Design, synthesis, evaluation, and structure of vitamin D analogues with furan side chains

Article abstract of DOI:10.1002/chem.201102695

Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1α,25-dihydroxy-vitamin D₃ (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a tetrahydrofuran ring at the side chain that optimize the aliphatic side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogues with aromatic furan side chains (3 a, 3 b, 4 a, 4 b) have now been developed. The triene system has been constructed by an efficient stereoselective intramolecular cyclization of an enol triflate (A-ring precursor) followed by a Suzuki-Miyaura coupling of the resulting intermediate with an alkenyl boronic ester (CD-side chain, upper fragment). The furan side chains have been constructed by gold chemistry. These analogues exhibit significant pro-differentiation effects and transactivation potency. The crystal structure of 3 a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations. Copyright

Full text of DOI:10.1002/chem.201102695

FULL PAPER
DOI: 10.1002/chem.201102695
Design, Synthesis, Evaluation, and Structure of Vitamin D Analogues
with Furan Side Chains
Ramꢀn Fraga,[a] Flavia Zacconi,[a] Fredy Sussman,[a] Paloma OrdꢀÇez-Morꢁn,[b]
Alberto MuÇoz,[b] Tiphaine Huet,[c] Ferdinand Molnꢁr,[d] Dino Moras,[c]
Natacha Rochel,[c] Miguel Maestro,*[e] and Antonio MouriÇo*[a]
Dedicated to Dr. Noburu Kubodera on the occasion of his retirement
Abstract: Based on the crystal struc-
tures of human vitamin D receptor
(hVDR) bound to 1a,25-dihydroxy-vi-
tamin D3 (1,25D) and superagonist li-
gands, we previously designed new su-
peragonist ligands with a tetrahydrofur-
an ring at the side chain that optimize
the aliphatic side-chain conformation
through an entropy benefit. Following
a similar strategy, four novel vitamin D
analogues with aromatic furan side
chains (3a, 3b, 4a, 4b) have now been
developed. The triene system has been
constructed by an efficient stereoselec-
tive intramolecular cyclization of an
enol triflate (A-ring precursor) fol-
lowed by a Suzuki–Miyaura coupling
of the resulting intermediate with an
alkenyl boronic ester (CD-side chain,
upper fragment). The furan side chains
have been constructed by gold chemis-
try. These analogues exhibit significant
pro-differentiation effects and transac-
tivation potency. The crystal structure
of 3a in a complex with the ligand-
binding domain of hVDR revealed that
the side-chain furanic ring adopts two
conformations.
Keywords: cell adhesion · furans ·
gold · synthesis design · vitamin D
analogues
Introduction
Vitamin D3 (1a), before eliciting its biological functions,
must be dihydroxylated to its active metabolite 1a,25-dihy-
droxy-vitamin D3 (1b, 1,25D, calcitriol), which induces gene
expression by signaling through the nuclear vitamin D re-
ceptor transcription factor (VDR). The seco-steroid hor-
mone 1,25D regulates a plethora of biological functions, in-
cluding calcium homeostasis, cell proliferation and differen-
tiation, and immunomodulation.[1]
[a] Dr. R. Fraga, Dr. F. Zacconi, Dr. F. Sussman, Prof. Dr. A. MouriÇo
Departamento de Quꢀmica Orgꢁnica
Universidad de Santiago y Unidad Asociada al CSIC
Avda de las Ciencias s/n, 15782 Santiago de Compostela (Spain)
Fax : (+34)981-595012
E-mail: antonio.mourino@usc.es
[b] Dr. P. OrdꢂÇez-Morꢁn, Prof. Dr. A. MuÇoz
Instituto de Investigaciones Biomꢃdicas “Alberto Sols” UAM-CSIC
C/Arturo Duperier 4, 28029 Madrid (Spain)
[c] T. Huet, Prof. Dr. D. Moras, Prof. Dr. N. Rochel
Department of Structural Biology and Genomics
IGBMC, 67404 Illkirch (France)
Although the applicability of 1,25D is at present limited
due to the parallel induction of hypercalcemia, its properties
open perspectives for the treatment of several diseases, in-
cluding osteoporosis, cancer, psoriasis, arthritis, and type 1
diabetes.[2,3] As a result, a great deal of attention is being fo-
cused on the synthesis of vitamin D analogues with selective
properties, although few have proceeded beyond the preclin-
ical stage.[4,5] Most of these analogues have been modified at
the side chain, as exemplified by calcipotriol[6] (2a, MC903,
Dovonex, Leo Pharmaceuticals, Denmark), used topically
for the treatment of psoriasis[7] and seocalcitol (2b, EB1089,
[d] Dr. F. Molnꢁr
School of Pharmacy, Faculty of Health Sciences,
University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio
(Finland)
[e] Prof. Dr. M. Maestro
Departamento de Quꢀmica Fundamental
Universidad de A CoruÇa
15071 A CoruÇa (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102695.
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Leo Pharmaceuticals, Denmark), a potent inhibitor of cell
proliferation.[8]
resulting lithium anion with acetone furnished, after desily-
lation with tetrabutylammonium fluoride (TBAF),[22] diol 12
(75%, two steps, Scheme 2). Unfortunately, several attempts
All synthetic vitamin D analogues that crystallize in com-
plexes with the VDR ligand-binding domain (LBD) have
been shown to be anchored by the same residues in the
ligand-binding pocket (LBP), with the hydroxyl moieties at
the A-ring and the side chain located in identical positions
and forming identical hydrogen bonds.[9,10] On the basis of
docking studies using the crystal structure of an engineered
active ligand-binding domain of the human vitamin D recep-
tor (hVDR LBD) bound to 1,25D[9] and to agonist li-
gands,[10] we have recently designed the new superagonist
analogue 2c, the conformation of which in the binding
pocket is stabilized by a side-chain tetrahydrofuran unit.[11]
Attracted by the potent biological activities of 2b,[8] which
possesses a conjugated double bond in the side chain, and
superagonist 2c,[11] and to further study the correlation be-
tween in silico ligand design and biological activity, we de-
signed the new analogues 3 and 4, which possess a rigid
side-chain fragment in the form of a furan ring and bind sig-
nificantly more efficiently to the hVDR in silico than the
natural hormone 1,25D.[12,13] We describe herein the synthe-
sis of the four analogues 3a,b and 4a,b. In addition, we pres-
ent the results of investigations of their biological behavior
and structural studies.
Scheme 2. Synthesis of furan 11 and furanic ketone 16. Reagents and
conditions: a) HC2CH2ZnBr, THF, 08C, 1 h, RT, 1.5 h, 98%; b) DMP,
CH2Cl2, RT, 1.5 h, 84%; c) Et3PAuCl (3 mol%), THF, then AgNO3
(3 mol%), RT, 4 h, 98%; d) nBuLi, THF, RT, 2 h, À788C, acetone,
À788C to RT, 80%; e) TBAF, THF, 508C, 72 h, 94%; f) nBuLi, THF,
08C, 2 h, À788C, then ClCO2Et, THF, À788C to RT, 91%; g) HF (48%,
50 drops), CH3CN, RT, 36 h, 92%; h) DMP, CH2Cl2, RT, 3.5 h, 93%.
TBS=SiMe2tBu. DMP=Dess–Martin periodinane. THF=tetrahydrofur-
an. TBAF=nBu4NF.
Results and Discussion
General retrosynthesis of analogues 3 and 4: The general
synthetic strategy for the synthesis of vitamin D analogues
3a, 3b, 4a, and 4b (depicted as the general structure 5) fol-
lows the convergent strategy recently developed in our labo-
ratory (Scheme 1).[14] In this route, the triene system is con-
structed by an efficient stereoselective intramolecular cycli-
zation of an enol triflate (A-ring precursor 7)[15] followed in
situ by a Suzuki–Miyaura coupling of the resulting palladi-
um intermediate with an alkenyl boronic ester (CD-side
chain upper fragment, 6). We envisaged the preparation of
the boronate ester 6 from the known protected aldehyde
to selectively oxidize alcohol 12 to the desired ketone 13
under different reaction conditions were unsuccessful.[23]
These results prompted us to attempt the installation of the
hydroxylated side chain at the end of the synthesis. Consid-
ering that the ester group tolerates the reaction conditions
chosen to introduce the vitamin D triene system,[14] we se-
lected this functionality instead of the previous tertiary hy-
droxy group to continue the synthesis. The required ester 14
was prepared in 91% yield by reaction of the lithium anion
of 11 with ethyl chloroformate. Removal of the TBS group
(HF/CH3CN) and oxidation of the resulting alcohol (DMP/
CH2Cl2) afforded the desired upper ketone 16 (85% yield
over the two steps; 62% yield from aldehyde 8, six steps).
Completion of the synthesis of analogues 3a and 3b is il-
lustrated in Scheme 3. Wittig reaction of 16 with ylide
Ph3P=CHBr[14] afforded alkenyl bromide 17 (75%), which
was treated with bis(pinacolato)diboron in the presence of
[1,1’-bis(diphenylphosphino)ferrocene]dichloropalladiu-
m(II)–dichloromethane complex as catalyst and tricyclohex-
ylphosphine as ligand to provide the desired boronate 6a in
75% yield. With the requisite upper boronate 6a in hand,
we next proceeded to install the triene unit. Treatment of an
equimolar mixture of 6a and 7 in aqueous K3PO4 (2m)/THF
8
[16] using gold chemistry to introduce the furan ring.
Scheme 1. General retrosynthesis of the target vitamin D3 analogues.
Preliminary studies on the conversion of furan 11 into
ketone 13 were not very promising. Deprotonation of the
furan ring with butyllithium and subsequent reaction of the
with a catalytic amount of [PdCl
2ACHTUNGTREN(UNGN Ph3P)2] (5 mol%) at RT
for 1 h delivered, after desilylation with hydrogen fluoride,
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Convergent Synthesis of Vitamin D Analogues
FULL PAPER
Scheme 3. Functionalization of the furan ring and synthesis of analogues
3a and 3b. Reagents and conditions: a) Ph3P=CHBr, toluene, À15 to
08C, 75%; b) [PdCl2ACHTUNGTRENNUNG(dppf)2]·CH2Cl2, Cy3P, KOAc, Pin2B2, DMSO, 808C,
2.5 h, 75%; c) [PdCl2ACHTUNGTRENNUNG(Ph3P)2], K3PO4, THF/H2O, RT, 1 h; HF (48%,
5 drops), CH3CN, 15 min, 85%; d) MeLi, THF, À788C to RT, 12 h, 88%;
e) EtMgBr, THF, À788C, 15 min, RT, 3 h, 82%. TES=SiEt3. dppf=1,1’-
bis(diphenylphosphino)ferrocene.
Scheme 5. Synthesis of the upper ketone 26a. Reagents and conditions:
a) MeLi addition to 8 in ClCH2I, THF, À788C, 30 min, RT, 1.5 h, 98%;
b) 22 and F3B·OEt2, THF, addition to 23a, À788C to RT, 12 h, 98%;
c) DMP, CH2Cl2, RT, 1.5 h, 91%; d) AuCl3, THF, RT, 15 min; TBAF,
THF, 508C, 4 days, 91%; e) DMP, CH2Cl2, RT, 1.5 h, 91%.
the ester 5a (85% yield, two steps). The ester 5a is a suita-
ble intermediate for further functionalization at the side
chain with the possibility of isotopic labeling. Finally, the
target analogue 3a was obtained in 88% yield by treatment
of ester 5a with methyllithium in THF (33% overall yield
from aldehyde 8, eleven steps). Replacing methyllithium by
ethylmagnesium bromide furnished the vitamin D analogue
3b (31% overall yield from aldehyde 8, eleven steps).
the unwanted allene 21 and dimer 22. However, the desired
alcohols 25a could be obtained in 96% yield through a two-
step sequence, which involved treatment of a mixture of
chloroiodomethane and 8 with methyllithium, followed by
opening of the resultant epoxide 23[25] with the lithium alky-
nide 24a in the presence of boron trifluoride diethyl ether-
ate. Oxidation of alcohols 25a with Dess–Martin periodi-
nane proceeded smoothly to produce ketone 26a (97%
yield) accompanied by a trace amount of the corresponding
isomeric allenone. As previously planned, exposure of
Synthesis of vitamin D analogues 4a and 4b: Our synthetic
efforts were first focused on alcohol 18, which contains the
side chain of the target analogues 4 (Scheme 4). Unfortu-
ketone 26a to goldACTHNUTRGNEU(GN III) chloride furnished, after desilylation
(TBAF), the desired diol 27a (91% yield over the two
steps). Diol 27a was then oxidized with Dess–Martin period-
inane to generate ketone 28a (91% yield).
Scheme 6 depicts the completion of the synthesis of 4a
following the same sequence of reactions as above. Olefina-
tion of ketone 28a with Ph3P=CHBr provided the alkenyl
bromide 29a (72%), exposure of which to Pin2B2 in the
Scheme 4. Retrosynthesis of 12a from aldehyde 8.
presence of [PdCl2ACHTUNTRGNE(UNG dppf)2]·CH2Cl2 as catalyst and Cy3P as a
ligand, furnished the expected boronate 30a (87%). The
cyclization–coupling cascade between enol triflate 7 and
boronate 30a proceeded smoothly under the standard reac-
tion conditions indicated in Scheme 3 to provide, after desi-
lylation (HF/CH3CN), the desired analogue 4a in 76% yield
(nine steps, 36.7% overall yield from aldehyde 8). Analogue
4b was synthesized in 26.6% yield from aldehyde 8 employ-
ing the same sequence of reactions.[26]
nately, our efforts to obtain 18 by treatment of the lithium
or copper anion of 11 with isobutylene oxide resulted only
in recovery of the starting material.[24] As an alternative, we
next focused our attention on the AuIII-assisted transforma-
tion of propargyl ketones into furans, as previously observed
by Hashmi and co-workers.[20] Thus, furan 18 was envisaged
as being accessible from ketone 19a, which in turn would be
prepared from aldehyde 8.
As shown in Scheme 5, our initial efforts to obtain a dia-
stereomeric mixture of propargylic alcohols 25a by reaction
of aldehyde 8 with propargyl zinc 20 produced a mixture of
Biological activity: The biological activities of the four vita-
min D analogues (3a, 3b, 4a, 4b) were assayed in human
SW480-ADH colon cancer cells. These cells express endoge-
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A. MouriÇo, M. Maestro et al.
Scheme 6. Synthesis of 4a. Reagents and conditions: a) Ph3P=CHBr, tol-
uene, À15 to 08C, 72%; b) [PdCl
2A
DMSO, 808C, 3 h, 87%; c) [PdCl
2A
d) HF (48%, 5 drops), CH3CN, 20 min, 76% (two steps).
nous VDR and respond to 1,25D treatment by inhibition of
proliferation and differentiation to an epithelial pheno-
type.[27] The ability of the four derivatives to activate VDR
was first examined by their capacity to induce in SW480-
ADH cells a morphological change towards a differentiated
adhesive phenotype. All four compounds displayed a similar
effect to that of 1,25D when assayed at 10À7 m, leading to
the formation of compact epitheloid islands (Figure 1A).
We subsequently studied the effect of the analogues in in-
creasing the cellular content of VDR in comparison with
that exerted by 1,25D, an effect that is believed to be a con-
sequence of both transcriptional and post-transcriptional
mechanisms.[28] Western blot analyses showed that they were
all able to increase the VDR protein level with comparable
potency to that of 1,25D (Figure 1B). Moreover, and in line
with the induction of intercellular adhesion, all four com-
pounds caused an increase in the amount of E-cadherin, the
crucial component of adherens junctions structures at the
plasma membrane that is mainly responsible for intercellular
adhesion in epithelia. E-Cadherin has been shown to be in-
duced by 1,25D through the activation of a rapid extranu-
clear signaling pathway that is required for CDH1/E-cadher-
in gene transcription.[29] Thus, our results indicate that com-
pounds 3a, 3b, 4a, and 4b are able to activate both non-ge-
nomic and genomic VDR actions.
Finally, we examined the ability of the compounds to
induce VDR transcriptional activity in transactivation ex-
periments using cells that were transfected with a plasmid
encoding the luciferase reporter gene under the control of a
vitamin D response element (VDRE; Figure 1C). Ana-
logues 3a and 4a showed potencies slightly lower than but
comparable to that of 1,25D, whereas analogues 3b and 4b
were an order of magnitude less potent. All in all, these re-
sults show that our compounds efficiently bind VDR in
vivo, inducing its ability to interact with target genes and to
activate transcription from a consensus VDRE, with the var-
Figure 1. Biological assays of 3a, 3b, 4a, and 4b. Numbers below tracks
correspond to the values of E-cadherin and VDR protein expression
levels normalized to that of b-tubulin in 1,25D- and analogues-treated
versus vehicle-treated cells. RLU=relative luciferase units.
iable potency observed in the assays being attributable to
gene- or sequence-specific differences.
Crystal structure of 3a bound to the hVDR ligand-binding
domain (PDB ID: 3TKC): To gain insight into structure–
function relationships, we solved the crystal structure of the
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Convergent Synthesis of Vitamin D Analogues
FULL PAPER
hVDR LBD bound to 3a at a resolution of 1.75 ꢅ (Table S1
in the Supporting Information). The complex hVDR LBD/
3a displays the canonical agonist conformation of all previ-
ously reported structures of VDR bound to agonist and su-
peragonist ligands, with helix H12 folded in the agonistic
position.[9–11] The ligand is buried in the predominantly hy-
drophobic pocket and adopts the same orientation as the
natural ligand. In contrast to all previous structures of
hVDR LBD complexes, the side chain of the bound 3a
ligand adopts two conformations, X and Y (Figure 2). Their
relative occupancies refined by PHENIX.REFINE were
evaluated as 60% and 40% for conformations 3a-X and 3a-
Y, respectively.
tively, and the distances between the Ne2 of His397 and 25-
OH are 2.91, 2.68, and 2.81 ꢅ for 3a-X, 3a-Y, and
1a,25(OH)2D3, respectively. Additional van der Waals inter-
actions stabilize each conformation. Thus, the flexibility of
compound 3a, illustrated by the presence of two distinct
conformations of the furan ring in the LBP, may explain the
slightly lower agonist property of this molecule.
Conclusion
We have designed by docking and efficiently synthesized
four novel 1a,25-dihydroxy-vitamin D3 analogues with furan
side chains. Key features of our work include the use of a
Pd0-catalyzed cyclization–coupling cascade for the stereose-
lective construction of the triene unit from an enol triflate
(A-ring precursor) and an alkenyl boronate (CD-side chain
fragment), and an AuIII-catalyzed intramolecular construc-
tion of the side-chain furan unit. These analogues efficiently
bind the vitamin D receptor (VDR) in vivo to induce VDR
transcriptional activity. Analogues 3a and 4a showed com-
parable potency to that of 1,25D, whereas analogues 3b and
4b were an order of magnitude less potent. All four com-
pounds exerted a similar effect in human SW480-ADH
colon cancer cells as the natural hormone at concentrations
of 10À7 m. In contrast to all previous structures of hVDR
LBD complexes, the side chain of the bound ligand 3a
adopts two conformations. The slightly lower agonist poten-
cy of 3a in comparison with 1,25D may be explained in
terms of intramolecular hydrogen-bonding between the hy-
droxy group of the side chain and the oxygen of the furan
ring, which diminishes the intermolecular interaction of the
analogue with His305 and His397 of the VDR.
Experimental Section
Figure 2. Conformations of 3a bound to VDR. A) Two views of 3a (in
white) in the 2FoÀFc electron density omit map contoured at 1.0 s. B) Su-
perimposition of the two conformations X and Y of 3a (light grey) with
that of 1,25D (grey). C) Intermolecular and intramolecular hydrogen
bonds around the side chain of 3a. X and Y are the two conformations of
the side chain of 3a.
General: Details of the general materials and methods have been provid-
ed elsewhere.[12,14] For details concerning the preparation of compounds
8, 23, 28a, 29a, 30a, 4a, 26b, 17b, 28b, 29b, 30b, and 4b, see the Sup-
porting Information.
8b-[(tert-Butyldimethylsilyl)oxy]-de-A,B-26,27-dinor-24-cholestyn-22-ol
(9):
A suspension of Zn (0.197 g, 3.01 mmol, 7 equiv) in dry THF
(10 mL) was heated at reflux for 10 min. 1,2-Dibromoethane (0.03 mL,
0.345 mmol, 0.8 equiv) was then added. The suspension was heated at
reflux for 10 min and then cooled to 08C, whereupon propargyl bromide
(0.16 mL, 1.5 mmol, 3.5 equiv) was added dropwise. The resulting mix-
ture was stirred in the dark for 1 h at 08C. A solution of aldehyde 8
(0.156 g, 0.43 mmol, 1 equiv) in THF (4 mL) was then added via a cannu-
la. The mixture was stirred for 1 h at 08C and for 1.5 h at RT. The reac-
tion was then quenched with saturated aqueous NH4Cl solution (10 mL).
The aqueous phase was extracted with Et2O (3ꢆ10 mL) and the com-
bined organic phases were dried, filtered, and concentrated. The residue
was purified by flash chromatography (SiO2, 1ꢆ12 cm, 5% EtOAc/hex-
anes) to give a mixture of isomers 9 [0.154 g, 0.42 mmol, 98%, Rf =0.44
(20% EtOAc/hexanes), colorless oil]. 1H NMR (400 MHz, CDCl3): d=
4.00 (m, 1H; H-8), 3.90 (m, 1H; H-22), 2.44 (ddd, J=16.6, 8.1, 2.6 Hz,
1H; H-23), 2.24 (ddd, J=16.6, 5.8, 2.6 Hz, 1H; H-23), 2.03 (t, J=2.6 Hz,
1H; H-25), 0.92 (s, 3H; H-18), 0.89–0.88 (m, 12H; Me3CSi and H-21),
0.00 (s, 3H; MeSi), À0.01 ppm (s, 3H; MeSi); 13C NMR (100 MHz,
CDCl3): d=81.8 (C; C-24), 71.8 (CH; C-22), 70.2 (CH; C-25), 69.4 (CH;
In the two conformations, the A, seco-B, and C/D rings
form identical hydrogen-bonding interactions as previously
described for the hVDR LBD/1a,25(OH)2D3 complex. The
presence of an oxygen atom in the tetrahydrofuran ring in
the vicinity of the 25-OH group of the side chain of 3a
favors an intramolecular hydrogen bond (darker grey cen-
tral dashed lines in Figure 2C; distances are 3.07 ꢅ in the
3a-X conformation and 2.81 ꢅ in the 3b-Y conformation).
Consequently, the side chain of 3a is more flexible in the
LBP and the hydrophobic and electrostatic environment sta-
bilizes two distinct conformations. The distances between
the Ne2 of His305 and the 25-OH of the ligand are 2.73,
3.02, and 2.82 ꢅ for 3a-X, 3a-Y, and 1a,25(OH)2D3, respec-
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A. MouriÇo, M. Maestro et al.
C-8), 53.2 (CH; C-17), 53.0 (CH; C-14), 42.1 (C; C-13), 40.7 (CH2; C-12),
39.1 (CH; C-20), 34.4 (CH2; C-9), 26.8 (CH2; C-11), 25.8 (3ꢆCH3;
Me3CSi), 25.4 (CH2; C-23), 22.9 (CH2; C-15), 18.0 (C; CSi), 17.6 (CH2; C-
16), 13.6 (CH3; C-18), 11.3 (CH3; C-21), À4.8 (CH3; MeSi), À5.2 ppm
(CH3; MeSi); IR (film): n˜ =3446, 3313 cmÀ1; HRMS (EI+): m/z: calcd for
[C22H39OSi]+: 347.2770 [M]+; found 347.2773.
26), 56.0 (CH; C-17), 53.0 (CH; C-14), 42.1 (C; C-13), 40.6 (CH2; C-12),
35.8 (CH; C-20), 34.4 (CH2; C-9), 28.6 (CH3; C-27 and C-28), 27.3 (CH2,
C-15), 25.8 (3ꢆCH3; Me3CSi), 23.0 (CH2; C-16), 19.7 (CH3; C-21), 18.0
(C; C-Si), 17.7 (CH2; C-11), 13.7 (CH3; C-18), À4.8 (CH3; MeSi),
À5.2 ppm (CH3; MeSi).
A solution of TBAF in THF (3.1 mL, 1m,
3 mmol, 5 equiv) was added to a solution of 12-TBS (0.260 g, 0.619 mmol,
1 equiv) in dry THF (10 mL), and the mixture was heated at 508C for
72 h. The reaction was then quenched at RT with saturated aqueous
NH4Cl solution (10 mL) and Et2O (5 mL), and the aqueous phase was ex-
tracted with Et2O (3ꢆ15 mL). The combined organic phases were dried,
filtered, and concentrated. The residue was purified by flash chromatog-
raphy (SiO2, 2.5ꢆ10 cm, 10% EtOAc/hexanes) to give 12 [0.178 g,
8b-[(tert-Butyldimethylsilyl)oxy]-de-A,B-26,27-dinor-23(24),24(25)-cho-
lesdien-22-one (10): Dess–Martin periodinane (DMP, 0.641 g, 1.51 mmol,
1.2 equiv) was added to a solution of 9 (0.460 g, 1.26 mmol, 1 equiv) in
dry CH2Cl2 (15 mL). After stirring at RT for 1.5 h, the reaction was
quenched with saturated aqueous NaCl solution (15 mL). The aqueous
phase was extracted with CH2Cl2 (3ꢆ15 mL) and the combined organic
phases were dried, filtered, and concentrated. The residue was purified
by flash chromatography (SiO2, 3ꢆ7 cm, hexanes) to give 10 [0.403 g,
1.07 mmol, 84%, Rf =0.68 (20% EtOAc/hexanes), pale-yellow solid].
M.p. 99–1018C (CH2Cl2/hexanes); 1H NMR (250 MHz, CDCl3): d=5.72
(t, J=6.5 Hz, 1H; H-23), 5.22 (m, 2H; H-25), 3.99 (m, 1H; H-8), 3.08
(dq, J=10.5, 6.8 Hz, 1H; H-20), 1.06 (d, J=6.6 Hz, 3H; H-21), 0.92 (s,
3H, H-18), 0.87 (s, 9H; Me3CSi), À0.01 (s, 3H; MeSi), À0.03 ppm (s, 3H;
MeSi); 13C NMR (62.9 MHz, CDCl3): d=216.7 (C; C-24), 204.7 (C; C-
22), 96.6 (CH; C-23), 79.3 (CH2; C-25), 69.2 (CH; C-8), 53.0 (CH; C-17),
52.3 (CH; C-14), 43.9 (CH; C-20), 42.3 (C; C-13), 40.5 (CH2; C-12), 34.3
(CH2; C-9), 26.5 (CH2; C-15), 25.8 (3ꢆCH3; Me3CSi), 23.1 (CH2; C-16),
18.0 (C; CSi), 17.6 (CH2; C-11), 17.1 (CH3; C-21), 13.9 (CH3; C-18), À4.8
1
0.583 mmol, 94%, Rf =0.26 (hexanes), colorless oil]. H NMR (250 MHz,
CDCl3): d=6.01 (d, J=3.1 Hz, 1H; H-24), 5.80 (d, J=3.1 Hz, 1H; H-23),
4.06 (m, 1H; H-8), 2.70 (dq, J=10.3, 6.9 Hz, 1H; H-20), 1.55 (s, 6H; H-
27 and H-28), 1.23 (d, J=6.9 Hz, 3H; H-21), 0.99 ppm (s, 3H; H-18);
13C NMR (62.9 MHz, CDCl3): d=160.4 (C; C-25), 157.6 (C; C-22), 103.6
(CH; C-23 and C-24), 69.2 (CH; C-8), 68.6 (COH; C-26), 55.8 (CH; C-
17), 52.4 (CH; C-14), 41.7 (C; C-13), 40.2 (CH2; C-12), 35.7 (CH; C-20),
33.5 (CH2; C-9), 28.5 (CH3; C-27 and C-28), 27.1 (CH2; C-15), 22.4 (CH2;
C-16), 19.7 (CH3; C-21), 17.4 (CH2; C-11), 13.4 ppm (CH3; C-18); HRMS
(CI+): m/z: calcd for [C19H31O3]+: 307.2273 [M+H]+; found 307.2271.
8b-[(tert-Butyldimethylsilyl)oxy]-(20S)-de-A,B-[(5-ethyloxycarbonyl)fur-
an-2-yl]pregnane (14): A solution of nBuLi in hexanes (2.4 mL, 2.3m,
5.51 mmol, 1.3 equiv) was added to a solution of 11 (1.53 g, 4.24 mmol,
1 equiv) in dry THF (20 mL) at 08C. The mixture was stirred for 2 h and
then cooled to À788C, whereupon ethyl chloroformate (2 mL, 21.2 mmol,
5 equiv) was slowly added dropwise. The reaction mixture was allowed to
warm to RT overnight. The reaction was then quenched with saturated
aqueous NaCl solution (20 mL) and Et2O (20 mL), and the aqueous
phase was extracted with Et2O (3ꢆ20 mL). The combined organic phases
were dried, filtered, and concentrated. The residue was purified by flash
chromatography (SiO2, 3ꢆ6 cm, 3% EtOAc/hexanes) to afford 14
[1.68 g, 3.87 mmol, 91%, Rf =0.7 (10% EtOAc/hexanes), colorless oil].
1H NMR (250 MHz, CDCl3): d=7.04 (d, J=3.3 Hz, 1H; H-24), 6.02 (d,
J=3.3 Hz, 1H; H-23), 4.32 (q, J=7.1 Hz, 2H; -OCH2CH3), 3.97 (m, 1H;
H-8), 2.80 (m, 1H; H-20), 1.35 (t, J=7.1 Hz, 3H; CH3CH2O-), 1.26 (d,
J=7.1 Hz, 3H; H-21), 0.98 (s, 3H; H-18), 0.88 (s, 9H; Me3CSi), 0.00 (s,
3H; MeSi), À0.02 ppm (s, 3H; MeSi); 13C NMR (62.9 MHz, CDCl3): d=
166.5 (C; COOEt), 159.0 (C, C-22), 142.5 (C; C-25), 118.0 (CH; C-24),
106.1 (CH; C-23), 69.3 (CH; C-8), 60.5 (CH2; -OCH2CH3), 55.2 (CH; C-
17), 52.8 (CH; C-14), 42.2 (C; C-13), 40.5 (CH2; C-12), 36.3 (CH; C-20),
34.3 (CH2; C-9), 27.3 (CH2; C-15), 25.8 (3ꢆCH3; Me3CSi), 22.9 (CH2; C-
16), 19.5 (CH3; C-21), 18.0 (C; C-Si), 17.6 (CH2; C-11), 14.4 (CH3;
CH3CH2O-), 13.7 (CH3; C-18), À4.8 (CH3; MeSi), À5.2 ppm (CH3;
MeSi); IR (film): n˜ =2934, 1729 cmÀ1; HRMS (CI+): m/z: calcd for
[C25H43O4Si]+: 435.2931 [M+H]+; found 435.2935.
(CH3; MeSi), À5.2 ppm (CH3; MeSi); IR (film): n˜ =1967, 1677 cmÀ1
;
HRMS (CI+): m/z: calcd for [C22H39O2Si]+: 363.2719 [M+H]+; found
363.2729.
8b-[(tert-Butyldimethylsilyl)oxy]-(20S)-de-A,B-(2-furyl)pregnane (11): A
solution of 10 (0.082 g, 0.225 mmol, 1 equiv) in dry THF (5 mL) was
added dropwise via
a cannula to a solution of Et3PAuCl (2.4 mg,
0.007 mmol, 3mol%) in THF (5 mL). AgNO3 (1.2 mg, 0.007 mmol,
3mol%) was added and the reaction mixture was stirred in the dark at
RT for 4 h. Et2O (15 mL) was then added, and the mixture was filtered
through Celite, washing with further Et2O (50 mL). The collected organic
phase was washed with saturated aqueous NaCl solution (40 mL), dried,
filtered, and concentrated. The residue was purified by flash chromatog-
raphy (SiO2, 1ꢆ10 cm, hexanes) to afford 11 [0.08 g, 0.22 mmol, 98%,
Rf =0.72 (10% EtOAc/hexanes), colorless oil]. 1H NMR (250 MHz,
CDCl3): d=7.26 (d, J=1.3 Hz, 1H; H-25), 6.25 (dd, J=3, 1.9 Hz, 1H; H-
24), 5.90 (d, J=3 Hz, 1H; H-23), 4.02 (m, 1H; H-8), 2.70 (dq, J=10.6,
6.9 Hz, 1H; H-20), 1.24 (d, J=6.8 Hz, 3H; H-21), 1.00 (s, 3H; H-18),
0.90 (s, 9H; Me3CSi), 0.03 (s, 3H; MeSi), 0.01 ppm (s, 3H; MeSi);
13C NMR (62.9 MHz, CDCl3): d=161.6 (C; C-22), 140.0 (CH; C-25),
109.7 (CH; C-24), 103.2 (CH; C-23), 69.4 (CH; C-8), 55.8 (CH; C-17),
53.0 (CH; C-14), 42.1 (C; C-13), 40.6 (CH2; C-12), 35.8 (CH; C-20), 34.4
(CH2; C-9), 27.6 (CH2; C-15), 25.8 (3ꢆCH3; Me3CSi), 23.0 (CH2; C-16),
19.7 (CH3; C-21), 18.0 (C; CSi), 17.7 (CH2; C-11), 13.7 (CH3; C-18), À4.8
(CH3; MeSi), À5.1 ppm (CH3; MeSi); IR (film): n˜ =2933, 2858 cmÀ1; ele-
mental analysis calcd (%) for C22H38O2Si: C 72.87, H 10.56; found: C
72.60, H 10.83.
AHCTUNGTERG(NNUN 20S)-De-A,B-[(5-ethyloxycarbonyl)furan-2-yl]-8b-pregnanol (15): Aque-
ous HF (48%, 50 drops) was added to a solution of 14 (0.430 g, 1 mmol,
1 equiv) in CH3CN (20 mL) and the mixture was stirred at RT for 36 h.
The reaction was quenched by the slow addition of saturated aqueous
NaHCO3 solution (20 mL) (CAUTION: CO2 evolution) and Et2O
(20 mL). The aqueous phase was extracted with EtOAc (4ꢆ20 mL) and
the combined organic phases were dried, filtered, and concentrated. The
residue was purified by flash chromatography (SiO2, 3.5ꢆ10 cm, 20%
EtOAc/hexanes) to give 15 [0.294 g, 0.92 mmol, 92%, Rf =0.3 (20%
EtOAc/hexanes), colorless oil]. 1H NMR (250 MHz, CDCl3): d=7.03 (d,
J=3.1 Hz, 1H; H-24), 6.02 (d, J=3.1 Hz, 1H; H-23), 4.30 (q, J=7.1 Hz,
2H; -OCH2CH3), 4.05 (s, 1H; H-8), 2.79 (m, 1H; H-20), 1.32 (t, J=
7.1 Hz, 3H; CH3CH2O-), 1.24 (d, J=7 Hz, 3H; H-21), 0.98 ppm (s, 3H;
H-18); 13C NMR (62.9 MHz, CDCl3): d=166.2 (C; COOEt), 158.9 (C; C-
22), 142.5 (C; C-25), 118.8 (CH; C-24), 106.1 (CH; C-23), 69.0 (CH; C-
8), 60.5 (CH2; -OCH2CH3), 55.0 (CH; C-17), 52.4 (CH; C-14), 41.9 (C;
C-13), 40.1 (CH2; C-12), 36.2 (CH; C-20), 33.5 (CH2; C-9), 27.1 (CH2; C-
15), 22.3 (CH2; C-16), 19.4 (CH3; C-21), 17.4 (CH2; C-11), 14.3 (CH3;
ACHTUNGTRENNUNG(20S)-De-A,B-[5-(2-hydroxypropan-2-yl)furan-2-yl]-8b-pregnanol (12): A
solution of nBuLi in hexanes (0.25 mL, 2.24m, 0.56 mmol, 1.2 equiv) was
added dropwise to a solution of 11 (0.170 g, 0.47 mmol, 1 equiv) in dry
THF (5 mL) at À788C. The mixture was allowed to warm to 08C, stirred
for 2 h, and then cooled to À788C once more. Dry acetone (0.14 mL,
1.86 mmol, 4 equiv) was added dropwise, and the reaction mixture was
allowed to warm slowly to RT. The reaction was quenched with saturated
aqueous NH4Cl solution (10 mL) and Et2O (10 mL), and the aqueous
phase was extracted with Et2O (3ꢆ15 mL). The combined organic phases
were dried, filtered, and concentrated. The residue was purified by flash
chromatography (SiO2, 2ꢆ10 cm, 10% EtOAc/hexanes) to afford 12-TBS
[0.156 g, 0.37 mmol, 80%, Rf =0.26 (10% EtOAc/hexanes), colorless oil].
1H NMR (250 MHz, CDCl3): d=6.02 (d, J=3.1 Hz, 1H; H-24), 5.80 (d,
J=3.1 Hz, 1H; H-23), 4.00 (m, 1H; H-8), 2.70 (dq, J=10.6, 6.9 Hz, 1H;
H-20), 1.56 (s, 6H; H-27 and H-28), 1.23 (d, J=6.9 Hz, 3H; H-21), 0.98
(s, 3H; H-18), 0.89 (s, 9H; Me3CSi), 0.01 (s, 3H; MeSi), À0.01 ppm (s,
3H; MeSi); 13C NMR (62.9 MHz, CDCl3): d=160.8 (C; C-25), 157.5 (C;
C-22), 103.6 (CH; C-24), 103.5 (CH; C-23), 69.4 (CH; C-8), 68.7 (C; C-
CH3CH2O-), 13.4 ppm (CH3; C-18); IR (film): n˜ =3529, 1712 cmÀ1
;
HRMS (CI+): m/z: calcd for [C19H29O4]+: 321.2069 [M+H]+; found
321.2066.
608
www.chemeurj.org
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 603 – 612

Convergent Synthesis of Vitamin D Analogues
FULL PAPER
A
C-21), 14.4 (CH3; CH3CH2O-), 12.0 ppm (CH3; C-18); IR (film): n˜ =2975,
1727 cmÀ1; HRMS (CI+): m/z: calcd for [C26H40O5B]+: 443.2969 [M+H]+
; found 443.2954.
Martin periodinane (0.528 g, 1.24 mmol, 1.5 equiv) was added to a solu-
tion of 15 (0.266 g, 0.83 mmol, 1 equiv) in dry CH2Cl2 (12 mL) and the
mixture was stirred at RT for 3.5 h. The reaction was then quenched with
saturated aqueous NaCl solution (20 mL), and the resulting mixture was
stirred for 30 min. The aqueous phase was extracted with Et2O (3ꢆ
20 mL) and the combined organic phases were dried, filtered, and con-
centrated. The residue was purified by flash chromatography (SiO2, 2ꢆ
8 cm, 10% EtOAc/hexanes) to afford 16 [0.245 g, 0.77 mmol, 93%, Rf =
0.47 (10% EtOAc/hexanes), colorless oil]. 1H NMR (250 MHz, CDCl3):
d=7.03 (d, J=3.3 Hz, 1H; H-24), 6.05 (d, J=3.3 Hz, 1H; H-23), 4.31 (q,
J=7.1 Hz, 2H; -OCH2CH3), 2.81 (dq, J=10.5, 6.9 Hz, 1H; H-20), 2.47
(dd, J=11.5, 7.2 Hz, 1H; H-14), 1.34 (t, J=7.1 Hz, 3H, CH3CH2O-), 1.24
(d, J=7.2 Hz, 3H; H-21), 0.63 ppm (s, 3H; H-18); 13C NMR (62.9 MHz,
CDCl3): d=211.3 (C; C-8), 165.2 (C; COOEt), 158.8 (C; C-22), 142.7 (C;
C-25), 118.7 (CH; C-24), 106.4 (CH; C-23), 61.6 (CH; C-14), 60.6 (CH2;
-OCH2CH3), 55.0 (CH; C-17), 49.6 (C; C-13), 40.8 (CH2; C-12), 38.6
(CH2; C-9), 36.3 (CH2; C-20), 27.3 (CH2; C-15), 23.9 (CH2; C-16), 19.5
(CH3; C-21), 18.9 (CH2; C-11), 14.3 (CH3; CH3CH2O-), 12.4 ppm (CH3;
C-18); IR (film): n˜ =2961, 1714 cmÀ1; HRMS (CI+): m/z: calcd for
[C19H26O4]+: 319.1909 [M+H]+; found 319.1907.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
0.05 equiv) was added and the reaction mixture was stirred vigorously for
1 h in the dark. The reaction was then quenched by the addition of H2O
(10 mL) and Et2O (10 mL). The aqueous phase was extracted with Et2O
(3ꢆ10 mL), and the combined organic phases were dried, filtered, and
concentrated. The residue was redissolved in CH3CN (3 mL), and then
HF (48%, 5 drops) was added by means of a syringe. After stirring the
solution for 20 min, the reaction was quenched with saturated aqueous
NaHCO3 solution (10 mL) and EtOAc (10 mL). The aqueous phase was
extracted with EtOAc (5ꢆ15 mL), and the combined organic phases
were dried, filtered, and concentrated. The residue was purified by flash
chromatography (SiO2, 2.5ꢆ10 cm, 60% EtOAc/hexanes) to give 5a
[0.052 g, 0.114 mmol, 85%, Rf =0.3 (60% EtOAc/hexanes), white foam].
1H NMR (500 MHz, CD2Cl2): d=7.05 (d, J=3.4 Hz, 1H; H-24), 6.36 (d,
J=11.2 Hz, 1H; H-6), 6.05 (d, J=3.4 Hz, 1H; H-23), 6.00 (d, J=11.2 Hz,
1H; H-7), 5.30 (s, 1H; H-19), 4.97 (s, 1H; H-19), 4.41 (m, 1H; H-1), 4.32
(q, J=7.1 Hz, 2H; -OCH2CH3), 4.21 (m, 1H; H-3), 1.35 (t, J=7.1 Hz,
3H; CH3CH2O), 1.28 (d, J=7 Hz, 3H; H-21), 0.59 ppm (s, 3H; H-18);
13C NMR (126 MHz, CD2Cl2): d=166.2 (CO; C-26), 158.9 (C; C-22),
147.5 (C; C-10), 142.4 (C; C-25), 142.2 (C; C-8), 133.4 (C; C-5), 124.5
(CH; C-6), 118.8 (CH; C-24), 117.3 (CH; C-7), 111.7 (CH2; C-19), 106.2
(CH; C-23), 70.7 (CH; C-1), 66.6 (CH; C-3), 60.5 (CH2; OCH2CH3), 56.0
(CH; C-17), 54.7 (CH; C-14), 45.7 (C; C-13), 45.0 (CH2; C-4), 42.7 (CH2;
C-2), 40.1 (CH2; C-12), 38.9 (CH; C-20), 29.0 (CH2; C-9), 27.3 (CH2; C-
16), 23.3 (CH2; C-11), 22.1 (CH2; C-15), 19.7 (CH3; C-21), 14.3 (CH3;
CH3CH2O), 11.9 ppm (CH3; C-18); IR (CHCl3): n˜ =3412, 2933,
1712 cmÀ1; HRMS (ESI-TOF): m/z: calcd for [C28H38O5Na]+: 477.2611
[M+Na]+; found 477.2604.
ACHTUNGTRENNUNG(20S),(8E)-Bromomethylene-de-A,B-[(5-ethyloxycarbonyl)furan-2-yl]-
pregnane (17): A suspension of (Ph3PCH2Br)Br (2.023 g, 4.640 mmol,
8 equiv) in dry toluene (15 mL) was sonicated for 30 min and then cooled
to À158C. KOtBu (0.454 g, 4.060 mmol, 7 equiv) was added and the mix-
ture was stirred for 2 h. A solution of ketone 16 (0.185 g, 0.58 mmol,
1 equiv) in toluene (15 mL) was then added, and the resulting mixture
was allowed to warm slowly to 08C. The reaction was quenched with sa-
turated aqueous NH4Cl solution (1 mL), and the mixture was filtered
through a layer of silica gel. The silica was washed with Et2O (3ꢆ20 mL)
and the resulting filtrate was concentrated. The residue was purified by
flash chromatography (SiO2, 2ꢆ12 cm, 1% EtOAc/hexanes) to afford 17
[0.172 g, 0.435 mmol, 75%, Rf =0.58 (10% EtOAc/hexanes), yellow oil].
1H NMR (250 MHz, CDCl3): d=7.04 (d, J=3.3 Hz, 1H; H-24), 6.04 (d,
J=3.3 Hz, 1H; H-23), 5.62 (s, 1H; H-7), 4.31 (q, J=7.1 Hz, 2H;
-OCH2CH3), 2.86 (m, 1H; H-9), 2.81 (dq, J=10.7, 7.1 Hz, 1H; H-20),
1.83 (q, J=9.4 Hz, 1H; H-17), 1.33 (t, J=7.1 Hz, 3H; CH3CH2O-), 1.28
(d, J=6.9 Hz, 3H; H-21), 0.60 ppm (s, 3H; H-18); 13C NMR (62.9 MHz,
CDCl3): d=165.9 (C; COOEt), 159.0 (C; C-22), 144.7 (C; C-8), 142.7 (C;
C-25), 118.8 (CH; C-24), 106.4 (CH; C-23), 97.8 (CH; C-7), 60.6 (CH2;
-OCH2CH3), 55.7 (CH; C-14), 54.3 (CH; C-17), 45.5 (C; C-13), 40.0
(CH2; C-12), 36.8 (CH2; C-20), 31.0 (CH2; C-9), 27.4 (CH2; C-11), 22.5
(CH2; C-16), 22.0 (CH2; C-15), 19.7 (CH3; C-21), 14.4 (CH3; CH3CH2O-),
11.9 ppm (CH3; C-18); IR (film): n˜ =2947, 1726 cmÀ1; HRMS (CI+): m/z:
calcd for [C20H28O3Br]+: 398.1235 [M+H]+; found 398.1221.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
1.85 mmol, 5 equiv) was added by means of a syringe to a solution of 5a
(0.168 g, 0.37 mmol, 1 equiv) in dry THF (20 mL) at À788C. The resulting
solution was stirred at À788C for 6 h and then allowed to warm to RT
overnight. The reaction was quenched by the slow addition of saturated
aqueous NH4Cl solution (10 mL) followed by EtOAc (10 mL). The aque-
ous phase was extracted with EtOAc (5ꢆ15 mL) and the combined or-
ganic phases were dried, filtered, and concentrated. The residue was puri-
fied by flash chromatography (SiO2, 2ꢆ8 cm, 70% EtOAc/hexanes) to
afford 3a [0.143 g, 0.325 mmol, 88%, Rf =0.15 (60% EtOAc/hexanes),
amorphous solid]. M.p. 84–868C (Et2O/hexanes); [a]2D5 =0.88 (c=1.3 in
96% EtOH); 1H NMR (500 MHz, CD2Cl2): d=6.38 (d, J=11.2 Hz, 1H;
H-6), 6.04 (d, J=3.1 Hz, 1H; H-24), 6.02 (d, J=11.2 Hz, 1H; H-7), 5.83
(d, J=3 Hz, 1H; H-23), 5.31 (s, 1H; H-19E), 4.99 (s, 1H; H-19Z), 4.42
(m, 1H; H-1), 4.22 (m, 1H; H-3), 2.72 (dq, J=10.1, 6.9 Hz, 1H; H-20),
1.56 (s, 6H; H-27 and H-28), 1.26 (d, J=6.8 Hz, 3H; H-21), 0.59 ppm (s,
3H; H-18); 13C NMR (CD2Cl2, 126 MHz): d=160.4 (C; C-25), 157.6 (C;
C-22), 147.6 (C; C-10), 142.8 (C; C-8), 133.1 (C; C-5), 124.8 (CH; C-6),
117.2 (CH; C-7), 111.8 (CH2; C-19), 104.0 (CH; C-24), 103.8 (CH; C-23),
70.8 (CH; C-1), 69.9 (COH; C-26), 66.8 (CH; C-3), 56.2 (CH; C-17), 55.6
(CH; C-14), 45.8 (C; C-13), 45.2 (CH2; C-4), 42.8 (CH2; C-2), 40.2 (CH2;
C-12), 36.3 (CH; C-20), 29.0 (CH2; C-9), 28.6 (2ꢆCH3; C-27 and C-28),
27.4 (CH2; C-16), 23.5 (CH2; C-11), 22.2 (CH2; C-15), 20.0 (CH3; C-21),
ACHTUNGTRENNUNG
0.0094 mmol, 0.03 equiv) were dissolved in dry DMSO (3 mL) and the
mixture was stirred for 20 min. A solution of 17 (0.120 g, 0.31 mmol,
1 equiv) in DMSO (2 mL) was then added via a cannula. KOAc (0.091 g,
0.930 mmol, 3 equiv) and Pin2B2 (0.157 g, 0.62 mmol, 2 equiv) were then
successively added. The reaction mixture was heated at 808C for 2.5 h,
then cooled to RT, and the reaction was quenched by the addition of
H2O (10 mL) and Et2O (10 mL). The aqueous phase was extracted with
Et2O (3ꢆ30 mL) and the combined organic phases were dried, filtered,
and concentrated. The residue was purified by flash chromatography
(SiO2, 2ꢆ7 cm, 2–5% EtOAc/hexanes) to give 6a [0.103 g, 0.233 mmol,
75%, Rf =0.42 (10% EtOAc/hexanes), yellow oil]. 1H NMR (250 MHz,
CDCl3): d=7.04 (d, J=3.4 Hz, 1H; H-24), 6.04 (d, J=3.4 Hz, 1H; H-23),
4.89 (s, 1H; H-7), 4.32 (q, J=7.1 Hz, 2H; -OCH2CH3), 3.18 (dd, J=13.2,
2.9 Hz; H-9), 2.82 (dq, J=10.5, 6.9 Hz, 1H; H-20), 1.34 (t, J=7.1 Hz,
3H; CH3CH2O-), 1.29 (d, J=6.9 Hz, 3H; H-21), 1.25 (s, 12H; CH3-pina-
col), 0.60 ppm (s, 3H; H-18); 13C NMR (62.9 MHz, CDCl3): d=166.1 (C;
COOEt), 165.4 (C; C-8), 158.9 (C; C-22), 142.5 (C; C-25), 118.8 (CH; C-
24), 106.2 (CH; C-23), 82.5 (C; COB), 60.5 (CH2; -OCH2CH3), 57.7 (CH;
C-14), 55.2 (CH; C-17), 46.2 (C; C-13), 40.2 (CH2; C-12), 36.9 (CH2; C-
20), 33.1 (CH2; C-9), 27.3 (CH2; C-16), 24.8 (2ꢆCH3; CH3-pinacol), 24.7
(2ꢆCH3; CH3-pinacol), 24.2 (CH2; C-11), 22.1 (CH2; C-15), 19.6 (CH3;
12.0 ppm (CH3; C-18); IR (CHCl3): n˜ =3405, 2961 cmÀ1
; UV (96%
EtOH): lmax (e)=220 nm (18500), l=266 nm (14500 molÀ1 m3 cmÀ1),
lmin =250 nm; HRMS (ESI-TOF): m/z: calcd for [C28H40O4Na]+:
463.2819 [M+Na]+; found 463.2822.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
0.66 mmol, 6 equiv) was added by means of a syringe to a solution of 5a
(0.052 g, 0.11 mmol, 1 equiv) in dry THF (8 mL) at À788C. The mixture
was stirred at À788C for 15 min and at RT for 3 h. The reaction was then
quenched by the slow addition of saturated aqueous NH4Cl solution
Chem. Eur. J. 2012, 18, 603 – 612
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. MouriÇo, M. Maestro et al.
(10 mL) followed by EtOAc (10 mL). The aqueous phase was extracted
with EtOAc (5ꢆ15 mL) and the combined organic phases were dried, fil-
tered, and concentrated. The residue was purified by flash chromatogra-
phy (SiO2, 1.5ꢆ6 cm, 70% EtOAc/hexanes) to give 3b [0.042 g,
0.089 mmol, 82%, Rf =0.2 (60% EtOAc/hexanes), amorphous solid].
M.p. 66–688C (Et2O/hexanes); [a]2D5 =1.06 (c=2.1 in 96% EtOH);
1H NMR (500 MHz, CDCl3): d=6.36 (d, J=11.2 Hz, 1H; H-6), 6.03 (d,
J=3 Hz, 1H; H-24), 6.00 (d, J=11.2 Hz, 1H; H-7), 5.80 (d, J=3 Hz, 1H;
H-23), 5.30 (s, 1H; H-19E), 4.97 (s, 1H; H-19Z), 4.40 (m, 1H; H-1), 4.20
(m, 1H; H-3), 2.69 (dq, J=10.1, 6.8 Hz, 1H; H-20), 1.24 (d, J=6.9 Hz,
3H; H-21), 0.81 (t, J=7.4 Hz, 6H; 2ꢆCH3CH2), 0.58 ppm (s, 3H; CH3-
18); 13C NMR (126 MHz, CDCl3): d=160.1 (C; C-25), 155.9 (C; C-22),
147.6 (C; C-10), 142.7 (C; C-8), 133.2 (C; C-5), 124.7 (CH; C-6), 117.2
(CH; C-7), 111.8 (CH2; C-19), 105.5 (CH; C-24), 103.7 (CH; C-23), 74.9
(COH; C-26), 70.7 (CH; C-1), 66.7 (CH; C-3), 56.1 (CH; C-17), 55.6
(CH; C-14), 45.7 (C; C-13), 45.1 (CH2; C-4), 42.8 (CH2; C-2), 40.2 (CH2;
C-12), 36.3 (CH; C-20), 31.7 (2ꢆCH2; C-27 and C-29), 29.0 (CH2; C-9),
27.6 (CH2; C-16), 23.5 (CH2; C-11), 22.2 (CH2; C-15), 20.0 (CH3; C-21),
12.0 (CH3; C-18), 7.9 ppm (2ꢆCH3; -CH2CH3); IR (CHCl3): n˜ =3386,
phase was extracted with TBME (4ꢆ15 mL) and the combined organic
phases were dried, filtered, and concentrated. The residue was purified
by flash chromatography (SiO2, 2.5ꢆ8 cm, 2% EtOAc/hexanes) to give
26a [0.270 g, 0.492 mmol, 97%, Rf =0.43 (30% EtOAc/hexanes), pale-
yellow oil], slightly contaminated with its allenic ketone. 1H NMR
(250 MHz, CDCl3): d=4.00 (m, 1H; H-8), 3.24 (t, J=2.2 Hz, 1H; H-23),
2.85 (dq, J=10.7, 6.8 Hz, 1H; H-20), 2.35 (t, J=2.2 Hz, 2H; H-26), 1.31
(s, 6H; H-28 and H-29), 1.10 (d, J=6.8 Hz, 3H; H-21), 0.97–0.91 (m, J=
7.9 Hz, 12H; CH3CH2Si and H-18), 0.88 (s, 9H; Me3Si), 0.61–0.54 (m,
6H; CH3CH2Si), 0.00 (s, 3H; MeSi), À0.02 ppm (s, 3H; MeSi); 13C NMR
(62.9 MHz, CDCl3): d=208.8 (CO; C-22), 82.5 (C; C-25), 74.0 (C; C-24),
73.1 (COH; C-27), 69.2 (CH; C-8), 52.6 (CH; C-14), 52.4 (CH; C-17),
46.9 (CH; C-20), 42.2 (C; C-13), 40.5 (CH2; C-12), 35.5 (CH2; C-26), 34.3
(CH2; C-9), 33.8 (CH2; C-23), 29.4 (2ꢆCH3; C-28 and C-29), 26.6 (CH2;
C-16), 25.8 (3ꢆCH3; Me3CSi), 23.2 (CH2; C-15), 18.0 (C; C-Si), 17.6
(CH2; C-11), 16.6 (CH3; C-21), 14.0 (CH3; C-18), 7.0 (2ꢆCH3;
CH3CH2Si), 6.6 (2ꢆCH2; CH3CH2Si), À4.8 (CH3; MeSi), À5.2 ppm (CH3;
MeSi); HRMS (CI+): m/z: calcd for [C36H70O3Si2]+: 564.4394 [M+H]+;
found 564.4387.
2925 cmÀ1
; UV (96% EtOH): lmax (e)=218 nm (18900), l=266 nm
AHCTUNGTERG(NNUN 20S)-De-A,B-[5-(2-hydroxy-2-methylpropan-1-yl)furan-2-yl]-8b-pregna-
(14600 molÀ1 m3 cmÀ1), lmin =245 nm; HRMS (ESI-TOF): m/z: calcd for
[C30H43O3]+: 451.3194 [MÀOH]+; found 451.3207.
nol (27a): AuCl3 (4.4 mg, 0.014 mmol, 0.03 equiv) was added to a solution
of 26a (0.265 g, 0.48 mmol, 1 equiv) in dry THF (10 mL) and the reaction
mixture was stirred at RT for 15 min. Saturated aqueous NaCl solution
(10 mL) and TBME (10 mL) were then successively added, and the aque-
ous phase was extracted with TBME (4ꢆ10 mL). The combined organic
phases were dried, filtered, and concentrated. The residue was redis-
solved in THF (15 mL), and then TBAF (1.5 mL, 1m, 1.5 mmol, 3 equiv)
was added. The reaction mixture was heated at 508C for 4 days. Saturat-
ed NH4Cl (15 mL) and EtOAc (15 mL) were then successively added,
and the aqueous phase was extracted with EtOAc (3ꢆ15 mL). The com-
bined organic phases were dried, filtered, and concentrated. The residue
was purified by flash chromatography (SiO2, 2.5ꢆ8 cm, 20% EtOAc/hex-
anes) to give 27a [0.140 g, 0.44 mmol, 91%, Rf =0.4 (40% EtOAc/hex-
anes), white amorphous solid]. M.p. 69–718C (CH2Cl2); 1H NMR
(250 MHz, CDCl3): d=5.96 (d, J=2.9 Hz, 1H; H-24), 5.82 (d, J=2.9 Hz,
1H; H-23), 4.06 (m, 1H; H-8), 2.73 (s, 2H; H-26), 2.67 (dq, J=10.5,
7.1 Hz, 1H; H-20), 1.22 (s, 9H; H-21, H-28 and H-29), 0.99 ppm (s, 3H;
H-18); 13C NMR (62.9 MHz, CDCl3): d=160.4 (C; C-25), 150 (C; C-22),
107.9 (C; C-24), 103.9 (CH; C-23), 70.4 (COH; C-27), 69.9 (CH; C-8),
55.5 (CH; C-14), 52.4 (CH; C-17), 42.0 (CH2; C-26), 41.6 (C; C-13), 40.1
(CH2; C-12), 35.7 (CH; C-20), 33.4 (CH2; C-9), 28.8 (2ꢆCH3; C-28 and
C-29), 27.3 (CH2; C-16), 22.3 (CH2; C-15), 19.6 (CH3; C-21), 17.3 (CH2;
C-11), 13.4 ppm (CH3; C-18); IR (film): n˜ =3377, 2935 cmÀ1; elemental
analysis calcd (%) for C20H32O3: C 74.96, H 10.06; found: C 74.90, H
10.35.
8b-[(tert-Butyldimethylsilyl)oxy]-de-A,B-22,23-epoxy-24-norcolane (23):
A solution of MeLi in Et2O (1.92 mL, 1.6m, 3.08 mmol, 2 equiv) was
added dropwise over 30 min to a solution of 8 (0.500 g, 1.54 mmol,
1 equiv) and ClCH2I (0.223 mL, 3.08 mmol, 2 equiv) in dry THF (10 mL)
at À788C. The reaction mixture was stirred at À788C for 30 min and
then at RT for 1.5 h. The reaction was stopped by the addition of Et2O
(10 mL) and brine (10 mL). The aqueous phase was extracted with Et2O
(3ꢆ15 mL) and the combined organic phases were dried, filtered, and
concentrated. The residue was purified by flash chromatography (SiO2,
3ꢆ10 cm, 5% EtOAc/hexanes) to afford a mixture of diastereoisomers
23[25] [0.513 g, 1.51 mmol, 98%, Rf =0.78 (2% Et2O/hexanes, two runs),
white foam].
8b-[(tert-Butyldimethylsilyl)oxy]-de-A,B-26,27-dinor-25-[2-methyl-(2-trie-
thylsilyloxy)prop-2-yl]-24-cholestin-22-ol (25a): A solution of 24a was
prepared at À788C by the addition of a solution of nBuLi in hexanes
(0.82 mL, 2.5m, 2.05 mmol, 2.5 equiv) to the corresponding alkyne
(0.600 g, 2.83 mmol, 3.5 equiv) in dry THF (10 mL) followed by stirring
for 40 min. F3B·OEt2 (0.520 mL, 4.10 mmol, 5 equiv) and a solution of 23
(0.280 g, 0.82 mmol, 1 equiv) in THF (5 mL) were then successively
added dropwise. The reaction mixture was allowed to warm to RT over-
night. The reaction was then quenched by the addition of saturated aque-
ous NaCl solution (10 mL) and Et2O (10 mL). The aqueous phase was
extracted with Et2O (4ꢆ15 mL), and the combined organic phases were
dried, filtered, and concentrated. The residue was purified by flash chro-
matography (SiO2, 3ꢆ10 cm, 2% EtOAc/hexanes) to give a mixture of
alcohols 25a [0.441 g, 0.80 mmol, 98%, Rf =0.39 (10% EtOAc/hexanes),
oil]. 1H NMR (250 MHz, CDCl3): d=4.00 (s, 1H; H-8), 3.84 (t, J=
6.8 Hz, 1H; H-22), 2.41 (dd, J=16.2, 7.9 Hz, 1H; H-23), 2.31 (s, 2H; H-
26), 2.23 (dd, J=16.2, 5.9 Hz, 1H; H-23), 1.29 (s, 6H; H-28 and H-29),
0.94 (t, J=7.9 Hz, 9H; CH3CH2Si), 0.91 (s, 3H; H-18), 0.89–0.87 (m,
12H; Me3CSi and H-21), 0.57 (q, J=7.9 Hz, 6H; CH3CH2Si), 0.01 (s, 3H;
MeSi), 0.00 ppm (s, 3H; MeSi); 13C NMR (62.9 MHz, CDCl3): d=80.2
(C; C-25), 78.6 (C; C-24), 73.1 (COH; C-27), 72.0 (CH; C-22), 69.4 (CH;
C-8), 53.2 (CH; C-14), 52.9 (CH; C-17), 42.0 (C; C-13), 40.7 (CH2; C-12),
38.9 (CH; C-20), 35.4 (CH2; C-26), 34.4 (CH2; C-9), 29.4 (2ꢆCH3; C-28
and C-29), 26.7 (CH2; C-16), 25.8 (3ꢆCH3; Me3CSi and CH2; C-23), 22.9
(CH2; C-15), 18.0 (C; C-Si), 17.7 (CH2; C-11), 13.6 (CH3; C-18), 11.3
(CH3; C-21), 7.0 (2ꢆCH3; CH3CH2Si), 6.6 (2ꢆCH2; CH3CH2Si), À4.8
(CH3; MeSi), À5.2 ppm (CH3; MeSi); HRMS (CI+): m/z: calcd for
[C34H67O3Si2]+: 579.4629 [M+H]+; found 579.4634.
AHCTUNGTERG(NNUN 20S)-De-A,B-[5-(2-hydroxy-2-methylpropan-1-yl)furan-2-yl]-8b-pre-
gnone (28a): Procedure as for 16. 28a [91%, Rf =0.4 (40% EtOAc/hex-
anes), colorless oil]. 1H NMR (250 MHz, CDCl3): d=5.96 (s, 1H; H-24),
5.84 (s, 1H; H-23), 2.73 (s, 2H; H-26), 2.69 (m, 1H; H-20), 2.48 (dd, J=
11.5, 7 Hz; 1H, H-14), 1.27 (d, J=6.3 Hz, 3H; H-21), 1.21 (s, 6H; H-28
and H-29), 0.68 ppm (s, 3H; H-18); 13C NMR (62.9 MHz, CDCl3): d=
211.7 (C=O; C-8), 159.6 (C; C-25), 150.3 (C; C-22), 108.1 (C; C-24),
104.4 (CH; C-23), 70.4 (COH; C-27), 61.8 (CH; C-14), 55.5 (CH; C-17),
49.6 (C; C-13), 42.1 (CH2; C-26), 40.8 (CH2; C-12), 36.7 (CH2; C-9), 35.8
(CH; C-20), 28.9 (2ꢆCH3, C-28 and C-29), 27.5 (CH2; C-16), 24.0 (CH2;
C-15), 19.8 (CH3; C-21), 18.9 (CH2; C-11), 12.4 ppm (CH3; C-18). IR
(film): n˜ =3468, 2935, 1712 cmÀ1
;
HRMS (CI+): m/z: calcd for
[C20H30O2]+: 302.2246 [MÀH2O]+; found 302.2252.
AHCTUNGTERG(NNUN 20S),(8E)-Bromomethylene-de-A,B-[5-(2-hydroxy-2-methylpropan-1-yl)-
furan-2-yl]pregnane (29a): Procedure as for 17. 29a [0.164 g, 0.417 mmol,
72%, Rf =0.4 (20% EtOAc/hexanes), yellow oil]. 1H NMR (250 MHz,
CDCl3): d=5.97 (d, J=2.9 Hz, 1H; H-24), 5.84 (d, J=2.9 Hz, 1H; H-23),
5.64 (s, 1H; H-7), 2.74 (s, 2H; H-26), 2.69 (m, 1H; H-20), 1.25 (d, J=
6.9 Hz, 3H; H-21), 1.22 (s, 6H; H-28 and H-29), 0.61 ppm (s, 3H; H-18);
13C NMR (62.9 MHz, CDCl3): d=160.2 (C; C-25), 150.2 (C; C-22), 144.8
(C; C-8), 108.1 (C; C-24), 104.2 (CH; C-23), 97.6 (CH; C-7), 70.5 (COH;
C-27), 55.7 (CH; C-14), 54.7 (CH; C-17), 45.3 (C; C-13), 42.1 (CH2; C-
26), 39.6 (CH2; C-12), 36.3 (CH; C-20), 31.0 (CH2; C-9), 29.0 (2ꢆCH3; C-
8b-[(tert-Butyldimethylsilyl)oxy]-de-A,B-26,27-dinor-25-[2-methyl-(2-trie-
thylsilyloxy)-prop-2-yl]-24-cholestin-22-one (26a): Dess–Martin periodi-
nane (0.284 g, 0.66 mmol, 1.3 equiv) was added to a solution of 25a
(0.280 g, 0.509 mmol, 1 equiv) in dry CH2Cl2 (15 mL) and the reaction
mixture was stirred at RT for 1.5 h. The reaction was then quenched by
the addition of saturated aqueous NaCl solution (15 mL). The aqueous
610
www.chemeurj.org
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 603 – 612

Convergent Synthesis of Vitamin D Analogues
FULL PAPER
28 and C-29), 27.6 (CH2; C-15), 22.5 (CH2; C-16), 21.9 (CH2; C-11), 20.0
M. J. Chao, A. D. Sadovnick, G. C. Ebers, J. C. Knight, PLoS Genet.
2009, 5, e1000369; b) L. A. Plum, H. F. Deluca, Nat. Rev. Drug Dis-
covery 2010, 9, 941–955.
(CH3; C-21), 11.8 ppm (CH3; C-18); IR (film): n˜ =3418, 2965 cmÀ1
;
HRMS (CI+): m/z: calcd for [C21H31O2Br]+: 396.1487 [M+H]+; found
396.1485.
[3] a) M. S. Stein, D. L. Wark, Expert Opin. Invest. Drugs 2003, 12, 825–
840; b) K. K. Deeb, D. L. Trump, C. S. Jonson, Nat. Rev. Cancer
2007, 7, 684–700.
[4] R. Bouillon, W. H. Okamura, A. W. Norman, Endocr. Rev. 1995, 16,
200–257.
ACHTUNGTRENNUNG(20S),(8E)-De-A,B-[5-(2-hydroxy-2-methylpropan-1-yl)furan-2-yl]-
[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]pregnane (30a):
Procedure as for 6a. 30a [87%, Rf =0.34 (20% EtOAc/hexanes), oil].
1H NMR (250 MHz, CDCl3): d=5.96 (d, J=2.9 Hz, 1H; H-24), 5.83 (d,
J=2.9 Hz, 1H; H-23), 4.90 (s, 1H; H-7), 3.18 (dd, J=13.3, 3 Hz; 1H, H-
9), 2.73 (s, 2H; H-26), 2.67 (dq, J=10.5, 7 Hz, 1H; H-20), 1.26–1.21 (m,
21H; H-21, H-28, H-29, and 4ꢆMe-pinacol), 0.59 ppm (s, 3H; H-18);
13C NMR (62.9 MHz, CDCl3): d=165.7 (C; C-8), 160.5 (C; C-25), 150.0
(C; C-22), 108.0 (C; C-24), 104.1 (CH; C-23), 82.5 (CO; pinacol), 70.4
(COH; C-27), 57.8 (CH; C-14), 55.7 (CH; C-17), 46.0 (C; C-13), 42.1
(CH2; C-26), 40.2 (CH2; C-12), 36.4 (CH; C-20), 33.1 (CH2; C-9), 28.9
(2ꢆCH3; C-28 and C-29), 27.4 (CH2; C-16), 24.9 (2ꢆCH3; Me-pinacol),
24.8 (2ꢆCH3; Me-pinacol), 24.2 (CH2; C-15), 22.1 (CH2; C-11), 20.0
[5] a) M. M. Kabat, R. Radinov, Curr. Opin. Drug Discovery Dev. 2001,
4, 808–833; b) K. Z. Guyton, T. W. Kensler, G. H. Posner, Annu.
Rev. Pharmacol. Toxicol. 2001, 41, 421–442; c) A. J. Brown, Am. J.
Kidney Dis. 2001, 38, S3–S19; d) G. J. C. M. van der Bernd, G. T. G.
Chang, Curr. Drug Targets 2002, 3, 85–94; e) C. Carlberg, A. Mouri-
Ço, Expert Opin. Ther. Pat. 2003, 13, 761–772; f) G. H. Posner, M.
Kahraman, Eur. J. Org. Chem. 2003, 3889–3895; g) A. J. Brown, E.
Slatopolsky, Mol. Cell Mol. Aspecs Med. 2008, 29, 433–452.
[6] M. J. Calverley, Tetrahedron 1987, 43, 4609–4619.
[7] K. Kragballe, L. Iversen, Dermatol. Clin. 1993, 11, 137–141.
[8] a) C. M. Hansen, K. J. Hamberg, E. Binderup, L. Binderup, Curr.
Pharm. Des. 2000, 6, 803–828; b) T. R. J. Evans, K. W. Colston, F. J.
Lofts, D. Cunningham, D. A. Anthoney, H. Gogas, J. S. de Bono,
K. J. Hamberg, T. Skov, J. L. Mansi, Br. J. Cancer 2002, 86, 680–685.
[9] N. Rochel, J. M. Wurtz, A. Mitschler, B. Klaholz, D. Moras, Mol.
Cell 2000, 5, 173–179.
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Moras, Proc. Natl. Acad. Sci. USA 2001, 98, 5491–5496; b) G. Toc-
chini-Valentini, N. Rochel, J. M. Wurtz, D. Moras, J. Med. Chem.
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[11] a) S. Hourai, L. C. Rodrigues, P. Antony, B. Reina-San-Martin, F.
Ciesielski, B. C. Magnier, K. Schoonjans, A. MouriÇo, N. Rochel, D.
Moras, Chem. Biol. 2008, 15, 383–392; b) P. Antony, R. Sigꢈeiro, T.
Huet, Y. Sato, N. Ramalanjaona, L. C. Rodrigues, A. MouriÇo, D.
Moras, N. Rochel, J. Med. Chem. 2010, 53, 1159–1171.
[12] For details, see the Supporting Information.
(CH3; C-21), 12.0 ppm (CH3; C-18); IR (film): n˜ =3459, 2974 cmÀ1
;
HRMS (CI+): m/z: calcd for [C27H44O4B]+: 443.3333 [M+H]+; found
443.3337.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
0.11 (50% EtOAc/hexanes), amorphous white solid]; m.p. 77–798C
(Et2O/hexanes); [a]2D5 =1.2 (c=2.9 in 96% EtOH; 1H NMR (500 MHz,
CDCl3): d=6.36 (d, J=11.2 Hz, 1H; H-6), 6.00 (d, J=11.2 Hz, 1H; H-7),
5.96 (d, J=2.9 Hz, 1H; H-24), 5.83 (d, J=2.9 Hz, 1H; H-23), 5.30 (s, 1H;
H-19E), 4.97 (s, 1H; H-19Z), 4.40 (m, 1H; H-1), 4.21 (m, 1H; H-3), 2.83
(dd, J=12.3, 3.4 Hz, 1H; H-9), 2.73 (s, 2H; H-26), 2.68 (m, 1H; H-20),
2.58 (dd, J=13.3, 2.5 Hz, 1H; H-4), 2.30 (dd, J=13.3, 6.5 Hz, 1H; H-4),
1.24 (d, J=6.9 Hz, 3H; H-21), 1.21 (s, 6H; H-28 and H-29), 0.59 ppm (s,
3H; CH3-18); 13C NMR (126 MHz, CDCl3): d=160.4 (C; C-25), 150.1
(C; C-22), 147.6 (C; C-10), 142.6 (C; C-8), 133.2 (C; C-5), 124.7 (CH; C-
6), 117.2 (CH; C-7), 111.8 (CH2; C-19), 108.1 (CH; C-24), 104.1 (CH; C-
23), 70.7 (CH; C-1), 70.5 (COH; C-27), 66.7 (CH; C-3), 56.2 (CH; C-17),
55.4 (CH; C-14), 45.7 (C; C-13), 45.2 (CH2; C-4), 42.8 (CH2; C-2), 42.1
(C; C-26), 40.2 (CH2; C-12), 36.4 (CH; C-20), 28.9 (CH2; C-9), 28.8 (2ꢆ
CH3; C-28 and C-29), 27.6 (CH2; C-16), 23.5 (CH2; C-11), 22.1 (CH2; C-
15), 20.0 (CH3; C-21), 12.0 ppm (CH3; C-18); IR (CHCl3): n˜ =3346,
[13] For active vitamin D analogues with aromatic fragments at the side
chain, see: a) B. Figadꢉre, A. W. Norman, H. J. Henry, H. P. Koef-
fler, J.-Y. Zhou, W. H. Okamura, J. Med. Chem. 1991, 34, 2452–
2463; b) Y. Fall, C. Barreiro, C. Fernꢁndez, A. MouriÇo, Tetrahedron
Lett. 2002, 43, 1433–1436; c) X. Pꢃrez-Garcꢀa, A. Rumbo, M. J. Lar-
riba, P. OrdꢂÇez, A. MuÇoz, A. MouriÇo, Org. Lett. 2003, 5, 4033–
4036.
2954 cmÀ1
; UV (96% EtOH): lmax (e)=218 nm (18900), l=266 nm
(15000 molÀ1 m3 cmÀ1), lmin =246 nm; HRMS (ESI-TOF): m/z: calcd for
[C29H43O4]+: 455.3156 [M]+; found 455.3155.
[14] P. Gogoi, R. Sigꢈeiro, S. Eduardo, A. MouriÇo, Chem. Eur. J. 2010,
16, 1432–1435.
[15] A. MouriÇo, M. Torneiro, C. Vitale, S. Fernꢁndez, J. Pꢃrez-Sestelo,
J. S. Annꢃ, C. Gregorio, Tetrahedron Lett. 1997, 38, 4713–4716.
[16] a) P. M. Wovkulich, F. Barcelos, A. D. Batcho, J. F. Sereno, E. G.
Baggiolini, B. M. Hennessy, M. R. Uskokovic, Tetrahedron 1984, 40,
2283; b) W. G. Dauben, R. R. Ollmann, A. S. Funhoff, R. Neidlein,
Tetrahedron Lett. 1989, 30, 677–680.
[17] B. Fernꢁndez, J. A. Martꢀnez-Pꢃrez, J. R. Granja, L. Castedo, A.
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[18] A. Yanagisawa, S. Habaue, H. Yamamoto, Tetrahedron 1992, 48,
1969–1980.
Acknowledgements
We thank the Spanish Ministry of Education and Innovation (MEI)
(projects SAF2007–67205, SAF2010–15291, and SAF2010–18302) and the
“Red Temꢁtica de Investigaciꢂn Cooperativa en Cꢁncer” (ISCIII, RD06/
0020/0009) for financial support, CESGA for computer time, and Dish-
man-Netherlands for a generous gift of vitamin D2. R.F. thanks the Span-
ish MEI for an FPI grant. F.Z. thanks the Universidad Nacional del Sur
(Argentina) for financial support. N.R. and D.M. thank the Association
de Recherche sur le Cancer (ARC), CNRS, INSERM, Universitꢃ de
Strasbourg, for support. We also thank the staff of the beamlines at
ESRF for experimental assistance. T.H. thanks the Conseil Rꢃgional
dꢇAlsace and the ARC for a Ph.D. fellowship.
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[23] PDC/CH2Cl2 or DMP/CH2Cl2 gave complex reaction mixtures diffi-
cult to identify by 1H NMR. Swern oxidation ((COCl)2/DMSO,
Et3N, CH2Cl2) resulted in dehydration or over-oxidized reaction
products.
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Received: August 29, 2011
Published online: December 8, 2011
612
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Chem. Eur. J. 2012, 18, 603 – 612