Vitamin D heterocyclic analogues. Part 1: A stereoselective route to CD systems with pyrazole rings in their side chains

Article abstract of DOI:10.1016/S0040-4039(02)00031-X

Efficient preparation of two vitamin D CD ring system synthons with pyrazole rings in their side chains is based on the formation of the pyrazole ring from an α-acetylenic ketone.

Full text of DOI:10.1016/S0040-4039(02)00031-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1433–1436
Vitamin D heterocyclic analogues. Part 1: A stereoselective
route to CD systems with pyrazole rings in their side chains
Yagamare Fall,a,* Candida Barreiro,a Carlos Ferna´ndeza and Antonio Mourin˜ob
aDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Spain
bDepartamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received 26 December 2001; accepted 28 December 2001
Abstract—Efficient preparation of two vitamin D CD ring system synthons with pyrazole rings in their side chains is based on
the formation of the pyrazole ring from an a-acetylenic ketone. © 2002 Elsevier Science Ltd. All rights reserved.
1a,25-Dihydroxyvitamin D3 [1, 1a,25-(OH)2-D3, cal-
of the numerous analogues of this type that have been
synthesized in recent decades have in fact proved useful
for the treatment of cancers1,2b or psoriasis3). In partic-
ular, analogues with rigid, conformationally restricted
structural units in the side chain tend to combine
non-negligible antiproliferative activity with low cal-
caemic activity.4 Inversion of the configuration at C20
can also substantially enhance antiproliferative action.1
In view of these considerations we propose a synthetic
approach to analogue 6 and its C20 epimer 7, which
both include a pyrazole ring in the side chain (Fig. 1).
Here we describe the preparation of their CD system
1
citriol], the hormonally active form of vitamin D3 (2,
cholecalciferol), is one of the most potent inducers of
calcitropic effects, notably intestinal calcium absorption
and bone calcium mobilization. Beside regulating the
metabolism of calcium and phosphorus, calcitriol pro-
motes cell differentiation, inhibits the proliferation of
tumor cells, and has certain indirect effects on the
immunological system.2 However, the clinical utility of
this hormone for treatment of cancers and skin disor-
ders 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
and side chain precursors, compounds
(Schemes 1 and 2).
4 and 5
In most potentially applicable vitamin D analogues it is
the side chain of 1 that is modified (although only a few
a-Acetylenic ketones having recently been described as
highly versatile building blocks for the synthesis of
N
N
N
N
OH
OH
OH
H
H
H
H
HO
OH
HO
OH
HO
OH
HO
1
7
6
2
Figure 1.
* Corresponding author. Fax: 34 986 81 23 82; e-mail: yagamare@uvigo.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00031-X

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Y. Fall et al. / Tetrahedron Letters 43 (2002) 1433–1436
OH
CHO
OBz
OH
ii
i
iii
H
OH
H
H
H
BzO
BzO
BzO
10
8
3
9
OH
N
N
O
OTES
OTES
11
OTES
OTES
v
vi
H
H
H
BzO
iv
BzO
BzO
13
14
12
N
N
N
N
OTES
vii
viii
OTES
H
O
H
OH
4
15
Scheme 1. Reagents and conditions: (i) BzCl, py, DMAP, 0°C (99%); (ii) KOH, EtOH, C6H6 (95%); (iii) TEMPO, BAIBE, CH2Cl2
rt (77%); (iv) 11, n-BuLi, THF, −78°C (78%); (v) PDC, CH2Cl2, rt (69%); (vi) NH2NH2, DMF, 0°C to rt (95%); (vii) n-BuLi, THF
(79%); (viii) PDC, CH2Cl2, rt, 4 h (83%).
OH
CHO
OTs
OTs
ii
i
iii
H
HO
H
H
H
HO
TBSO
TBSO
OH
17
18
16
3
CHO
OH
iv
v
+
H
H
H
TBSO
TBSO
TBSO
21
20
19
N
N
OH
O
OMOM
OMOM
22
OMOM
OMOM
vii
viii
H
H
H
TBSO
TBSO
TBSO
vi
23
24
5
Scheme 2. Reagents and conditions: (i) p-TsCl, py (93%); (ii) TBSOTf, 2,6-lutidine, CH2Cl2, −10°C (99%); (iii) NaHCO3, DMSO,
120°C (68%); (iv) DBU, THF, 85°C; NaBH4, MeOH, 0°C (75% 19+20); (v) TEMPO/BAIBE, CH2Cl2, rt (75%); (vi) 22, nBuLi,
THF, −78°C (70%); (vii) PDC, CH2Cl2, rt (63%); (viii) NH2NH2, DMF, 0°C to rt (84%).

Y. Fall et al. / Tetrahedron Letters 43 (2002) 1433–1436
1435
heterocyclic systems,9 we decided to construct the side
chain of 4 via the a-acetylenic ketone 13. The Inhof-
fen–Lythgoe diol (3), which is readily obtained by
degradation of vitamin D2,5 was converted to diben-
zoate 8 in almost quantitative yield (99%); selective
reduction of the primary benzoate of 8 afforded alco-
hol 9 in 95% yield;6 oxidation of 9 using 2,2,6,6-tetra-
methylpiperidine-1-oxyl and [bis(acetoxy)yodo]benzene
(TEMPO/BAIBE) gave aldehyde 10 in 77% yield; 10
reacted with the anion obtained by treatment of 117
with n-butyllithium, affording propargyl alcohol 128
(78%); and PDC oxidation of 12 afforded the desired
a-acetylenic ketone 138 (69%). Gratifyingly, reaction of
13 with aqueous hydrazine afforded 14,8 which bears
the desired side chain, in excellent yield (95%) and
without any epimerization at C20. Removal of the
benzoyl group of 14 with n-BuLi (79%), followed by
PDC oxidation of the resulting alcohol (15),8 gave the
target CD synthon 410a in 83% yield.
2. For general reviews of vitamin D chemistry and biol-
ogy, see: (a) Vitamin D: Chemistry, Biology and Clinical
Applications of the Steroid Hormone; Norman, A. W.,
Bouillon, R., Thomasset, M., Eds.; Vitamin D Work-
shop, Inc.: Riverside, CA, 1997; (b) Feldman, D.; Glo-
rieux, F. H.; Pike, J. W. Vitamin D; Academic Press:
San Diego, 1997; (c) Dai, H.; Posner, G. H. Synthesis
1994, 1383–1398; (d) Zhu, G.-D., Okamura. W. H.
Chem. Rev. 1995, 95, 1877–1952.
3. (a) Calcipotriol, an analogue of 1a,25-(OH)2-D3, has
been commercialized under the name of Dovonex by
Leo Pharmaceuticals for the local treatment of psoria-
sis: Binderup, L.; Kragballe, K. Rev. Contemp. Pharma-
cother. 1992, 3, 357; (b) For vitamin D analogues in
the treatment of psoriasis, see: Kragballe, K. J. Cell.
Biochem. 1992, 49, 46.
4. (a) White, M. C.; Burke, M. D.; Peleg, S.; Brem, H.;
Posner, G. H. Bioorg. Med. Chem. 2001, 9, 1691–1699;
(b) Posner, G. H.; Crawford, K. R.; Peleg, S.; Welsh,
J. E.; Romu, S.; Gewirtz, D. A.; Gupta, M. S.; Dolan,
P.; Kensler, T. W. Bioorg. Med. Chem. 2001, 9, 2365–
2371.
For the synthesis of 5 we designed a slightly different
route (Scheme 2).
5. (a) Leyes, G. A.; Okamura, W. H. J. Am. Chem. Soc.
1982, 104, 6099–6105; (b) Sardina, F. J.; Mourin˜o, A.;
Castedo, L. J. Org. Chem. 1986, 51, 1264–1269.
6. Lythgoe, B.; Roberts, D. A.; Waterhouse, I. J. Chem.
Soc., Perkin 1 1977, 2608–2612.
Selective tosylation of the primary alcohol of diol 3
gave tosylate 16 in 93% yield, and protection of the
secondary alcohol of 16 (99%), followed by a Korn-
blum reaction, afforded a 68% yield of aldehyde 18,11
from which a mixture of epimeric aldehydes was
obtained by equilibration under basic conditions.
Reduction of this mixture with NaBH4 gave the corre-
sponding C20- epimeric alcohols 19 and 20,12 chro-
matographic separation of which afforded the desired
alcohol 20 in 44% yield (epimer 19 was obtained in
31% yield). Oxidation of 20 gave aldehyde 218 in 75%
yield, reaction of the latter with the anion obtained by
treatment of 227 with n-butyllithium afforded propar-
gyl alcohol 238 in 70% yield, and PDC oxidation of 23
gave a-acetylenic ketone 248 (63%). As hoped, reaction
of 24 with aqueous hydrazine afforded a good yield
(84%) of compound 5,10b which bears the desired side
chain.
7. Torneiro, M.; Fall, Y.; Castedo, L.; Mourin˜o, A. J.
Org. Chem. 1997, 62, 6344–6352.
8. All new compounds exhibited satisfactory 1H and 13C
NMR, analytical, and/or high resolution mass spectral
data.
9. Cabarrocas, G.; Ventura, M.; Maestro, M.; Mah´ıa, J.;
Villalgordo, J. M. Tetrahedron: Asymmetry 2000, 11,
2483–2493.
10. (a) Compound 4: 1H NMR (300 MHz, CDCl3), l: 5.8
(1H, s), 2.75 (1H, m), 2.47 (1H, dd, J=11.4, 7.1), 1.55
(6H, s, CH3-26 and CH3-27), 1.27 (3H, d, J=6.9, CH3-
21), 0.90 (9H, t, J=7.9, SiCH2CH3), 0.70 (3H, s, CH3-
18), 0.53 (6H, q, J=7.9, SiCH2CH3); 13C NMR
(CDCl3), l: 211.75 (CꢀO), 156.63 (C), 153.58 (C), 97.96
(Cꢀ), 71.24 (C-25), 61.89, 56.70, 49.71 (C-13), 40.89
(CH2), 38.86 (CH2), 35.76, 31.56, 27.82 (CH2), 24.01
(CH2), 21.16, 18.94 (CH2), 12.38, 6.92, 6.32 (CH2).
HRMS calcd for C24H42N2O2Si: 419.3049; found:
419.3078; (b) Compound 5: white solid, mp 119–120°C.
1H NMR (300 MHz, CDCl3), l: 5.93 (1H, s), 4.55
(2H, s, OCH2O), 3.97 (1H, br s, CH-8), 3.31 (3H, s,
OCH3), 2.72 (1H, dd, J=10.5, 6.9), 1.97 (1H, d, J=
12.3), 1.80 (1H, m), 1.65 (1H, m), 1.59 (6H, s, CH3-26
and CH3-27), 1.22 (3H, d, J=6.9, CH3-21), 0.97 (3H, s,
CH3-18), 0.86 (9H, s, t-BuSi), −0.02 (3H, s, MeSi),
−0.04 (3H, s, MeSi); 13C NMR (CDCl3), l: 154.18 (C),
153.55 (C), 99.94 (CHꢀ), 92.18 (CH2), 74.18 (C), 69.35,
56.92, 55.32, 53.03, 42.19, 40.66 (CH2), 35.00 (C), 34.39
(CH2), 28.04, 27.81 (CH2), 265.79, 22.89 (CH2), 20.94,
18.00, 17.65 (CH2), 11.63, −4.81 (SiCH3), −5.18
(SiCH3). LRMS; m/z (I, %): 464 (M+, 3), 404 (64), 377
(28), 345 (100), 271 (19), 135 (25). HRMS calcd for
C26H48N2O3Si: 464.3434; found: 464.3422. Anal. calcd
for C26H48N2O3Si: C, 67.19; H, 10.41; N, 6.03; found:
C, 66.92; H, 10.50; N, 6.33.
The synthesis of analogues 6 and 7, and of a series of
derivatives with substituents on the pyrazole ring,13 is
currently under way in our laboratory with a view to
their biological evaluation.
Acknowledgements
This work was supported by a grant from the Vicerec-
torate for Research of the University of Vigo. The
assistance of the CACTI NMR service of the Univer-
sity of Vigo is gratefully acknowledged. We are also
grateful to Solvay Pharmaceuticals (Weesp, The
Netherlands) for the gift of starting materials.
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Y. Fall et al. / Tetrahedron Letters 43 (2002) 1433–1436
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