Vitamin D side chain triazole analogs via cycloaddition 'click' chemistry

Article abstract of DOI:10.1016/j.tetlet.2004.04.118

Cycloaddition of a vitamin D side chain terminal acetylene with phenyl azide and separately with a vitamin D side chain terminal azide produced the corresponding 1,2,3-triazole monomeric and dimeric analogs of 1α-hydroxyvitamin D₃ in good yields.

Full text of DOI:10.1016/j.tetlet.2004.04.118

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4623–4625
Vitamin D side chain triazole analogs via cycloaddition
‘click’ chemistry
Byung-Chul Suh, HeungBae Jeon, Gary H. Posner* and Steven M. Silverman
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA
Received 22 March 2004; revised 16 April 2004; accepted 21 April 2004
Abstract—Cycloaddition of a vitamin D side chain terminal acetylene with phenyl azide and separately with a vitamin D side
chain terminal azide produced the corresponding 1,2,3-triazole monomeric and dimeric analogs of 1a-hydroxyvitamin D3 in good
yields.
Ó 2004 Published by Elsevier Ltd.
Many azasteroids are biologically active.1 For example,
some 1- and 6-azasteroids are 5a-reductase inhibitors2;3
as well as antifungal agents,4;5 and 8,13-diazasteroids
have analgesic activity.6 Also, 8,16-diazasteroids have
cardiotonic and hypotensive activities,7 and 11-azaster-
oids have glucocorticoid activity.8 Some 17-azasteroids
are GABAA receptor modulators.9 Very few aza-ana-
logs of vitamin D, however, have been reported despite
previous analogs23 (1H NMR C6–H d 6.37 for 1a, d 6.38
for 1b).
‘Click’ chemistry18–20 allowed cycloaddition also of a
vitamin D C-23 terminal acetylene with a vitamin D side
chain azide to form dimer 2 in which two of the same
vitamin D units are linked through their side chains via
a 1,2,3-triazole unit (Scheme 2).
vitamin D’s broad spectrum of biological activities.10
A
24-amino vitamin D3 has been reported,11 as well as
heterocyclic diazirine12 and pyrazole13 side chain vita-
min D analogs in which the pyrazole unit was assembled
via a cycloaddition reaction.13–15 Only one side chain
Each of the chemical transformations in Scheme 2
proceeded in at least 69% yield, and the key cycloaddi-
tion step to form vitamin D dimer triazole 13 proceeded
in 73%.
triazole vitamin
D
analog, however, has been
described,16;17 prepared via triazole displacement of a
22-tosylate.16 We report here synthesis of a vitamin D3
side chain 1,2,3-triazole analog via cycloaddition18 of a
terminal acetylene with phenyl azide (Scheme 1).
Evaluation of the in vitro antiproliferative activity of
monomer phenyl triazole 1a was done in murine kerati-
nocytes using our standard protocol.24 No significant
antiproliferative activity, however, was found even at
1 lM concentration of monomer phenyl triazole 1a. For
comparison, a somewhat similar 1-a-hydroxyvitamin D
C-25 oxime methyl ether analog, even though lack-
ing the traditional C-25 hydroxyl group, showed high
in vitro antiproliferative activity,24 and various side
chain aromatic vitamin D analogs (arocalciferols) have
significant biological activities.25 Dimer triazole 2 did
not show any interesting in vitro antiproliferative
activity.
In Scheme 1, after acetylide displacement of the C-22
primary tosylate, the first key step involved successful
cycloaddition of the C-23 acetylene with phenyl azide,
an example of ‘click’ chemistry.18–20 The second key step
involved successful Lythgoe-type21 coupling of the
racemic A-ring allylic phosphine oxide with the C-8 keto
side chain triazole; vitamin D3 triazole analog 1a was
isolated pure in 65% yield from this final coupling and
desilylation protocol,22 and its A-ring stereochemistry
was assigned based on NMR spectroscopic analogy with
In summary, cycloaddition of a vitamin D side chain
terminal acetylene with phenyl azide and separately with
a vitamin D side chain azide successfully produced the
corresponding 1,2,3-triazole analogs of 1-a-hydroxy-
vitamin D3 in good yields. This is the first report of
‘click’ chemistry in the vitamin D field and the first
Keywords: Vitamin D; Triazole; ‘Click’ chemistry.
* Corresponding author. Tel.: +1-410-516-4670; fax: +1-410-516-8420;
e-mail: ghp@jhu.edu
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.04.118

4624
B.-C. Suh et al. / Tetrahedron Letters 45 (2004) 4623–4625
Scheme 1.
Scheme 2.

B.-C. Suh et al. / Tetrahedron Letters 45 (2004) 4623–4625
4625
9. Covey, D. F.; Han, M.; Kumar, A. S.; de la Cruz, M. A.
M.; Meadows, E. S.; Hu, Y.; Tonnies, A.; Nathan, D.;
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Mennerick, S. J. Med. Chem. 2000, 43, 3201.
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monomeric vitamin D units are linked via a side chain
heteroaromatic ring.26
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Academic: San Diego, CA, 1997.
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