A short practical approach to 24R,25-dihydroxyvitamin D3

Article abstract of DOI:10.1016/j.jsbmb.2010.03.071

A synthesis of the vitamin D₃ metabolite 24R,25-dihydroxyvitamin D₃ (1) by Lythgoe's Wittig-Horner approach is described. The key step of the synthesis is the stereocontrolled introduction of the 24-hydroxyl group by a palladium(0)-induced [3,3]-sigmatropic rearrangement on a 22R-allylic acetate (7).

Full text of DOI:10.1016/j.jsbmb.2010.03.071

Journal of Steroid Biochemistry & Molecular Biology 121 (2010) 43–45
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ଝ
A short practical approach to 24R,25-dihydroxyvitamin D3
Daniel Nicolettia, Carlos Gregorioa, Antonio Mourin˜oa,1, Miguel Maestrob,∗
a Departamento de Química Orgánica y Unidad Asociada al C.S.I.C., Universidad de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
b Departamento de Química Fundamental, Universidad de A Coru˜na, E-15071 A Coru˜na, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of the vitamin D3 metabolite 24R,25-dihydroxyvitamin D3 (1) by Lythgoe’s Wittig–Horner
approach is described. The key step of the synthesis is the stereocontrolled introduction of the 24-
hydroxyl group by a palladium(0)-induced [3,3]-sigmatropic rearrangement on a 22R-allylic acetate (7).
Received 23 October 2009
Received in revised form 8 March 2010
Accepted 25 March 2010
© 2010 Elsevier Ltd. All rights reserved.
Keywords:
24R,25-Dihydroxyvitamin D3
Wittig–Horner approach
[3,3]-Sigmatropic rearrangement
Catalytic palladium(0)
1. Introduction
A few syntheses of 24R,25-dihydroxyvitamin D3 have been car-
ried out in the past by the biomimetic classical route [16–26].
The principal pathway of vitamin D3 metabolism involves
hydroxylation of vitamin D3 (Fig. 1) in the liver and
In 1998 Stepanenko and Wicha [27] described the synthesis
of this metabolite using an optically active hydroxylactone to
build the side chain. Shortly afterwards, an alternative route to
24R,25(OH)2D3 was completed by Kütner and co-workers [28]
using a diastereoselective ␣-hydroxylation of a side chain ester as
the key step. In 2002 Sarandeses described a synthesis of 24R,25-
dihydroxyvitamin D3 using an ultrasonically induced aqueous
conjugate addition of an iodide to a dioxolanone or oxazolidinone
to generate the stereocenter at C24 [29a,30] and Fernández et al.
developed a method to construct the side chain using aminoacids
[31].
a
second hydroxylation of the resulting 25-hydroxyvitamin D3
[25(OH)D3] either at C1 or C24 in the kidney to produce 1␣,25-
dihydroxyvitamin D3 [1␣,25(OH)2D3] or 24R,25-dihydroxyvitamin
D3 [1, 24R,25(OH)2D3] [1–5]. While 1␣,25(OH)2D3 is considered
the hormonally active form of vitamin D3 responsible for the
regulation of gene transcription in over 30 target organs, only a
few biological actions have also been attributed to 24R,25(OH)2D3
[6–9], namely activation of extracellular signal-related kinase
phosphorylation [10], regulation of bone fracture healing [6,10],
inhibition of rapid actions of 1␣,25(OH)2D3 on stimulation of cal-
cium transport in perfused duodena, as well as activation of protein
kinases C and A [11], mediation of rapid non-genomic responses
in intestinal cells [12,13], regulation of cartilage and bone via
autocrine mechanisms [14], and inhibition of colon carcinogene-
sis [15]. 24R,25-Dihydroxyvitamin D3 (1) are also intermediates on
a catabolic pathway finally leading to excretion of calcitroic acid
[4].
We disclose here a short and practical synthesis of 24R,25-
dihydroxyvitamin D3 (1) that involves the construction of the
vitamin
D triene system employing Lythgoe’s Wittig–Horner
approach [32] (coupling between ketone 2 and the phosphine oxide
anion 3) (Fig. 2).
2. Results and discussion
Our synthesis of 24R,25-dihydroxyvitamin D3 (1) uses aldehyde
4, which can be prepared in 50% yield from commercially avail-
able vitamin D2 [33]. The addition of alkenyl lithium reagent 5 [34]
to aldehyde 4 proceeded stereoselectively to afford, after medium
pressure liquid chromatography separation from the minor iso-
mer, the known alcohol 6a in 75% yield (Fig. 3) [34]. Alcohol
6a was then acetylated in the usual way to the corresponding
acetate 7 in 93% yield. Treatment of 7 with a catalytic amount
ଝ
Special issue selected article from the 14th Vitamin D Workshop held at Brugge,
Belgium on October 4–8, 2009.
∗
Corresponding author. Tel.: +34 607556067; fax: +34 981167065.
E-mail addresses: antonio.mourino@usc.es (A. Mourin˜o), qfmaestr@udc.es
(M. Maestro).
1
Tel.: +34 600942435; fax: +34 981595012.
0960-0760/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jsbmb.2010.03.071

44
D. Nicoletti et al. / Journal of Steroid Biochemistry & Molecular Biology 121 (2010) 43–45
Fig. 3. (a) THF, −78 ◦C (75%); (b) Ac2O, Et3N, DMAP, CH2Cl2, 0 ◦C, 30 min (93%); (c)
(CH3CN)2PdCl2 (8 mol%), THF, rt, 48 h.
Fig. 1. Biosynthesis and metabolism of vitamin D3.
of bis(acetonitrile)palladium(II) chloride in THF [35] afforded an
inseparable mixture of acetates 8a and 8b in 75% yield (ratio 85:15)
together with the elimination products 9a and 9b in 15% yield
(ratio 80:20) (Fig. 3). A formal [3,3]-sigmatropic-type rearrange-
ment has been previously proposed for the palladium(0)-assisted
rearrangement of allylic acetates [36].
Catalytic hydrogenation of mixture of acetates 8 followed by
purification by flash-chromatography provided alcohol 10a (85%),
which was desilylated with hydrofluoric acid to diol 11 (93%).
Pyridinium dichromate oxidation of 11 gave the desired ketone 2
(92%), which was coupled with phosphine oxide anion 3 to afford
[32], after desilylation and saponification, the desired metabolite
24R,25-dihydroxyvitamin D3 (1) [29b] in 82% yield (Fig. 4).
Fig. 4. Synthesis of 24R,25(OH)2D3. (d) H2, PtO2, EtOAc (85%); (e) HF (48%),
CH3CN–CH2Cl2, 72 h (93%); (f) PDC, CH2Cl2 (92%); (g) THF, −78 ◦C (96%); (h) TBAF,
THF; NaOMe, THF (88%).
Acknowledgements
We thank the Spanish Ministry of Education and Science
(Projects SAF2004-1885 and SAF2007-67205) and Xunta de Gali-
cia (INCITE08PXIB-209130PR, ACEUIC-2006/XA050, GRC-2006/65)
for financial support and Dishman-Netherlands B.V. for the gift of
vitamin D2. D.N. thanks the Argentine National Council for Scientific
Research (CONICET) for a postdoctoral fellowship.
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Fig. 2. Synthetic strategy (Wittig–Horner approach).

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