An efficient synthesis of the 25-hydroxy Windaus-Grundmann ketone

Article abstract of DOI:10.1016/S0040-4039(00)01224-7

A short and efficient synthesis of the 25-hydroxy Windaus-Grundmann ketone from the Inhoffen-Lythgoe diol is described (seven steps, 70% overall). The most relevant feature of the synthesis is the preparation of the Wittig reagent 3 from cheap and commerc

Full text of DOI:10.1016/S0040-4039(00)01224-7

Tetrahedron Letters 41 (2000) 7337±7340
An ecient synthesis of the 25-hydroxy
Windaus±Grundmann ketone
Yagamare Fall, * Cristian Vitale and Antonio Mourin
Ä
ob
a,
b
aDepartamento de QuõÂmica FõÂsica y QuõÂmica Org a nica, Facultade de Ciencias, Universidad de Vigo,
6200 Vigo, Spain
Departamento de QuõÂmica Org a nica, y Unidad Asociada al CSIC, Universidad de Santiago de Compostela,
5706 Santiago de Compostela, Spain
3
b
1
Received 31 May 2000; accepted 18 July 2000
Abstract
A short and ecient synthesis of the 25-hydroxy Windaus±Grundmann ketone from the Inho€en±
Lythgoe diol is described (seven steps, 70% overall). The most relevant feature of the synthesis is the
preparation of the Wittig reagent 3 from cheap and commercially available starting materials. Pure 3 can
be obtained in multigram quantities for achieving clean and ecient Wittig reactions. # 2000 Elsevier
Science Ltd. All rights reserved.
1
a,25-Dihydroxyvitamin D [1a, 1a,25-(OH) -D , calcitriol], the hormonally active form of
3
2
3
1
vitamin D3 (1b, calciferol), has a much broader spectrum of activities than originally thought
and has been used together with its analogues in the treatment of a diverse range of human
illnesses, including osteoporosis, psoriasis, cancer and AIDS. The 25-hydroxy Windaus±
Grundmann ketone (2a) has proven useful in the convergent synthesis of 1a.6
2
3
4
5
*
Corresponding author. Fax: 34 986 81 23 82; e-mail: yagamare@uvigo.es
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01224-7

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338
As outlined in Scheme 1, our synthetic approach takes advantage of the readily available
7
8
Inho€en±Lythgoe diol (6), a direct precursor of the aldehyde 4. The Wittig reaction between the
aldehyde 4 and the ylide 3, followed by hydrogenation of the resulting ole®n, would a€ord the
target compound 2a.
Scheme 1.
The use of the ylide 3 to perform the Wittig reaction is not unprecedented. Indeed, Salmond et
9
al. reported the ®rst synthesis of 3 and its use for the preparation of 25-hydroxycholesterol.
Salmond's synthesis of 3 is described in Scheme 2.
Methylenetriphenylphosphorane 8, was prepared in tetrahydrofuran from methyltriphenyl-
ꢀ
phosphonium bromide 7 and n-butyllitium. Reaction of 8 with isobutene oxide at 0 C gave the
betaine 10, which reacted with a further mol of n-butyllitium to yield the ylide 3. Salmond and
co-workers have already discussed the problems associated with the in situ preparation of the
Wittig reagent 3 according to the sequence developed in Scheme 2, this in order to get the reagent
3 as pure as possible, and hence pointing out that this sequence might be quite tricky and dicult
9
to achieve in order to get clean and ecient reactions with aldehydes.
Scheme 2.
Indeed, Andrews et al.10 reported the preparation of ylide 3 with low purity using Salmond's
methodology (Scheme 3). They modi®ed the method using phenyllithium as a base instead of
n-butyllithium. The ylide 3 thus obtained was acidi®ed with hydrogen bromide to give the
hydroxyphosphonium salt 11 in a rather low yield (58%). The latter resisted all attempts at
crystallization, and was then treated with a concentrated aqueous solution of sodium tetraphenyl
borate to yield phosphonium tetraphenyl borate 12 as a pure stable salt which was used to
generate a better quality ylide 3 by treatment with phenyllithium (2 equiv.).
Scheme 3.

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339
To overcome all of the problems associated with the preparation of 3, we designed an alternative
and straightforward synthesis using the cheap and commercially available ethyl 3-bromopropionate
(Scheme 4).
Scheme 4.
ꢀ
Reaction of 5 with methyl magnesium iodide (2 equiv.) in ether at 0 C a€orded the corresponding
bromoalcohol 13,11 which was treated with triphenylphosphine in re¯uxing acetonitrile to yield
quantitatively the phosphonium bromide 11 as a pure stable salt. Treatment of 11 with methyl-
ꢀ
12
lithium (2 equiv.) in ether at ^20 C provided the ylide 3.
Reaction of 3 with the aldehyde 4 (Scheme 5) gave the Á E-25-hydroxy compound 14 as the
22
only detectable isomer, in 95% yield. Hydrogenation of 14 (H , PtO , EtOH), followed by
2
2
desilylation and oxidation a€orded the 25-hydroxy Windaus±Grundmann ketone (2a) (86%
yield, four steps from the aldehyde 4).
Scheme 5.
In conclusion, we have found an excellent method for the preparation of salt 11 as a pure and
stable compound from the cheap and commercially available ethyl 3-bromopropionate. The
usefulness of compound 11 is illustrated by the ecient and multigram synthesis of 25-hydroxy
Windaus±Grundmann ketone. This method is useful for the preparation of calcitriol analogues
modi®ed at the rings or the triene system.
Acknowledgements
We are grateful to the DGES (Spain, project PM97-0166) for ®nancial support and Solvay
Pharmaceuticals (Weesp, The Netherlands) for the gift of starting material.

7
340
References
1
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1
1
1
1. Hesse, R. H. EP 78, 704, 1983 (Chem. Abs. 1983, 99, 176164q).
2. The ylide 3 was prepared as follows: To a solution of the bromoalcohol 13 (3 g, 17.9 mmol) in acetonitrile (40 ml)
was added triphenylphosphine (25g, 96 mmol). The mixture was re¯uxed for 24 h. The acetonitrile was evaporated
to give a solid. Diethylether (300 ml) was added and the mixture stirred at rt for 3 h. After removal of the ether by
®ltration or decantation the resulting solid was stirred again with ether (300 ml) for 3 h and the ether removed.
This procedure allows complete removal of excess of triphenylphosphine by dissolving it in ether and should be
repeated until a ®ne powder was obtained. Filtration and drying yielded quantitatively the pure phosphonium salt
ꢀ
11 (7.7 g, mp: 164 C). An alternative to this procedure is to dissolve the solid mixture of the phosphonium salt 11
and triphenylphosphine in dichloromethane and reprecipitate 11 by adding ether. The ylide 3 was generated as
ꢀ
follows: To a suspension of phosphonium salt 11 (7 g, 16.3 mmol) in ether (100 ml) at ^20 C was added
Methyllithium (2 equiv.) and the mixture was allowed to reach rt over 12 h. The resulting red solution of ylide 3
ꢀ
was recooled to ^20 C and was ready to be used for the Wittig reaction.