70
A. Rumbo et al. / Journal of Steroid Biochemistry & Molecular Biology 121 (2010) 68–70
organozinc derivative and its subsequent addition of the latter to
cyclopropylaldehyde in the presence of (+)-DAIB. After desilylation,
this procedure afforded the desired compound calcipotriol (2) in
55% overall yield from 3 (Scheme 4).
In conclusion, we have developed a short and efficient synthesis
of the clinically important drug calcipotriol from the Lythgoe-
Inhoffen diol. A key feature of this synthesis is the generation of
the C24 stereocenter by (+)-DAIB-catalyzed addition of alkenylzinc
to aldehyde, which works despite the presence of the labile vita-
min D triene system. Application of this strategy to the synthesis
of other vitamin D metabolites and analogs will be reported in due
course.
(c) M.M. Kabat, R. Radinov, The practical synthesis of vitamin D analogs. A chal-
lenge for process research, Curr. Opin. Drug Discov. Dev. 4 (2001) 808–833;
(d) C. Carlberg, A. Mourin˜o, New vitamin D receptor ligands, Expert Opin. Ther.
Pat. 13 (2003) 761–772.
[4] Quinkert (Ed.), Vitamin D Active Compounds Part III, Synform 5 (1987) 1–86.
[5] Y. Fall, M. Torneiro, L. Castedo, A. Mourin˜o, An efficient stereoselective synthesis
of 1␣,24(R)-dihydroxyvitamin D3 by the dienyne route, Tetrahedron 53 (1997)
4703–4714.
[6] J. Pérez-Sestelo, I. Cornella, O. de Un˜a, A. Mourin˜o, L. Sarandeses, Stereoselective
convergent synthesis of 24,25-dihydroxyvitamin D3 metabolites: a practical
approach, Chem. Eur. J. 8 (2002) 2747–2752.
[7] Calcipotriol (MC 903) is marketed with the name DOVONEX by Leo Pharma-
ceutical Co. To the best of our knowledge only one synthesis of calcipotriol
has been reported: M.C. Calverley, Synthesis of MC-903, a biologically-active
vitamin-D analog, Tetrahedron 43 (1987) 4609–4619.
[8] (a) J. Granja, M. Rey, J.A. Martínez, A. Fernanez, L. Castedo, A. Mourin˜o, in: A.W.
Norman, K. Schaefer, H.G. Grigoleit (Eds.), Vitamin D: Molecular, Cellular and
Clinical Endocrinology, Walter de Gruyter, Berlin, 1996, p. 46;
(b) P. Barbier, F. Bauer, P. Mohr, M. Muller, W. Pirson, EP 47866 (1998).
[9] (a) W. Oppolzer, R.N. Radinov, Catalytic asymmetric synthesis of secondary (E)-
allyl alcohols from acetylenes and aldehydes via (1-alkenyl)zinc intermediates.
Preliminary communication, Helv. Chim. Acta 75 (1992) 170–173;
(b) W. Oppolzer, R.N. Radinov, E. El-Sayed, Catalytic asymmetric synthe-
sis of macrocyclic (E)-allylic alcohols from -alkynals via intramolecular
1-alkenylzinc/aldehyde additions, J. Org. Chem. 66 (2001) 4766–4770;
(c) For a review on the subject, see: L. Pu, H. Yu, Catalytic asymmetric organ-
iczinc additions to carbonyl compounds, Chem. Rev. 101 (2001) 757–824;
(d) For the recent use of related amino alcohols in this process, see: S. Dahmen,
S. Braese, [2,2]Paracyclophane-based N,O-ligands in alkenylzinc additions to
aldehydes, Org. Lett. 3 (2001) 4119–4122.
Acknowledgements
We thank the Spanish MEC (Project SAF2007-67205) and
Xunta de Galicia (Project GRC-2006/65) for financial support, and
Dishman-Netherlands for the gift of vitamin D2. X.P.-G. thanks the
Xunta de Galicia for a predoctoral research grant. A.R. thanks the
Spanish Ministry of Education and Technology for a Ramon y Cajal
grant.
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