Vitamin D and click chemistry. Part 1: A stereoselective route to vitamin D analogues with triazole rings in their side chains

Article abstract of DOI:10.1016/j.tetlet.2004.04.117

Efficient preparation of vitamin D CD ring system synthons with triazole rings in their side chains is based on the formation of the triazole ring from a [3+2]-cycloaddition of a vitamin D side chain terminal azide with a terminal acetylene.

Full text of DOI:10.1016/j.tetlet.2004.04.117

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4619–4621
Vitamin D and click chemistry. Part 1: A stereoselective route to
vitamin D analogues with triazole rings in their side chains
*
ꢀ
Pedro Lois Suarez, Zoila Gandara, Generosa Gomez and Yagamare Fall
ꢀ
Departamento de Quꢀımica Orgꢀanica, Facultad de Quꢀımica. Universidad de Vigo, 36200 Vigo, Spain
Received 22 March 2004; revised 16 April 2004; accepted 21 April 2004
Abstract—Efficient preparation of vitamin D CD ring system synthons with triazole rings in their side chains is based on the
formation of the triazole ring from a [3þ2]-cycloaddition of a vitamin D side chain terminal azide with a terminal acetylene.
Ó 2004 Elsevier Ltd. All rights reserved.
1a,25-Dihydroxy vitamin D3 [1, 1a,25-(OH)2-D3, calci-
triol], the hormonally active form of vitamin D3 (2,
vitamin D have been reported.3–5 As part of our research
programme on the synthesis of vitamin D analogues
with heterocyclic side chains we previously reported the
synthesis of the side chain of analogue 3 (Fig. 1) con-
taining a pyrazole ring.5c We now report our preliminary
results on the synthesis of vitamin D analogues with a
triazole ring in their side chain based on the use of click
chemistry6 (Scheme 1).
1
cholecalciferol), exerts control over important physio-
logical processes, including calcium and phosphorus
metabolism, cellular differentiation and immune reac-
tions.2 However, the clinical utility of this hormone for
treatment of cancers and skin disorders is limited by its
hypercalcaemic effects. There is accordingly much
interest in the design and synthesis of analogues of 1
with more selective (or even different) biological effects.2
Selective tosylation of the primary alcohol of diol 5 gave
tosylate 7 in 93% yield, and protection of the secondary
alcohol of 7 (99%), followed by azide displacement
of the C-22 primary tosylate afforded a 99% yield of
azide 8,7 which underwent a [3þ2]-cycloaddition with
terminal acetylene 98 to afford triazole 107 in 85% yield.
Removal of the silyl protecting groups of 10 by reaction
Most of the analogues of 1 synthesized so far show
modifications at the side chain but only a limited num-
ber of these analogues are in use as drugs.2f It is well
known that azasteroids show noteworthy pharmaco-
logical activity,3;4 however very few aza-analogues of
N
N
OH
N
N
OH
OH
N
H
H
H
H
HO
OH
HO
HO
OH
HO
OH
2
1
4
3
Figure 1.
Keywords: Vitamin D; Analogues; Wittig–Horner; Triazole; Side chain; Antiproliferative.
* Corresponding author. Tel.: +34-986-81-23-20; fax: +34-986-81-22-62; e-mail: yagamare@uvigo.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.117

4620
P. L. Suarez et al. / Tetrahedron Letters 45 (2004) 4619–4621
OH
OTs
N3
OTs
ii
i
iii
H
OH
H
H
H
N
HO
TBSO
TBSO
8
6
5
7
OTES
N
N
OTES
OH
OH
N
N
N
9
N
v
vi
N
N
N
H
TBSO
iv
10
H
HO
H
O
11
12
Ph3PO
OH
OH
N
N
N
N
N
TBSO
13
viii
H
H
14
15
vii
TBSO
HO
Scheme 1. Reagents and conditions: (i) p-TsCl, py (93%); (ii) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ10 °C (99%); (iii) NaN3, DMF, rt (99%); (iv) 9,
CuSO4Æ3H2O, sodium ascorbate, H2O/tBuOH 2:1(85%); (v) HF, MeCN (86%); (vi) PDC, CH 2Cl2, rt (50%); (vii) 13; n-BuLi, THF, ꢀ78 °C (50%);
(viii) n-Bu4NF, THF, rt (83%).
O
N3
O
N3
N
OEt
N
N
OEt
i
17
ii
H
H
HO
H
TBSO
8
16
18
HO
Ph3PO
O
N
N
OEt
O
N
TBSO
N
N
OEt
13
iii
N
H
v
20
iv
H
O
19
TBSO
Ph3PO
TBSO
OTBS
21
OH
N
N
N
R
OH
R
N
H
N
N
15
H
HO
22
HO
OH
Scheme 2. Reagents and conditions: (i) HF, MeCN, rt (98%); (ii) 16, CuSO4Æ3H2O, sodium ascorbate, H2O/tBuOH 2:1(99%); (iii) TPAP, NMO,
CH2Cl2, rt (80%); (iv) 13; n-BuLi, THF, ꢀ78 °C (75%); (v) (a) MeLi, Et2O, ꢀ20 °C; (b) n-Bu4NF, THF, rt (49%, two steps).

P. L. Suarez et al. / Tetrahedron Letters 45 (2004) 4619–4621
4621
2. For general reviews of vitamin D chemistry and biology,
see: Vitamin D: Chemistry, Biology and Clinical Applica-
tions of the Steroid Hormone; (a) Norman, A. W.,
Bouillon, R., Thomasset, M., Eds.; Vitamin D Workshop:
Riverside, CA, 1997; (b) Feldman, D.; Glorieux, F. H.;
Pike, J. W. Vitamin D; Academic: San Diego, 1997; (c)
Pardo, R.; Santelli, M. Bull. Soc. Chim. Fr. 1985, 98–114;
(d) Dai, H.; Posner, G. H. Synthesis 1994, 1383–1398; (e)
Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877–
1952; (f) Posner, G. H.; Kahraman, M. Eur. J. Org. Chem.
2003, 3889–3895.
3. Suh, B.-C.; Jeon, H. B.; Posner, G. H.; Silverman,
S. M. See following paper, Tetrahedron Lett. 2004, 45,
doi:10.1016/j.tetlet.2004.04.118
ꢀ
4. Oves, D.; Ferrero, M.; Fernandez, S.; Gotor, V. J. Org.
Chem. 2003, 68, 1154–1157, and references cited
with HF in acetonitrile at room temperature, gave diol
11.7 Oxidation of 11 with pyridinium dichromate affor-
ded ketone 12,7 so setting the stage for the Wittig–
Horner reaction with phosphine oxide 139 leading to the
desired analogue 15.7
Evaluation of the in vitro antiproliferative activity of
analogue 15 was done in murine keratinocytes using
Johns Hopkins’s standard protocol.10 However no
antiproliferative activity was found for 15. We then
designed a more versatile route that would allow not only
the synthesis of analogues 4 and 15 but also a wide range
of analogues of 4 such as compounds 22 (Scheme 2).
[3þ2]-Cycloaddition of azide 167 with ethylpropiolate 17
afforded nearly quantitatively triazole 18.7 Oxidation of
alcohol 18 with TPAP gave key ketone 197 in 80% yield.
Wittig–Horner reaction of 19 with phosphine oxide 13
generated the labile triene unit, affording key interme-
diate 20,7 which leads to 15 upon reaction with MeLi
followed by desilylation. The synthesis of analogues 22
is currently under way in our laboratory with a view to
their biological evaluation.
therein.
5. (a) Fall, Y.; Puente, M.; Gomez, G.; Bolasimno, T.;
ꢀ
Suarez, P. L.; Gandara, Z. Abstracts of the 12th Workshop
ꢀ
on Vitamin D; Maastricht: The Netherlands, July 6–7,
ꢀ
ꢀ
2003; (b) Gomez, G.; Suarez, P. L.; Saa, C.; Fall, Y.;
Puente, M. Abstracts of the 12th Workshop on Vitamin D;
Maastricht: The Netherlands, July 6–7, 2003 (c) Fall, Y.;
ꢀ
Barreiro, C.; Fernandez, C.; Mourino, A. Tetrahedron
Lett. 2002, 43, 1433–1436; (d) Sestelo, J. P.; de Una, O.;
~
~
~
Mourino, A.; Sarandeses, L. A. Synlett 2002, 5, 719–722;
ꢀ
~
(e) Fernandez-Gacio, A.; Mourino, A. Eur. J. Org. Chem.
2002, 2529–2534.
Acknowledgements
6. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2001, 40, 2004–2021; (b) Rostovtsev, V. V.;
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596–2599; (c) Torn/e, C. W.;
Christensen, M.; Meldal, M. J. Org. Chem. 2002, 67,
3057–3064.
This work was supported by grants from the Xunta de
Galicia (PGIDT01PXI30105PR) and the Vicerectorate
for Research of the University of Vigo. We also thank
Solvay Pharmaceuticals (Weesp, The Netherlands) for
the gift of starting materials; the NMR service of the
CACTI, University of Vigo, for NMR studies and Johns
Hopkins Prof. Gary Posner, Thomas Kensler and Mr.
Patrick Dolan for the in vitro antiproliferative assays.
7. All new compounds exhibited satisfactory 1H and 13C
NMR, analytical, and/or high resolution mass spectral
data.
~
8. Torneiro, M.; Fall, Y.; Castedo, L.; Mourino, A. J. Org.
Chem. 1997, 62, 6344–6352.
~
9. (a) Sardina, F. J.; Mourino, A.; Castedo, L. J. Org. Chem.
~
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