Y. Fall et al. / Tetrahedron Letters 42 (2001) 7815–7817
7817
O
H
OTs
OTES
HO
2
H
TBAF/THF
1
TBSO
1) LAH
2) TBAF/THF
OH
H
3
HO
Scheme 3. Synthesis of vitamin D analogues 2 and 3.
3, respectively; see Scheme 3). Gratifyingly, reaction of
1 with TBAF afforded 27 in one pot and 70% yield through
desilylation and in situ cyclization; while its reaction with
LAH(10equivLAH, ether, 0°Ctort, overnight), followed
by desilylation, afforded the (22R)-22-methyl analogue
3 (68% yield, two steps).
istry of vitamin D, see: (a) Vitamin D: Chemistry, Biol-
ogy and Clinical Applications of the Steroid Hormone;
Norman, A. W.; Bouillon, R.; Thomasset, M., Eds;
Vitamin D Workshop, Inc.: Riverside, CA, 1997; (b)
Feldman, D.; Glorieux, F. H.; Pike, J. W. Vitamin D;
Academic Press: San Diego, 1997; (c) Zhu, G.-D.; Oka-
mura, W. H. Chem. Rev. 1995, 95, 1877–1952.
In conclusion, we have developed a potentially powerful
method by which a large series of vitamin D analogues
with modifications affecting C-22 can be synthesized from
a common precursor in which the vitamin D triene system
is already present. This method will undoubtedly facilitate
investigation of the relationship between the structure of
an analogue and its activity at vitamin D receptors, and
we are currently using it to prepare a relevant series for
biological evaluation. Finally, we note that tosylate 1
appears to be eminently suitable for the application of
the solid support vitamin D synthesis procedures recently
developed by Takahashi and co-workers,8 and we are
accordingly pursuing the synthesis of resin-bound 1.
2. Figade`re, B.; Norman, A. W.; Henry, H. L.; Koeffler,
H. P.; Zhou, J.-Y.; Okamura, W. H. J. Med. Chem.
1991, 34, 2452–2463.
3. (a) Yamamoto, K.; Takahashi, J.; Hamano, K.;
Yamada, S.; Yamaguchi, K.; DeLuca, H. F. J. Org.
Chem. 1993, 58, 2530–2537; (b) Yamamoto, K.; Yan
Sun, W.; Ohta, M.; Hamada, K.; DeLuca, H. F.;
Yamada, S. J. Med. Chem. 1996, 39, 2727–2737.
4. Fall, Y.; Ferna´ndez, C.; Vitale, C.; Mourin˜o, A. Tetra-
hedron Lett. 2000, 41, 7323–7326.
5. (a) Vitale, C.; Fall, Y.; Carril, A. G.; Rey, M. A.;
Moma´n, E.; Mourin˜o, A. In Vitamin D: Chemistry,
Biology and Clinical Applications of the Steroid Hormone:
Proceedings of the Tenth Workshop on Vitamin D; Nor-
man, A. W.; Bouillon, R.; Thomasset, M., Eds.; Univer-
sity of California, Printing and Reprographics: Riverside,
1997; p. 34; (b) Fujishima, T.; Zhaopeng, L.; Kouno,
K.; Nakagawa, K.; Okano, T.; Yamaguchi, K.;
Takayama, H. Bioorg. Med. Chem. 2001, 9, 525–535.
6. (a) Sardina, F. J.; Mourin˜o, A.; Castedo, L. J. Org.
Chem. 1986, 51, 1264–1269; (b) Mascaren˜as, J. L.;
Mourin˜o, A.; Castedo, L. J. Org. Chem. 1986, 51, 1269–
1272.
Acknowledgements
This work was supported by a grant from the Vicerrec-
torado de Investigacio´n of the University of Vigo. The
CACTI NMR service of the University of Vigo is
gratefully acknowledged. We are also grateful to Solvay
Pharmaceuticals (Weesp, The Netherlands) for the gift of
starting materials.
7. Small samples of this analogue are available upon
request for biological evaluation.
8. (a) Doi, T.; Hijikuro, I.; Takahashi, T. J. Am. Chem.
Soc. 1999, 121, 6749–6750; (b) Hijikuro, I.; Doi, T.;
Takahashi, T. J. Am. Chem. Soc. 2001, 123, 3716–3722.
References
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