Synthesis of C-19-functionalized 1α-hydroxyvitamin D2 analogues via ring-closing metathesis

Article abstract of DOI:10.1021/ol027406w

(Matrix presented) A heteroatom-tethered regioselective ring-closing metathesis reaction was used for the C-19 functionalization of lot-hydroxy-5,6-trans-vitamin D₂ analogues. Applications of the reaction to form a range of analogues by manipul

Full text of DOI:10.1021/ol027406w

ORGANIC
LETTERS
2003
Vol. 5, No. 5
669-672
Synthesis of C-19-Functionalized
1r-Hydroxyvitamin D Analogues via
2
Ring-Closing Metathesis
Mahmood Ahmed, Catherine E. Atkinson, Anthony G. M. Barrett,*
Karine Malagu, and Panayiotis A. Procopiou
Department of Chemistry, Imperial College of Science, Technology and Medicine,
London SW7 2AY, U.K., and GlaxoSmithKline, Research and DeVelopment Ltd.,
Medicines Research Centre, Gunnels Wood Road, SteVenage,
Hertfordshire, SG1 2NY, U.K.
agmb@ic.ac.uk
Received December 4, 2002
ABSTRACT
A heteroatom-tethered regioselective ring-closing metathesis reaction was used for the C-19 functionalization of 1r-hydroxy-5,6-trans-vitamin
D analogues. Applications of the reaction to form a range of analogues by manipulation of the tether using both organolithium reagents and
2
Diels−Alder cycloadditions are described.
It has long been established that the hormonally active form
of vitamin D3, 1R,25-dihydroxyvitamin D3 1, acts as a
regulator in calcium and phosphate homeostasis.1 More recent
discoveries that the hormone can promote cell differentiation
while inhibiting tumor cell proliferation led to the speculation
that 1 could be used in the treatment of diseases such as
leukemia and psoriasis.2 However, at the doses of 1 required
to produce therapeutically useful results, severe hypercal-
cemia is observed as a side effect.3 Therefore, the synthesis
of analogues that show the required discrimination between
antiproliferation and calcemic activities has been the focus
of much research. Structural changes in the A, C, and D
(1) Norman, A. W. Vitamin D the Calcium Homeostatic Steroid
Hormone; Academic Press: New York, 1979.
(2) (a) Zhou, J. Y.; Norman, A. W.; Chen, D. L.; Sun, G. W.; Uskokovic,
M.; Koeffler, H. P. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 3929. (b) Anzano,
M. A.; Smith, J. M.; Uskokovic, M. R.; Peer, C. W.; Mullen, L. T.; Letterio,
J. J.; Welsh, M. C.; Shrader, M. W.; Logsdon, D. L.; Driver, C. L.; Brown,
C. C.; Roberts, A. B.; Sporn, M. B. Cancer Res. 1994, 54, 1653. (c) Colston,
K. W.; Chander, S. K.; Mackay, A. G.; Coombes, R. C. Biochem.
Pharmacol. 1992, 44, 693.
Figure 1. Structures of 1R,25-dihydroxyvitamin D3 1 and vitamin
D2 2.
rings as well as in the side chain region have led to analogues
exhibiting the above discrimination.3,4 Thus far, however,
(3) Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr. ReV. 1995,
16, 200.
10.1021/ol027406w CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/01/2003

very few examples of C-19 functionalized analogues have
been reported.5
Scheme 2. RCM with a Silyl Ether Tethera
The use of tethered heteroatoms such as silicon and boron
in ring-closing metathesis (RCM) reactions has been shown
to be synthetically very useful in the preparation of di- and
trisubstituted alkenes.6,7 We considered that this methodology
could be applied to the regiospecific C-19 monosubstitution
of 1R,25-dihydroxyvitamin D3 1. The desired selectivity
should be achieved due to the greater susceptibility of the
terminal alkenes to RCM and the proximity of the tethered
allylic substituent. Removal of the heteroatom tether fol-
lowing RCM should afford a range of functionalized C-19
alkenes. Herein we report preliminary studies of this strategy
(Scheme 1) that are focused on the analogous 1R-hydroxy-
Scheme 1. Heteroatom Tethered RCM with 5,6-trans-vitamin
D Derivatives
a Reagents and conditions: (i) CH2dCHCH2SiMe2Cl, Et3N,
CH2Cl2, 25 °C 12 h, 76%; (ii) 8, CH2Cl2, reflux, 3 h, 82%.
To show that the selective RCM was not limited to the
use of silicon as a tether, the phosphorus analogue 10 was
prepared by reaction of sterol 6 with the phosphonyl chloride
12 and triethylamine. Subsequent RCM afforded the cyclic
phosphonate 11 in an excellent 79% yield (Scheme 3).
Scheme 3. RCM with a Phosphonate Ester Tethera
5,6-trans-vitamin D2 6, which can be easily prepared from
commercially available ergocalciferol 2.8
Reaction of alcohol 6 with allylchlorodimethylsilane in
the presence of triethylamine gave the silyl ether 7 in a 76%
yield. Ring-closing metathesis was performed by heating a
solution of 7 in dichloromethane at reflux with the ruthenium
carbene 8 (20 mol %, Scheme 2). Gratifyingly, the only
isolated product was the desired adduct 9 (82%) formed from
reaction between the two terminal alkenes. It is noteworthy
that the delicate triene system of the steroid survived the
reaction without any significant decomposition or rearrange-
ment reactions.
a Reagents and conditions: (i) 12, Et3N, CH2Cl2, 25 °C, 12 h,
60%; (ii) 8, CH2Cl2, reflux, 3 h, 79%.
(4) (a) Muralidharan, K. R.; De Lera, A. R.; Isaeff, S. D.; Norman, A.
W.; Okamura, W. H. J. Org. Chem. 1993, 58, 1895. (b) Perlman, K. L.;
Sicinski, R. R.; Schnoes, H. K.; DeLuca, H. F. Tetrahedron Lett. 1990, 31,
1823. (c) Kanzler, S.; Halkes, S.; van de Velde, J. P.; Reischl, W. Bioorg.
Med. Chem. Lett. 1996, 6, 1865.
With the RCM product 9 in hand, several methods were
used to transform the product to afford a variety of C-19
functionalized analogues. We expected that on Tamao
oxidation9 the diol 13 should be formed as the major product
(5) (a) Yamada, S.; Suzuki, T.; Takayama, H. Tetrahedron Lett. 1981,
22, 3085. (b) Yamada, S.; Nakayama, K.; Takayama, H.; Itai, A.; Iitaka,
Y. J. Org. Chem. 1983, 48, 3477. (c) Addo, J. K.; Ray, R. Steroids 1998,
63, 218. (d) Swamy, N.; Addo, J. K.; Ray, R. Bioorg. Med. Chem. Lett.
2000, 10, 361. (e) Addo, J. K.; Swamy, N.; Ray, R. Bioorg. Med. Chem.
Lett. 2002, 12, 279.
(6) (a) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757. (b)
Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38, 7861.
(7) Micalizio, G. C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2002, 41,
152.
(8) (a) Andrews, D. R.; Barton, D. H. R.; Cheng, K. P.; Finet, J. P.;
Hesse, R. H.; Johnson, G.; Pechet, M. M. J. Org. Chem. 1986, 51, 1635.
(b) Calverley, M. J. Tetrahedron 1987, 43, 4609.
670
Org. Lett., Vol. 5, No. 5, 2003

(Scheme 4). However, when 9 was allowed to react with
hydrogen peroxide and a fluoride source in a variety of
Scheme 5. Diels-Alder Cycloadditions of Tetraene 14a
Scheme 4. Tetraene Synthesis via Peterson Olefinationa
a Reagents and conditions: (i) H2O2, KF, DMF, 25 °C, 3 h, 50%;
(ii) Bu4NF, THF, 25 °C, 15 h, 64%.
a Reagents and conditions: (i) Cookson’s reagent, EtOAc, 0 °C,
30 min, 75%; (ii) (NC)2CdC(CN)2 19, CDCl3, 25 °C, 24 h, 67%;
(iii) air, seco-porphyrazine 20, CDCl3, 25 °C, 8 h, 8%.
solvents, none of the expected product 13 was isolated.
Instead, in DMF as solvent, the tetraene 15 (50%) was
formed, presumably by a vinylogous Peterson olefination
reaction.10 Consistent with this hypothesis, reaction of the
cyclic adduct with tetrabutylammonium fluoride in THF gave
the deprotected tetraene 14 in 64% yield.
While the outcome of the oxidation reaction was not the
expected one, the tetraene 14 could still be used to form
C-19-functionalized derivatives via Diels-Alder reactions.
A variety of dienophilies were examined; however, only
highly electron-deficient dienophiles were effective (Scheme
5). Both Cookson’s dienophile11 and tetracyanoethylene 19
afforded the Diels-Alder cycloadducts 16 and 17 in good
yields. In both cases, no significant diastereoselectivity of
reaction was observed and both C-1 isomers were formed
in a 1:1 ratio (Scheme 5). Singlet oxygen, generated using
the seco-porphyrazine sensitizer12 20 (Figure 2), was allowed
to react with the tetraene 14 to form the endoperoxide 18,
although due to the instability of the product, the isolated
yield was low on chromatographic purification. The reactions
to produce adducts 17 and 18 were carried out in deuterio-
chloroform to facilitate monitoring by NMR spectroscopy.
Figure 2. seco-Porphyrazine sensitizer 20.
(9) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694.
(10) (a) Takano, S.; Otaki, S.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1985, 485. (b) Angell, R.; Parsons, P. J.; Naylor, A.; Tyrrell, E.
Synlett 1992, 599.
(11) Cookson, R. C.; Gilani, S. S. H.; Stevens, I. D. R. Tetrahedron
Lett. 1962, 3, 615.
(12) Baum, S. M.; Trabanco, A.-A.; Garrido Montalban, A.; Micallef,
A. S.; Zhong, C.; Meunier, H. G.; Suhling, K.; Phillips, D.; White, A. J.
P.; Williams, D. J.; Barrett, A. G. M.; Hoffman, B. M. J. Org. Chem. 2003,
68, in press.
The manipulation of the silicon tether was also achieved
using organolithium reagents. Reaction of silyl ether 9 with
phenyl- and methyllithium gave, after hydrolytic workup,
the adducts 21 and 22 (Scheme 6).
In summary, we have shown that heteroatom-tethered
regioselective ring-closing metathesis reactions can be used
Org. Lett., Vol. 5, No. 5, 2003
671

pared. Application of the process to form a range of
analogues has been shown by the manipulation of the silicon
tether using both substitution with phenyllithium and me-
thyllithium or by elimination and subsequent Diels-Alder
cycloaddition reactions.
Scheme 6. Ring Cleavage of Silyl Ether 9 Using PhLi and
MeLia
Acknowledgment. We thank the EPSRC for their support
of this research, Glaxo SmithKline for the generous endow-
ment (to A.G.M.B.) and for support of our research on alkene
metathesis, the Royal Society and Wolfson Foundation for
a Royal Society-Wolfson Research Merit Award (to
A.G.M.B.), the Ramsay Memorial Fellowship Trust for
postdoctoral support (to C.E.A.), and the Wolfson Foundation
for establishing the Wolfson Centre for Organic Chemistry
in Medical Science at Imperial College. We also thank Sven
Baum (Imperial College) for providing a sample of seco-
porphyrazine 20.
a Reagents and Conditions: (i) RLi, PhMe, -30 °C, 2 h.
for the C-19 functionalization of 1R-hydroxy-trans-vitamin
D2 analogues.13 Using this method, both silicon- and
phosphorus-tethered systems have been successfully pre-
Supporting Information Available: All experimental
procedures, and characterization of all novel compounds 7,
9-11, 14, 15, 16 (both isomers), 17, 18, 21, and 22 including
copies of 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) All new compounds were characterized by spectroscopic data (1H
NMR, 13C NMR, IR, UV, and LRMS) and HRMS except for 11 (1H NMR,
13C NMR, UV, LRMS .and HRMS), 18 (1H NMR, 13C NMR, IR, and UV),
1
and 17 for which H NMR, 13C NMR, and LRMS were obtained, due to
instabilities of the products.
OL027406W
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Org. Lett., Vol. 5, No. 5, 2003