ). Pd on carbon (0.03 g, 5% Pd) was added to a
solution of 42a (0.07 g, 0.26 mmol) in EtOAc (6 mL). The
resulting suspension was deoxygenated by alternating vacuum
with H2 bubbling and then stirred for 16 h under H2 atmo-
sphere (balloon pressure). H2 was removed by Ar bubbling.
The mixture was filtered through silica gel and concentrated.
The residue was purified by flash chromatography (12 × 0.5
cm, 35% EtOAc/hexanes) to give 43a [0.07 g, 98%, Rf ) 0.4
(50% EtOAc/hexanes), colorless oil]. 1H NMR (CDCl3, 250
MHz): δ 3.64 (1H, dt, J ) 10, 5 Hz, H-8), 2.05-1.93 (2H, m),
1.17 (6H, s, H-26, H-27). 13C NMR (CDCl3, 63 MHz): δ 71.0
(C-8), 70.7 (C-25), 56.9 (C-14), 45.7 (C-13), 43.9 (CH2), 36.2
(CH2), 35.9 (CH2), 34.0 (CH2), 31.2 (CH2), 29.1 (C-26, C-27),
27.1 (CH2), 24.44 (CH2), 24.36 (CH2), 23.5 (CH2), 21.5 (CH2),
20.2 (CH2). MS [CI-, m/z]: 269 (M+ + H, 3), 268 (M+, 16), 267
(M+ - H, 100), 251 (M+ - OH, 12). HRMS (CI-): calcd for
23.9 (CH2), 20.6 (CH2), 19.7 (CH2). MS [CI+, m/z]: 403 (M+
+
H, 1), 402 (M+, 1), 401 (M+ - H, 3), 385 (M+ - OH, 3), 384 (3),
383 (7), 367 (M+ - OH - H2O, 5), 291 (6), 249 (8), 136 (3), 135
(30), 121 (26). HRMS (CI+): calcd for C26H41O3 401.3056; found
401.3066.
C
17H31O2 267.2324, found 267.2325.
(5-Ca r b oxyp en t yl)t r ip h en ylp h osp h on iu m Br om id e
(21b). Ph3P (26.80 g, 102.2 mmol) was added to a solution of
6-bromohexanoic acid (5.00 g, 25.6 mmol) in dry CH3CN (17
mL). The reaction mixture, vigorously stirred, was refluxed
over 24 h. The solution was concentrated. The residue was
rinsed consecutively with benzene (3 × 20 mL), hexanes (20
mL), and Et2O (2 × 20 mL). The crystalline white solid was
20(17f18)-a beo-De-A,B-25-h yd r oxy-21-n or ch olesta n -8-
on e (3a ). Pyridinium dichromate (0.300 g, 0.797 mmol) was
added to a solution of 43a (0.060 g, 0.224 mmol) in CH2Cl2 (6
mL). After 16 h, Et2O (4 mL) was added. The reaction mixture
was stirred for an additional 15 min and filtered through a
silica gel layer. The residue obtained after concentration was
purified by flash chromatography (12 × 0.5 cm, 20% EtOAc/
hexanes) to give 3a [0.055 g, 92%, Rf ) 0.3 (20% EtOAc/
hexanes), colorless oil]. 1H NMR (CDCl3, 250 MHz): δ 1.17
(6H, s, H-26, H-27). 13C NMR (CDCl3, 63 MHz): δ 212.0 (C-8),
70.9 (C-25), 61.5 (C-14), 50.7 (C-13), 43.8 (CH2), 41.0 (CH2),
36.1 (CH2), 33.9 (CH2), 30.8 (CH2), 29.1 (C-26, C-27), 27.6
(CH2), 24.3 (CH2), 23.6 (CH2), 23.4 (CH2), 20.2 (CH2), 20.0
(CH2). MS [FAB+, m/z]: 289 (M+ + Na, 5), 267 (M+ + H, 7),
266 (M+, 2), 265 (M+ - H, 4), 249 (M+ - OH, 100), 137 (46).
HRMS (FAB+): calcd for C17H30O2 266.2246, found 266.2243.
20(17f18)-a beo-3-(ter t-Bu t yld im et h ylsilyl)-1r-[(ter t-
b u t yld im et h ylsilyl)oxy]-25-h yd r oxy-21-n or vit a m in D3
(44a ). n-Hexyllithium in hexanes (0.45 mL, 2.24 M) was added
dropwise, over 10 min, to a cooled solution of 4 (0.600 g, 1.029
mmol) in THF (3 mL) at -78 °C. The intense red mixture was
stirred for 40 min. A solution of 3a (0.040 g, 0.150 mmol) in
THF (4 mL) was slowly added. The mixture was stirred for
an additional 2 h. The temperature was allowed to reach -20
°C. After 1 h, the reaction was quenched with H2O (10 mL).
The aqueous fraction was extracted with Et2O (3 × 10 mL).
The combined organic fraction was washed with aqueous
saturated NaCl (20 mL), dried, filtered, and concentrated. The
residue was purified by flash chromatography (10 × 0.4 cm,
12% Et2O/hexanes) to give the protected analogue 44a [0.080
g, 87%, Rf ) 0.6 (20% EtOAc/hexanes), colorless oil]. 1H NMR
(CD2Cl2, 250 MHz): δ 6.27, 6.04 (2H, AB, J ) 11.3 Hz, H-6,
H-7), 5.19 (1H, dd, J ) 2.5, 0.8 Hz, H-19E), 4.86 (1H, d, J )
2.5 Hz, H-19Z), 4.38 (1H, dd, J ) 6.4, 3.6 Hz, H-1), 4.20 (1H,
tt, J ) 7.5, 3.75 Hz, H-3), 2.87 (1H, dd, J ) 12.5, 3.6 Hz, H-9â),
2.46 (1H, dd, J ) 13.0, 3.8 Hz, H-4), 2.20 (1H, dd, J ) 13.0,
7.5 Hz, H-4), 1.16 (6H, s, H-26, H-27), 0.88 (18H, s, t-BuSi),
0.07 (12H, s, SiMe2). 13C NMR (CD2Cl2, 63 MHz): δ 148.5 (C),
141.2 (C), 135.1(C), 123.2 (CH), 118.1 (CH), 111.3 (C-19), 72.2
(C-1), 70.8 (C-25), 67.7 (C-3), 56.0 (C-14), 46.5 (C-13), 46.1
(CH2), 45.0 (CH2), 44.1 (CH2), 36.4 (CH2), 35.4 (CH2), 31.3
(CH2), 29.1 (C-26, C-27), 28.8 (CH2), 27.2 (CH2), 25.8, 25.7 (t-
BuSi), 24.6 (CH2), 23.6 (CH2), 23.3 (CH2), 23.2 (CH2), 20.2
1
dried to give 21b (11.7 g, 99%). H NMR (CDCl3, 250 MHz):
δ 7.80-7.68 (15H, m), 3.58 (2H, bs), 2.34-2.32 (2H, m), 1.63
(6H, bs). 13C NMR (CDCl3, 63 MHz): δ 175.5 (C), 134.7 (CH,
d, J ) 2.4 Hz), 133.1 (CH, d, J ) 10.0 Hz), 130.1 (CH, d, J )
12.5 Hz), 117.5 (C, d, J ) 86.0 Hz), 33.6 (CH2), 29.0 (CH2, d,
J ) 16.2 Hz), 23.5 (CH2), 22.3 (CH2), 21.5 (CH2). MS [CI, m/z]:
360 (M+ - OH, 3), 359 (M+ - H2O, 11), 358 (M+ - H3O+, 5),
262 (Ph3P+, 54), 185 (Ph2P+, 100), 81 (Br+, 81), 79 (Br+, 58).
(18Z)-20(17f18)-a beo-8r-[(ter t-Bu tyldim eth ylsilyl)oxy]-
24-ca r boxyd e-A,B-22-h om o-21-n or ch ol-18-en e (40b). Fol-
lowing the same experimental procedure as for 40a , the
coupling of the aldehyde 31 (0.15 g, 0.5 mmol) with the ylide
formed from Wittig salt 21b (1.00 g, 2.2 mmol) and KO-t-Bu
(0.75 g, 6.7 mmol) afforded, after purification by flash chro-
matography (16 × 2 cm, 35% EtOAc/hexanes), 40b [0.15 g,
76%, Rf ) 0.2 (30% EtOAc/hexanes), white solid]. 1H NMR
(CDCl3, 300 MHz): δ 5.30-5.27 (2H, m, H-18, H-20), 3.66 (1H,
dt, J ) 10.2, 4.7 Hz, H-8), 2.36 (2H, t, J ) 7.4 Hz), 2.18-2.15
(2H, m), 1.90-1.82 (2H, m), 0.88 (9H, s, t-BuSi), 0.05 (6H, s,
Me2Si). 13C NMR (CDCl3, 75.5 MHz): δ 180.0 (C-25), 133.0
(CH), 131,0 (CH), 72.1 (C-8), 57.5 (C-14), 48.3 (C-13), 39.5
(CH2), 37.2 (CH2), 36.5 (CH2), 34.0 (CH2), 29.0 (CH2), 28.8
(CH2), 25.9 (CH3, t-BuSi), 25.7 (CH2), 24.4 (CH2), 22.6 (CH2),
20.5 (CH2), 18.0 (C, t-BuSi), -4.2, -4.6 (Me2Si). MS [CI+, m/z]:
381 (M+ + H, 32), 380 (M+, 7), 379 (M+ - H, 15), 365 (M+
Me, 22), 363 (M+ - OH, 21), 323 (M+ - t-Bu, 81), 249 (M+
-
-
OTBS, 100). HRMS (CI+): calcd for C22H41O3Si 381.2825, found
381.2826.
(18Z)-20(17f18)-a beo-8r-[(ter t-Bu tyld im eth ylsilyl)oxy]-
d e-A,B-22-h om o-21-n or ch olest-18-en -25-ol (41b). Follow-
ing the same experimental procedure as for 41a , the reaction
of the carboxylic acid 40b in two stages with MeLi in Et2O
(1.5 mL, 1.25 M) afforded, after purification by flash chroma-
tography (12 × 0.5 cm, 6% EtOAc/hexanes), 41b [0.07 g, 80%,
Rf ) 0.6 (20% EtOAc/hexanes), colorless oil]. 1H NMR (CDCl3,
300 MHz): δ 5.34-5.24 (2H, m, H-18, H-20), 3.66 (1H, dt, J )
4622 J . Org. Chem., Vol. 69, No. 14, 2004

Synthesis of Analogues of 1R,25-Dihydroxyvitamin D3
10.1, 4.7 Hz, H-8), 2.16-2.10 (2H, m), 1.95-1.79 (2H, m), 1.20
(6H, s, H-26, H-27), 0.88 (9H, s, t-BuSi), 0.05 (6H, s, Me2Si).
13C NMR (CDCl3, 75.5 MHz): δ 132.6 (CH), 131,6 (CH), 72.0
(C-8), 71,0 (C-25), 57.5 (C-14), 48.3 (C-13), 43.9 (CH2), 39.5
(CH2), 37.3 (CH2), 36.5 (CH2), 30.1 (CH2), 29.2 (C-26, C-27),
25.9 (CH3, t-BuSi), 25.7 (CH2), 24.1 (CH2), 22.6 (CH2), 20.5
(CH2), 18.1 (C, t-BuSi), -4.2, -4.6 (Me2Si). MS [CI-, m/z]: 395
(M+ + H, 4), 394 (M+, 8), 393 (M+ - H, 33), 337 (M+ - t-Bu,
4). HRMS (CI-): calcd for C24H45O2Si 393.3189, found 393.3195.
(18Z)-20(17f18)-a beo-De-A,B-8r,25-dih ydr oxy-22-h om o-
21-n or ch olest-18-en e (42b). Following the same experimen-
tal procedure as for 42a , the deprotection of 41b (0.06 g, 0.15
mmol) with aqueous HF (9 drops, 48%) afforded, after puri-
fication by flash chromatography (10 × 0.4 cm, 35% EtOAc/
hexanes), 42b [0.027 g, 63%, Rf ) 0.4 (50% EtOAc/hexanes),
colorless oil]. 1H NMR (CDCl3, 300 MHz): δ 5.34-5.23 (2H,
m, H-18, H-20), 3.69 (1H, dt, J ) 10.5, 4.6 Hz, H-8), 2.18-
2.09 (2H, m), 2.00-1.80 (2H, m), 1.19 (6H, s, H-26, H-27). 13C
NMR (CDCl3, 75.5 MHz): δ 132.1 (CH), 131,7 (CH), 71.5 (C-
8), 70,7 (C-25), 57.5 (C-14), 48.6 (C-13), 43.8 (CH2), 39.3 (CH2),
37.2 (CH2), 35.9 (CH2), 30.1 (CH2), 29.2 (C-26, C-27), 24.7
(CH2), 24.1 (CH2), 22.6 (CH2), 20.7 (CH2). MS [CI-, m/z]: 281
(M+ + H, 10), 280 (M+, 8), 279 (M+ - H, 10), 278 (M+ - 2H,
23), 265 (M+ - Me, 25), 263 (M+ - OH, 100). HRMS (CI-):
calcd for C18H31O2 279.2324, found 279.2314.
20(17f18)-a beo-De-A,B-8r,25-d ih yd r oxy-22-h om o-21-
n or ch olest a n e (43b ). Following the same experimental
procedure as for 43a , the catalytic hydrogenation of 42b (0.020
g, 0.071 mmol) with Pd on carbon (0.02 g, 5% Pd) afforded,
after purification by flash chromatography (9 × 0.4 cm, 35%
EtOAc/hexanes), 43b [0.019 g, 96%, Rf ) 0.4 (50% EtOAc/
hexanes), colorless oil]. 1H NMR (CDCl3, 250 MHz): δ 3.68
(1H, dt, J ) 10.5, 4.7 Hz, H-8), 2.06-1.97 (2H, m), 1.20 (6H,
s, H-26, H-27). 13C NMR (CDCl3, 63 MHz): δ 71.0 (C-25), 70.8
(C-8), 57.0 (C-14), 45.8 (C-13), 44.0 (CH2), 36.3 (CH2), 36.0
(CH2), 34.1(CH2), 30.7 (CH2), 30.2 (CH2), 29.2 (C-26, C-27), 27.1
(CH2), 24.4 (CH2), 24.3 (CH2), 23.5 (CH2), 21.5 (CH2), 20.3
(CH2). MS [CI-, m/z]: 283 (M+ + H, 12), 282 (M+, 18), 281
(M+ - H, 100). HRMS (CI-): calcd for C18H33O2 281.2481,
found 281.2474.
(C-25), 67.6 (C-3), 56.0 (C-14), 46.4 (C-13), 46.1 (CH2), 44.9
(CH2), 44.1 (CH2), 36.4 (CH2), 35.3 (CH2), 30.8 (CH2), 30.4
(CH2), 29.1 (C-26, C-27), 28.8 (CH2), 27.2 (CH2), 25.74, 25.71
(t-BuSi), 24.4 (CH2), 23.6 (CH2), 23.3 (CH2), 23.2 (CH2), 20.2
(CH2), 18.2, 18.1 (C, t-BuSi), -4.8, -4.9, -5.0, -5.2 (SiMe2).
MS [FAB+, m/z]: 645 (M+ + H, 1), 644 (M+, 2), 643 (M+ - H,
3), 629 (M+ - Me, 1), 627 (M+ - OH, 1), 587 (M+ - t-Bu, 1),
529 (M+ - TBS, 2), 513 (M+ - OTBS, 2), 512 (M+ - HOTBS,
2), 511(5), 414 (M+ - 2TBS, 1), 382 (M+ - 2OTBS, 2), 381 (4),
380 (2), 367 (3), 277 (3), 147 (36), 137 (100). HRMS (FAB+):
calcd for C39H72O3Si2 644.5020, found 644.5030.
20(17f18)-a beo-1r,25-Dih yd r oxy-22-h om o-21-n or vita -
m in D3 (2b). Following the same experimental procedure as
for 2a , 44b (0.007 g, 0.011 mmol) was deprotected with TBAF
in THF (0.4 mL, 1 M) to afford, after purification by flash
chromatography (6 × 0.4 cm, 12% i-PrOH/hexanes), the
analogue 2b [0.004 g, 81%, Rf ) 0.2 (90% EtOAc/hexanes),
white solid]. 1H NMR (CDCl3, 250 MHz): δ 6.36, 6.01 (2H,
AB, J ) 11.2 Hz, H-6, H-7), 5.30 (1H, bs, H-19E), 4.98 (1H,
bs, H-19Z), 4.40 (1H, m, H-1), 4.19 (1H, m, H-3), 1.18 (6H, s,
H-26, H-27). 13C NMR (CDCl3, 63 MHz): δ 147.6 (C), 142.8
(C), 132.9 (C), 124.8 (CH), 117.1 (CH), 111.9 (C-19), 71.0 (C-
1), 70.8 (C-25), 66.5 (C-3), 55.9 (C-14), 46.5 (C-13), 45.2 (CH2),
43.9 (CH2), 42.8 (CH2), 36.3 (CH2), 35.2 (CH2), 30.6 (CH2), 30.1
(CH2), 29.6 (CH2), 29.1 (C-26), 29.1 (C-27), 27.1 (CH2), 24.2
(CH2), 23.5 (CH2), 23.2 (CH2), 23.2 (CH2), 20.1 (CH2). MS [CI+,
m/z]: 417 (M+ + H, 1), 416 (M+, 1), 415 (M+ - H, 2), 401 (M+
- Me, 1), 399 (M+ - OH, 2), 398 (3), 397 (5), 277 (3), 136 (3),
135 (8), 121 (2). HRMS (CI+): calcd for C27H43O3 415.3212,
found 415.3223.
E t h yl (18E)-20(17f18)-a beo-8r-[(ter t-Bu t yld im et h yl-
silyl)oxy]d e-A,B-p r egn -18-en -21-a te (37). A solution of di-
ethyl ethoxycabonylmethylphosphonate (0.46 mL, 2.30 mmol)
in THF (3 mL) was slowly added to a cooled suspension of NaH
(0.05 g, 2.08 mmol) in dry THF (3 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 10 min and at rt for 1 h. A
solution of 31 (0.19 g, 0.67 mmol) in THF (6 mL) was added.
The reaction mixture was quenched after 72 h by addition of
H2O (20 mL). The aqueous fraction was extracted with EtOAc
(3 × 15 mL). The combined organic fraction was washed with
saturated aqueous NaCl (20 mL), dried, filtered, and concen-
trated. The residue was purified by flash chromatography (10
× 1 cm, 3% EtOAc/hexanes) to give 37 [0.22 g, 93%, Rf ) 0.5
(10% EtOAc/hexanes), colorless oil]. 1H NMR (CDCl3, 250
MHz): δ 7.08 (1H, d, J ) 16.1 Hz, H-18), 5.83 (1H, d, J ) 16.1
Hz, H-20), 4.19 (2H, q, J ) 7.1 Hz), 3.55 (1H, dt, J ) 10.0, 4.4
Hz, H-8), 1.30 (3H, t, J ) 7.1 Hz), 0.86 (9H, s, t-BuSi), 0.03
(6H, s, Me2Si). 13C NMR (CDCl3, 63 MHz): δ 167.0 (C-21),
152.4 (C-18), 120,3 (C-20), 71.7 (C-8), 60.2 (CH2, CO2Et), 56.8
(C-14), 49.5 (C-13), 39.7 (CH2), 36.7 (CH2), 36.0 (CH2), 25.8
(CH3, t-BuSi), 25.6 (CH2), 22.0 (CH2), 20.0 (CH2), 18.1 (C,
t-BuSi), 14.3 (CH3, CO2Et), -4.2, -4.7 (Me2Si). MS [CI+, m/z]:
20(17f18)-a beo-De-A,B-25-h yd r oxy-22-h om o-21-n or -
ch olesta n -8-on e (3b). Following the same experimental
procedure as for 3a , the oxidation of 43b (0.015 g, 0.053 mmol)
with PDC (0.060 g, 0.160 mmol) afforded, after purification
by flash chromatography (9 × 0.4 cm, 20% EtOAc/hexanes),
3b [0.013 g, 90%, Rf ) 0.3 (20% EtOAc/hexanes), colorless oil].
1H NMR (CDCl3, 250 MHz): δ 1.19 (6H, s, H-26, H-27). 13C
NMR (CDCl3, 63 MHz): δ 212.1 (C-8), 71.0 (C-25), 61.6 (C-14),
50.8 (C-13), 43.9 (CH2), 41.0 (CH2), 36.2 (CH2), 33.9 (CH2), 30.3
(CH2), 30.1 (CH2), 29.2 (C-26, C-27), 27.7 (CH2), 24.3 (CH2),
23.6 (CH2), 23.4 (CH2), 20.2 (CH2), 20.1 (CH2). MS [FAB+, m/z]:
303 (M+ + Na, 6), 281 (M+ + H, 9), 280 (M+, 2), 279 (M+
-
253 (M+ + H, 25), 352 (M+, 8), 351 (M+ - H, 28), 337 (M+
Me, 68), 307 (M+ - OEt, 31), 221 (M+ - t-Bu, 76), 221 (M+
-
-
H, 4), 278 (M+ - 2H, 12), 264 (M+ - H2O, 14), 263 (M+ - H3O+,
69), 153 (94), 137 (100). HRMS (FAB+): calcd for C18H31O2
279.2324, found 279.2324.
OTBS, 100). HRMS (CI+): calcd for C20H35O3Si 351.2355, found
351.2352.
20(17f18)-a beo-3-(ter t-b u t yld im et h ylsilyl)-1r-[(ter t-
bu tyld im eth ylsilyl)oxy]-25-h yd r oxy-22-h om o-21-n or vita -
m in D3 (44b). Following the same experimental procedure as
for 44a , the coupling of 3b (0.009 g, 0.032 mmol) with the
phosphine oxide anion formed by reaction of 4 (0.130 g, 0.223
mmol) with n-HexLi in hexanes (0.10 mL, 2.24 M) afforded,
after purification by flash chromatography (10 × 0.4 cm, 12%
Et2O/hexanes), the protected analogue 44b [0.019 g, 93%, Rf
) 0.6 (20% EtOAc/hexanes), colorless oil]. 1H NMR (CD2Cl2,
250 MHz): δ 6.27, 6.04 (2H, AB, J ) 11.3 Hz, H-6, H-7), 5.19
(1H, dd, J ) 2.5, 0.8 Hz, H-19E), 4.86 (1H, d, J ) 2.5 Hz,
H-19Z), 4.38 (1H, dd, J ) 6.4, 3.6 Hz, H-1), 4.20 (1H, tt, J )
7.5, 3.74 Hz, H-3), 2.86 (1H, dd, J ) 12.5, 3.6 Hz, H-9â), 2.46
(1H, dd, J ) 13.0, 3.8 Hz, H-4), 2.20 (1H, dd, J ) 13.0, 7.5 Hz,
H-4), 1.16 (6H, s, H-26, H-27), 0.88 (18H, s, t-BuSi), 0.07 (12H,
s, SiMe2). 13C NMR (CD2Cl2, 63 MHz): δ 148.5 (C), 141.2 (C),
135.0(C), 123.2 (CH), 118.0 (CH), 111.3 (C-19), 72.2 (C-1), 70.7
E t h yl 20(17f18)-a beo-8r-[(ter t-Bu t yld im et h ylsilyl)-
oxy]d e-A,B-p r egn a n -21-a te (38). Pd on carbon (0.05 g, 5%
Pd) was added to a solution of 37 (0.16 g, 0.45 mmol) in EtOAc
(12 mL). The resulting suspension was deoxygenated by
alternating vacuum with H2 bubbling and then stirred for 20
h under H2 atmosphere (balloon pressure). H2 was removed
by Ar bubbling. The mixture was filtered through silica gel
and concentrated. The residue was purified by flash chroma-
tography (9 × 1 cm, 3% EtOAc/hexanes) to give 38 [0.16 g,
98%, Rf ) 0.5 (10% EtOAc/hexanes), colorless oil]. 1H NMR
(CDCl3, 250 MHz): δ 4.11 (2H, q, J ) 7.1 Hz), 3.64 (1H, dt, J
) 10.0, 4.7 Hz, H-8), 2.18 (1H, dd, J ) 10.5, 1.7 Hz, H-20),
2.14 (1H, d, J ) 10.5 Hz, H-20), 1.24 (3H, t, J ) 7.1 Hz), 0.85
(9H, s, t-BuSi), 0.02 (6H, s, Me2Si). 13C NMR (CDCl3, 63
MHz): δ 174.5 (C-21), 71.0 (C-8), 60.3 (CH2, CO2Et), 56.7 (C-
14), 45.0 (C-13), 36.4 (CH2), 36.1 (CH2), 33.8 (CH2), 29.1 (CH2),
J . Org. Chem, Vol. 69, No. 14, 2004 4623

Moma´n et al.
25.8 (CH3, t-BuSi), 25.2 (CH2), 22.3 (CH2), 21.3 (CH2), 19.8
(CH2), 18.1 (C, t-BuSi), 14.2 (CH3, CO2Et), -4.2, -4.7 (Me2-
H-8), 1.20 (6H, s, H-26, H-27). 13C NMR (CDCl3, 75.5 MHz): δ
130.6 (CH), 129,4 (CH), 71.0 (C-25), 70,8 (C-8), 56.9 (C-14),
45.8 (C-13), 43.5 (CH2), 36.2 (CH2), 35.9 (CH2), 34.0 (CH2), 29.7
(CH2), 29.2 (C-26, C-27), 27.5 (CH2), 24.4 (CH2), 21.5 (CH2),
20.3 (CH2). MS [FAB+, m/z]: 295 (M+ + H, 2), 294 (M+, 2),
293 (M+ - H, 7), 137 (100), 121 (13).
Si). MS [CI+, m/z]: 355 (M+ + H, 4), 354 (M+, 5), 353 (M+
H, 19), 339 (M+ - Me, 49), 309 (M+ - OEt, 20), 297 (M+
-
-
t-Bu, 52), 223 (M+ - OTBS, 100). HRMS (CI+): calcd for
C
20H37O3Si 353.2512, found 353.2511.
20(17f18)-a beo-8r-[(ter t-Bu t yld im et h ylsilyl)oxy]d e-
20(17f18)-a beo-De-A,B-8r,25-d ih yd r oxy-22,23-d ih om o-
21-n or ch olesta n e (43c). Following the same experimental
procedure as for 43a , the catalytic hydrogenation of 42c (0.010
g, 0.034 mmol) with Pd on carbon (0.01 g, 5% Pd) afforded,
after purification by flash chromatography (6 × 0.4 cm, 35%
EtOAc/hexanes), 43c [0.010 g, 98%, Rf ) 0.4 (50% EtOAc/
hexanes), colorless oil]. 1H NMR (CDCl3, 300 MHz): δ 3.68
(1H, dt, J ) 10.5, 4.7 Hz, H-8), 1.20 (6H, s, H-26, H-27). 13C
NMR (CDCl3, 75.5 MHz): δ 71.0 (C-8), 70.9 (C-25), 57.0 (C-
14), 45.8 (C-13), 44.0 (CH2), 36.3 (CH2), 36.0 (CH2), 34.1(CH2),
30.7 (CH2), 30.2 (CH2), 29.7 (CH2), 29.2 (C-26, C-27), 27.1
(CH2), 24.5 (CH2), 24.3 (CH2), 23.6 (CH2), 21.6 (CH2), 20.3
(CH2). MS [CI-, m/z]: 296 (M+, 5), 295 (M+ - H, 18), 278 (M+
- H2O, 2). HRMS (CI-): calcd for C19H35O2 295.2637, found
295.2627.
A,B-p r egn a n -21-a l (39). A solution of diisobutylaluminum
hydride in hexanes (0.40 mL, 1 M) was added dropwise over
40 min to a cooled solution of 38 (0.13 g, 0.37 mmol) in dry
toluene (10 mL) at -80 °C. The reaction was quenched by rapid
addition, via syringe, of cooled H2O (0.5 mL, 0 °C) and aqueous
NH4Cl (20 mL, 10%). The aqueous fraction was extracted with
Et2O (4 × 10 mL). The combined organic fraction was washed
with H2O (20 mL), dried, filtered, and concentrated. The
residue was purified by flash chromatography (9 × 1 cm, 5%
EtOAc/hexanes) to give 39 [0.09 g, 81%, Rf ) 0.5 (20% EtOAc/
hexanes), colorless oil]. 1H NMR (CDCl3, 250 MHz): δ 9.81
(1H, t, J ) 1.6 Hz, H-21), 3.64 (1H, dt, J ) 10.1, 4.7 Hz, H-8),
2.34 (1H, d, J ) 8.2 Hz, H-20), 2.31 (1H, dd, J ) 8.2, 1.6 Hz,
H-20), 0.86 (9H, s, t-BuSi), 0.03 (6H, s, Me2Si). 13C NMR
(CDCl3, 63 MHz): δ 202.9 (C-21), 71.0 (C-8), 56.6 (C-14), 45.0
(C-13), 39.0 (CH2), 36.4 (CH2), 36.2 (CH2), 33.9 (CH2), 25.8
(CH3, t-BuSi), 25.2 (CH2), 21.3 (CH2), 19.8 (CH2), 19.1 (CH2),
18.1 (C, t-BuSi), -4.2, -4.7 (Me2Si). MS [CI+, m/z]: 311 (M+
+ H, 64), 310 (M+, 5), 309 (M+ - H, 18), 295 (M+ - Me, 36),
253 (M+ - t-Bu, 39), 179 (M+ - OTBS, 74), 161 (100). HRMS
(CI+): calcd for C18H35O2Si 311.2406, found 311.2401.
20(17f18)a beo-De-A,B-25-h yd r oxy-22,23-d ih om o-21-
n or ch olesta n -8-on e (3c). Following the same experimental
procedure as for 3a , the oxidation of 43c (0.009 g, 0.030 mmol)
with PDC (0.040 g, 0.106 mmol) afforded, after purification
by flash chromatography (6 × 0.4 cm, 20% EtOAc/hexanes),
3c [0.008 g, 90%, Rf ) 0.3 (20% EtOAc/hexanes), colorless oil].
1H NMR (CDCl3, 300 MHz): δ 1.20 (6H, s, H-26, H-27). 13C
NMR (CDCl3, 75.5 MHz): δ 212.5 (C-8), 71.0 (C-25), 61.6 (C-
14), 50.8 (C-13), 44.0 (CH2), 41.0 (CH2), 36.2 (CH2), 34.0 (CH2),
30.3 (CH2), 30.1 (CH2), 29.6 (CH2), 29.2 (C-26, C-27), 27.7
(CH2), 24.3 (CH2), 23.7 (CH2), 23.4 (CH2), 20.3 (CH2), 20.1
(CH2). MS [FAB+, m/z]: 317 (M+ + Na, 2), 295 (M+ + H, 3),
(22Z)-20(17f18)-a beo-8r-[(ter t-Bu tyldim eth ylsilyl)oxy]-
24-ca r boxyd e-A,B-22,23-d ih om o-21-n or ch ol-22-en e (40c).
Following the same experimental procedure as for 40a , the
coupling of the aldehyde 39 (0.08 g, 0.26 mmol) with the ylide
formed from Wittig salt 21a (0.40 g, 0.90 mmol) and KO-t-Bu
(0.30 g, 2.67 mmol) afforded, after purification by flash
chromatography (12 × 2 cm, 35% EtOAc/hexanes), 40c as a
mixture of Z/E isomers [0.07 g, 71%, Rf ) 0.2 (30% EtOAc/
hexanos), white solid]. 1H NMR (CDCl3, 300 MHz): δ 5.48-
5.27 (2H, m, H-22, H-22′), 3.64 (1H, dt, J ) 10.5, 4.7 Hz, H-8),
2.37 (2H, t, J ) 7.4 Hz), 0.87 (9H, s, t-BuSi), 0.03 (6H, s, Me2-
Si). 13C NMR (CDCl3, 75.5 MHz): δ 131.8 (CH), 128,0 (CH),
71.3 (C-8), 56.8 (C-14), 44.5 (C-13), 36.5 (CH2), 36.3 (CH2), 34.0
(CH2), 27.4 (CH2), 26.3 (CH2), 25.84 (CH3, t-BuSi), 25.81 (CH2),
25.4 (CH2), 24.6 (CH2), 21.6 (CH2), 20.0 (C, t-BuSi), -4.2, -4.7
(Me2Si). MS [CI+, m/z]: 325 (M+ + H, 23), 323 (M+ - H, 4),
309 (M+ - Me, 58), 291 (29), 279 (23), 267 (7). HRMS (CI+):
calcd for C23H41O3Si 393.2825, found 393.2827.
294 (M+, 1), 279 (M+ - Me, 6), 278 (M+ - O, 19), 277 (M+
-
OH, 19), 137 (100). HRMS (FAB+): calcd for C19H35O2 295.2637,
found 295.2633.
20(17f18)-a beo-3-(ter t-Bu t yld im et h ylsilyl)-1r-[(ter t-
bu tyldim eth ylsilyl)oxy]-25-h ydr oxy-22,23-dih om o-21-n or -
vita m in D3 (44c). Following the same experimental procedure
as for 44a , the coupling of 3c (0.004 g, 0.014 mmol) with the
phosphine oxide anion formed by reaction of 4 (0.055 g, 0.094
mmol) with n-HexLi in hexanes (0.04 mL, 2.24 M) afforded,
after purification by flash chromatography (6 × 0.4 cm, 12%
Et2O/hexanes), the protected analogue 44c [0.009 g, 96%, Rf
) 0.6 (20% EtOAc/hexanes), colorless oil]. 1H NMR (CD2Cl2,
250 MHz): δ 6.27, 6.04 (2H, AB, J ) 11.3 Hz, H-6, H-7), 5.19
(1H, dd, J ) 2.5, 0.8 Hz, H-19E), 4.85 (1H, d, J ) 2.5 Hz,
H-19Z), 4.38 (1H, dd, J ) 6.4, 3.6 Hz, H-1), 4.20 (1H, tt, J )
7.5, 3.75 Hz, H-3), 2.88 (1H, dd, J ) 12.6, 3.5 Hz, H-9â), 2.46
(1H, dd, J ) 13.0, 3.8 Hz, H-4), 2.20 (1H, dd, J ) 13.0, 7.5 Hz,
H-4), 1.16 (6H, s, H-26, H-27), 0.88 (18H, s, t-BuSi), 0.06 (12H,
s, SiMe2). 13C NMR (CD2Cl2, 63 MHz): δ 148.5 (C), 141.2 (C),
135.0(C), 123.2 (CH), 118.0 (CH), 111.2 (C-19), 72.2 (C-1), 70.7
(C-25), 67.6 (C-3), 56.0 (C-14), 46.4 (C-13), 46.1 (CH2), 44.9
(CH2), 44.1 (CH2), 36.4 (CH2), 35.3 (CH2), 30.8 (CH2), 30.4
(CH2), 29.9 (CH2), 29.1 (C-26, C-27), 28.8 (CH2), 27.2 (CH2),
25.71, 25.69 (t-BuSi), 24.4 (CH2), 23.6 (CH2), 23.3 (CH2), 23.2
(CH2), 20.2 (CH2), 18.2, 18.1 (C, t-BuSi), -4.8, -4.9, -5.0, -5.3
(SiMe2). MS [FAB+, m/z]: 659 (M+ + H, 3), 657 (M+ - H, 5),
656 (M+ - 2H, 2), 643 (M+ - Me, 3), 641 (M+ - OH, 2), 601
(22Z)-20(17f18)-a beo-8r-[(ter t-Bu tyld im eth ylsilyl)oxy]-
d e-A,B-22,23-d ih om o-21-n or ch olest-22-en -25-ol (41c). Fol-
lowing the same experimental procedure as for 41a , the
reaction of the carboxylic acid 40c (0.05 g, 0.13 mmol) in two
stages with MeLi in Et2O (1 mL, 1.25 M) afforded, after
purification by flash chromatography (10 × 0.5 cm, 6% EtOAc/
hexanes), 41c [0.04 g, 82%, Z/E isomers mixture, Rf ) 0.6 (20%
1
EtOAc/hexanes), colorless oil]. H NMR (CDCl3, 300 MHz): δ
5.40-5.29 (2H, m, H-22, H-22′), 3.63 (1H, dt, J ) 9.6, 4.7 Hz,
H-8), 1.20 (6H, s, H-26, H-27), 0.86 (9H, s, t-BuSi), 0.02 (6H,
s, Me2Si). 13C NMR (CDCl3, 75.5 MHz): δ 130.8 (CH), 129,3
(CH), 71.2 (C-8), 70,9 (C-25), 56.8 (C-14), 45.5 (C-13), 43.5
(CH2), 36.5 (CH2), 36.4 (CH2), 34.0 (CH2), 29.2 (C-26, C-27),
27.5 (CH2), 27.4 (CH2), 25.8 (CH3, t-BuSi), 25.4 (CH2), 24.4
(CH2), 21.6 (CH2), 20.0 (CH2), 18.1 (C, t-BuSi), -4.2, -4.7 (Me2-
(M+ - t-Bu, 2), 542 (3), 527 (M+ - OTBS, 3), 526 (M+
-
Si). MS [CI-, m/z]: 409 (M+ + H, 10), 408 (M+, 27), 407 (M+
-
HOTBS, 3), 525 (6), 428 (M+ - 2TBS, 2), 396 (M+ - 2OTBS,
4), 395 (8), 367 (6), 291 (4), 147 (100). HRMS (FAB+): calcd
for C40H74O3Si2 658.5176, found 658.5187.
H, 100), 406 (M+ - 2H, 25), 349 (14), 393 (14). HRMS (CI-):
calcd for C25H47O2Si 407.3345, found 407.3347.
(22Z)-20(17f18)-a beo-De-A,B-8r,25-d ih yd r oxy-22,23-d i-
h om o-21-n or ch olest-22-en e (42c). Following the same ex-
perimental procedure as for 42a , the deprotection of 41c (0.030
g, 0.073 mmol) with aqueous HF (9 drops, 48%) afforded, after
purification by flash chromatography (9 × 0.5 cm, 35% EtOAc/
hexanes), 42c [0.013 g, 60%, Z/E isomers mixture, Rf ) 0.4
(50% EtOAc/hexanes), colorless oil]. 1H NMR (CDCl3, 300
MHz): δ 5.43-5.27 (2H, m, H-22, H-22′), 3.75-3.60 (1H, m,
20(17f18)-a beo-1r,25-Dih yd r oxy-22,23-d ih om o-21-n or -
vita m in D3 (2c). Following the same experimental procedure
as for 2a , 44c (0.005 g, 0.008 mmol) was deprotected with
TBAF in THF (0.1 mL, 1 M) to afford, after purification by
flash chromatography (6 × 0.4 cm, 12% i-PrOH/hexanes), the
analogue 2c [0.003 g, 80%, Rf ) 0.2 (90% EtOAc/hexanes),
white solid]. 1H NMR (CDCl3, 250 MHz): δ 6.35, 6.00 (2H,
AB, J ) 11.1 Hz, H-6, H-7), 5.31 (1H, bs, H-19E), 4.98 (1H,
4624 J . Org. Chem., Vol. 69, No. 14, 2004

Synthesis of Analogues of 1R,25-Dihydroxyvitamin D3
bs, H-19Z), 4.38 (1H, m, H-1), 4.18 (1H, m, H-3), 1.18 (6H, s,
H-26, H-27). 13C NMR (CDCl3, 63 MHz): δ 147.6 (C), 142.8
(C), 132.9 (C), 124.8 (CH), 117.2 (CH), 111.8 (C-19), 71.1 (C-
1), 70.7 (C-25), 66.6 (C-3), 55.9 (C-14), 46.4 (C-13), 45.1 (CH2),
43.9 (CH2), 42.7 (CH2), 36.4 (CH2), 35.2 (CH2), 30.6 (CH2), 30.1
(CH2), 29.6 (CH2), 29.1 (C-26), 29.1 (C-27), 28.9 (CH2), 27.0
(CH2), 24.2 (CH2), 23.5 (CH2), 23.2 (CH2), 23.2 (CH2), 20.1
(CH2). MS [CI+, m/z]: 430 (M+, 1), 429 (M+ - H, 2), 415 (M+
- Me, 1), 413 (M+ - OH, 2), 412 (M+ - H2O, 2), 411(4), 291
(2), 290 (3), 136 (2), 135 (5), 121 (2). HRMS (CI+): calcd for
C28H45O3 429.3369, found 429.3380.
thank J . P. van de Velde and J . Zorgdrager (Solvay
Pharmaceuticals BV, Weesp, The Netherlands) for the
gift of starting materials. D.N. thanks the Argentinian
National Council for Scientific Research (CONICET) for
a postdoctoral fellowship. This paper is based in part
on the Ph.D. Thesis of Edelmiro Moma´n, University of
Santiago de Compostela, Spain, 2003. CD-Rom Edition
ISBN 84-9750-189-6. This paper is dedicated to Prof.
Hector F. DeLuca on the occasion of his 75th birthday.
Su p p or tin g In for m a tion Ava ila ble: General methods
and materials,26,27 and spectral data (1H and 13C NMR). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. Financial support for this re-
search was provided by the Spanish Directorate General
for Scientific and Technological Research (DIGICYT)
under Projects PM97-0166 and SAF2001-3187. We
J O0498664
J . Org. Chem, Vol. 69, No. 14, 2004 4625