A key intermediate for the convenient synthesis of series of vitamin D3 analogues with modified side chains

Article abstract of DOI:10.1016/S0040-4039(01)01673-2

Tosylate 1, which features the vitamin D triene unit, was stereoselectively synthesized from commercially available starting materials. This key intermediate undergoes a very efficient one-pot, two-step reaction with tetrabutyl ammonium fluoride to afford vitamin D analogue 2, which bears a cyclic side chain. Reaction of 1 with lithium aluminium hydride and removal of the silyl protecting groups affords the 22-methylated vitamin D analogue 3.

Full text of DOI:10.1016/S0040-4039(01)01673-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7815–7817
A key intermediate for the convenient synthesis of series of
vitamin D3 analogues with modified side chains
Yagamare Fall,a,* Carlos Fernandez,a Victoria Gonza´leza 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 C.S.I.C., Universidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Received 9 August 2001; revised 5 September 2001; accepted 6 September 2001
Abstract—Tosylate 1, which features the vitamin D triene unit, was stereoselectively synthesized from commercially available
starting materials. This key intermediate undergoes a very efficient one-pot, two-step reaction with tetrabutyl ammonium fluoride
to afford vitamin D analogue 2, which bears a cyclic side chain. Reaction of 1 with lithium aluminium hydride and removal of
the silyl protecting groups affords the 22-methylated vitamin D analogue 3. © 2001 Elsevier Science Ltd. All rights reserved.
1a,25-Dihydroxyvitamin D3 (calcitriol, 4a) (Fig. 1) is
the hormonally active form of vitamin D3 (4b). Besides
regulating calcium homeostasis, it is also involved in
other cellular processes, including cell differentiation,
immune system regulation and gene transcription.1 The
latter function, mediated by the nuclear vitamin D
receptor (found in more than thirty different tissues and
cancer cell lines), raises the possibility of developing
1a,25-(OH)2-D3 analogues for specific therapeutic
applications.
In initial studies aimed at determining the topography
of the side chain of the receptor-bound hormone, Oka-
mura and co-workers synthesized new vitamin D ana-
logues possessing
a
side-chain made rigid by
incorporation of an aromatic ring.2 Later, Yamada and
co-workers3 synthesized a series of analogues with side
chains with restricted orientations (Fig. 2).
We have recently synthesized analogues with restricted
side chain conformations by a route based on the
retrosynthetic analysis depicted in Scheme 1,4 an
approach that also allows preparation of other ana-
logues with modified side chains, including Yamada’s.5
However, a rational design of such analogues requires
information about the conformation of the hydroxyl-
ated side-chain in the structure binding to the VDR
receptor(s).
However, since this strategy involves construction of
the triene unit on the CD fragment following the
introduction of the side chain, it is inconvenient if a
lengthy series of analogues with modified side chains
are to be prepared for systematic biological evaluation.
We have therefore, now examined the possibility of
preparing C22-modified analogues from a common
intermediate, in which the labile triene system is already
present, namely the tosylate 1. Compound 1 was
obtained by selective tosylation of the known diol 14 in
82% yield,4 PDC oxidation of the resulting tosyl alco-
hol 15 to ketone 16 (75%), and formation of the
vitamin D triene system in a 84% yield by reaction of
ketone 16 with the ylide derived from phosphine oxide
17,6 (Scheme 2).
R2
H
1a, R1 = R2 = OH
1b, R1 = OH, R2 = H
HO
R1
Figure 1.
To test the utility of compound 1 as a key intermediate,
we investigated its transformation in vitamin D ana-
logues with cyclic and 22-methylated side chains (2 and
* Corresponding author. Fax: 34 986 81 23 82; e-mail: yagamare@
uvigo.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01673-2

7816
Y. Fall et al. / Tetrahedron Letters 42 (2001) 7815–7817
HO
HO
OH
OH
HO
HO
H
H
H
H
OH
HO
OH
HO
OH
O
H
7
8
6
5
Figure 2. Yamada’s type analogues.
CN
Y
X
Y
X
H
HO
H
O
H
Ph2PO
Br
HO
OH
OTES
TBSO
OTBS
OH
Scheme 1. Retrosynthetic analysis for 13a and 13b.
CN
TsCl/ pyr, 0ßC
82%
OTES
H
H
HO
14
HO
10
OTs
OTs
OTES
OTES
PDC, CH2Cl2
75%
H
H
O
15
HO
16
OTs
Ph2PO
OTES
TBSO
17
H
nBuli, THF, -78ßC
84%
1
TBSO
Scheme 2. Synthesis of key intermediate 1.

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
1. For a general review on the chemistry and/or biochem-