Rapid access to a series of calcitriol analogues with restricted side chain conformation

Article abstract of DOI:10.1016/j.tetlet.2016.05.045

The synthesis of a series of calcitriol analogues with restricted side chain conformation is described. C-22 modified calcitriol analogues have been prepared from a common intermediate, in which the labile triene system is already present.

Full text of DOI:10.1016/j.tetlet.2016.05.045

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
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Rapid access to a series of calcitriol analogues with restricted side
chain conformation
⇑
⇑
Carlos Fernández, Hugo Santalla, Fátima Garrido, Generosa Gómez , Yagamare Fall
Departamento de Química Orgánica, Facultad de Química and Instituto de Investigación Biomédica (IBI), University of Vigo, Campus Lagoas de Marcosende, 36310 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a series of calcitriol analogues with restricted side chain conformation is described. C-22
modified calcitriol analogues have been prepared from a common intermediate, in which the labile triene
system is already present.
Received 10 March 2016
Revised 10 May 2016
Accepted 12 May 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Calcitriol
Stereoselective synthesis alkylation
Nitriles
22-Substituted analogues
Side chains
22
25
21
Introduction
20
OH
1a,25-Dihydroxyvitamin D3 (calcitriol, 1) (Fig. 1) is the hormon-
H
H
ally active form of vitamin D3 (2) and not only regulates calcium
homoeostasis, but is also involved in cell differentiation and gene
transcription.1 There has been great interest in the synthesis of
calcitriol analogues for specific applications.
1
HO
HO
OH
2
1
For a rational design of the desired analogues, information
about the conformation of the hydroxylated side chain in the
structure binding to the VDR receptor(s) is needed. The specific
interaction of ligands with the ligand-binding domain (LBD) of
VDR has focused the attention of the scientific community, since
the X-ray crystal structure of deletion mutant VDR complexed with
the natural ligand 1 was solved by Moras and co-workers.2
Since Okamura and coworkers described the synthesis of
calcitriol analogues with an aromatic ring in their side chains,3a
several other examples of calcitriol analogues with restricted side
chain conformation have been described,3b–h among them worth
mentioning those described by Yamada and co-workers,4 having
C-22 substituted side chain (Fig. 2).
Figure 1. Structures of calcitriol (1) and vitamin D3 (2).
22
22
OH
22
OH
OH
H
H
H
HO
OH
HO
OH
HO
OH
5
4
3
These calcitriol analogues proved to have very interesting bio-
logical properties. For example analogue 7 was 100 times more
efficient than 1,25-dihydroxyvitamin D3 (1) in cell differentiation,
although its affinity for the vitamin D receptor (VDR) was one-sev-
enth of that of 1. Analogue 5 showed the highest VDR binding
activity so far known. Recently, Yamamoto and co-workers5
22
22
OH
OH
H
H
HO
OH
HO
OH
7
6
⇑
Corresponding authors. Tel.: +34 986 81 23 20; fax: +34 986 81 22 62.
E-mail addresses: ggomez@uvigo.es (G. Gómez), yagamare@uvigo.es (Y. Fall).
Figure 2. Yamada’s type calcitriol analogues.
http://dx.doi.org/10.1016/j.tetlet.2016.05.045
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Fernández, C.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.05.045

2
C. Fernández et al. / Tetrahedron Letters xxx (2016) xxx–xxx
R1
Bu
Bu OH
R2
Bu
Bu OH
S
CN
OH
R
S
OTES
S
OH
S
S
i
ii
Br
H
H
a: R1 = CN; R2 = H
b: R1 = H; R2 = CN
H
HO
R2
HO
H
H
H
OTES
16
17
15
R1
HO
OH
R1
HO
OH
R2
HO
OH
HO
OH
OTES
9
10
8
11
iOiiTES
iv
a: R1 = CH2OTs; R2 = H
b: R1 = H; R2 = CH2OTs
Figure 3. Some of Yamamoto’s type calcitriol analogues.
H
HO
19
H
a: R1 = CH2OH; R2 = H
b: R1 = H; R2 = CH2OH
HO
18
showed that 22-butyl vitamin D derivatives were a new class of
vitamin D analogues that induce structural rearrangement of the
ligand binding pocket of vitamin D receptor (Fig. 3).
R1
R2
OTES
R1
v
R2
H
Results and discussion
OTES
a: R1 = CH2OTs; R2 = H
b: R1 = H; R2 = CH2OTs
Ph PO
2
a: R1 = CH2OTs; R2 = H
b: R1 = H; R2 = CH2OTs
21
We previously described a synthetic approach to not only Yama-
da’s analogues,6 but also other new vitamin D analogues with mod-
ification at C-22.7 We now describe a more versatile approach which
allows access to a huge series of C-22 modified calcitriol analogues
from a common intermediate in which the labile triene system is
already present. Our retrosynthetic basis is outlined in Scheme 1.
We anticipated that nitrile 15,8 readily available from the
Inhoffen-Lythgoe diol could lead to intermediate 14 already bearing
the calcitriol triene system. Accordingly target tosylates 14 were pre-
pared as outlined in Scheme 2. Nitrile 15 was uneventfully trans-
formed into known diols 18a and 18b6a and their primary alcohols
were selectively tosylated, affording 19a and 19b in 82% and 76%
yield, respectively. Pyridinium dichromate oxidation of the alcohols
19a and 19b afforded ketones 20a and 20b in 91% and 93% yield,
respectively. With these key precursors in hand the stage was set
for the Wittig–Horner reaction using phosphine oxide 21.9 Coupling
reaction of 20a and 20b with 21 afforded the corresponding targets
14a10and 14b11 in 67% and 59% yield, respectively.
H
20
O
TBSO
OTBS
TBSO
OTBS
14
vii
vi
H
H
O
O
OH
OH
H
H
H
H
HO
OH
HO
OH
HO
OH
HO
OH
3
12
13
4
Scheme 2. Reagents and conditions: (i) LDA, HMPA, THF, À78 °C, 16 (89%); (ii)
DIBAH, CH2Cl2, À10 °C; HCl; NaBH4, MeOH [18a (21%); 18b (20%); two steps ]; (iii)
TsCl, Pyr, 0 °C, 12 h [19a (82%); 19b (76%)]; (iv) PDC, CH2Cl2, rt, 5 h [20a (91%); 20b
(93%)]; (v) 21; n-BuLi, THF, À78 °C [14a (67%); 14b (59%)]; (vi) n-Bu4NF, THF, rt [12
(69%); 13 (71%)]; (vii) (a) LiAlH4, Et2O, 0 °C to rt; (b) n-Bu4NF, THF, rt [3 (33%, two
steps); 4 (34%, two steps)].
Tosylates 14, on reaction with TBAF afforded known6a calcitriol
analogues with cyclic side chains 12 and 13 in 69% and 71% yield,
respectively. Reaction of tosylates 14 with LiAlH4 followed by
H
H
O
O
OH
OH
removal of the silyl protecting groups with TBAF afforded
known6b target compounds 3 and 4 in 33% and 34% overall yield,
respectively.
H
H
H
H
In conclusion, we have developed a methodology which allows
a straightforward synthesis of a large series of calcitriol analogues
with restricted side chain conformation which will be used for
biological evaluation. This method will allow the study of struc-
ture–activity relationship of vitamin D analogues.
HO
OH
HO
OH
HO
R2
OH
HO
OH
3
13
12
4
R1
Acknowledgments
OTES
This work was supported financially by the Xunta de Galicia
(N° EXPTE. CN 2012/184). The work of the NMR and MS divisions
of the research support services of the University of Vigo (CACTI)
is also gratefully acknowledged.
H
a: R1 = CH2OTs; R2 = H
b: R1 = H; R2 = CH2OTs
TBSO
OTBS
14
References and notes
1. (a)For a general review on the chemistry and/or biochemistry of vitamin D, see:
Vitamin D: Chemistry, Biology and Clinical Applications of the Steroid Hormone;
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 Press:
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. Chem. Rev. 1995,
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Academic Press: Burlington, MA, 2005; (h) Feldman, D.; Pike, J. W.; Adams, J. S.
Vitamin D, 3rd ed.; Elsevier Academic Press: San Diego, CA, 2011.
CN
H
HO
15
Scheme 1. Retrosynthetic scheme.
Please cite this article in press as: Fernández, C.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.05.045

C. Fernández et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
2. (a) Rochel, N.; Wurtz, J. M.; Mitschler, A.; Klaholz, B.; Moras, D. Mol. Cell 2000, 5,
173–179; (b) Tocchini-Valentini, G.; Rochel, N.; Wurtz, J. M.; Mitschler, A.;
Moras, D. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 5491–5496.
10. Selected data for compound 14a: Colourless oil, Rf = 0.75 (30% EtOAc/Hexane);
1H NMR (CDCl3, d): 7.78 (2H, d, J = 8.28 Hz, H-Ar), 7.33 (2H, d, J = 8.48 Hz, H-Ar),
6.22 (1H, d, J = 11.1 Hz, H-6), 6.00 (1H, d, J = 11.1 Hz, H-7), 5.17 (1H, br s, H-19),
4.86 (1H, br s, H-19), 4.37 (1H, dd, J = 6.5 y J = 3.7 Hz, H-1), 4.19 (1H, q,
J = 3.5 Hz, H-3), 4.10 (1H, dd, J = 9.63 y J = 4.5 Hz, H-28), 3.81 (1H, dd, J = 9.6 y
J = 4.7 Hz, H-28), 2.81 (1H, d, J = 12.2 Hz. H-14), 2.43 (4H, s, CH3-Ar y H-9), 2.21
(1H, dd, J = 13.03 y J = 7.25 Hz, H-9), 1.15 (3H, s, H-26 o 27), 1.13 (3H, s, H-26 o
27), 0.91 (9H, t, J = 7.9 Hz, CH3-TES), 0.87 (18H, s, CH3-t-BuSi), 0.76 (3H, d,
J = 6.90 Hz, H-21), 0.52 (9H, m, H-18 y CH2-TES), 0.06 (6H, s, CH3-MeSi), 0.05
(6H, s, CH3-MeSi); 13C-RMN (CDCl3, d): 148.33 (C-10), 144.51 (C-Ar), 140.50 (C-
8), 135.17 (C-5), 133.28 (C-Ar), 129.72 (CH-Ar), 127.89 (CH-Ar), 123 (CH-6),
118.00 (CH-7), 111.07 (CH-19), 73.07 (C-25), 71.95 (CH-3), 71.61 (CH2-22),
67.47 (CH-1), 56.18 (CH-17), 53.85 (CH-14),45.97 (CH2), 45.74 (C-13), 44.78
(CH2), 42.68 (CH2), 40.50 (CH2), 40.26 (CH-22), 36.96 (CH-20), 29.96 (CH3-26 o
27), 29.52 (CH3-26 o 27), 28.81 (CH2), 27.52 (CH2), 25.81 (CH3-t-BuSi), 25.77
(CH3-t-BuSi), 24.40 (CH2), 23.40 (CH2), 21.95 (CH2), 21.56 (CH3-Ar), 18.18 (C-t-
BuSi), 18.09 (C-t-BuSi), 13.57 (CH3-21), 11.52 (CH3-18), 7.06 (CH3-TES), 6.73
(CH2-TES), À4.71 (CH3-MeSi), À4.82 (CH3-MeSi); MS [m/z, (%)]: 943 [M++1,
(11)], 942 [M+, (15)], 812 (25), 811 [M+–OTBS, (28.45)], 810 (52), 638 (34), 266
(26), 257 (34), 249 (24), 248 (100); HRMS: Calcd for C53H94O6SSi3, 942.6078;
found, 942.6034.
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11. Selected data for compound 14b: Colourless oil, Rf = 0.69 (30% EtOAc/Hexane);
1H NMR (CDCl3, d): 7.78 (2H,d, J = 8.27 Hz, H-Ar), 7.33 (2H, d, J = 8.25 Hz, H-Ar),
6.22 (1H, d, J = 11.14 Hz, H-6), 6.01 (1H, d, J = 11.16 Hz, H-7), 5.19 (1H, br s, H-
19), 4.86 (1H, br s, H-19), 4.37 (1H, m, H-1), 4.19 (1H, m, H-3), 3.99 (1H, dd,
J = 9.85 y J = 4.5 Hz, H-28), 3.85 (1H, t, J = 9.56 Hz, H-28), 2.81 (1H, m, H-14),
2.46 (1H, m, H-9), 2.44 (3H, s, CH3-Ar), 2.22 (1H, dd, J = 13.1 y J = 7.46 Hz, H-9),
1.16 (3H, s, H-26 ó 27), 1.12 (3H, s, H-26 ó 27), 0.91 (9H, t, J = 7.92 Hz, CH3-TES),
0.87 (18H, s, CH3-t-BuSi), 0.64 (3H, d, J = 6.69 Hz, H-21), 0.53 (6H, c, J = 7.91 Hz,
CH2-TES), 0.48 (3H; s, H-18), 0.07 (6H, s, CH3-MeSi), 0.06 (6H, s, CH3-MeSi); 13
C
NMR (CDCl3, d): 148.29 (C-10), 144.53 (C-Ar), 140.64 (C-8), 135.19 (C-5),
133.36 (C-Ar), 129.73 (CH-Ar), 127.90 (CH-Ar), 123.04 (CH-6), 118.00 (CH-7),
111.24 (CH2-19), 73.06 (C-25), 72.18 (CH2-22), 72.06 (CH-3), 67.51 (CH-1),
56.34 (CH-17), 53.45 (CH-14), 46.02 (CH2), 45.71 (C-13), 44.80 (CH2), 43.69
(CH2), 40.66 (CH2), 40.59 (CH-22), 35.48 (CH-20), 30.32 (CH3-26 o 27), 29.24
(CH3-26 o 27), 28.86 (CH2), 27.37 (CH2), 25.84 (CH3-t-BuSi), 25.81 (CH3-t-BuSi),
23.46 (CH2), 21.98 (CH2), 21.59 (CH3-Ar), 19.05 (CH2), 18.24 (C-t-BuSi), 18.13
(C-t-BuSi), 13.04 (CH3-21), 11.89 (CH3-18), 7.12 (CH3-TES), 6.78 (CH2-TES),
À4.60 (CH3-MeSi), À4.69 (CH3-MeSi), À4.79 (CH3-MeSi), À5.08 (CH3-MeSi); MS
[m/z, (%)]: 943 [M++1, (12)], 942 [M+, (21)], 941 [M+–H, (26)], 811 [M+–OTES,
(51)], 711 [M+–OTs, (10)], 757 [M+–CH2OTs, (5)], 678 (9), 638 (44), 507 (16),
355 (11), 257 (39), 248 (100), 173 (41); HRMS: calcd for
942.6078; found, 942.6079.
C53H94O6SSi3,
Please cite this article in press as: Fernández, C.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.05.045