Site-selective modification of vitamin D analogue (Deltanoid) through a resin-based version of organoselenium 2,3-sigmatropic rearrangement

Article abstract of DOI:10.1021/ol101879k

Figure Presented. A site-selective modification of a vitamin D analogue (Deltanoid) through a two-step 2,3-sigmatropic rearrangement of organoselenium resin to prepare the key intermediate of calcipotriol has been developed. The polystyrene-supported sele

Full text of DOI:10.1021/ol101879k

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4431-4433
Site-Selective Modification of Vitamin D
Analogue (Deltanoid) through a
Resin-Based Version of Organoselenium
2,3-Sigmatropic Rearrangement
Wei-Ming Xu,* Jun He, Min-Qiang Yu, and Guo-Xiang Shen
College of Material Chemistry and Chemical Engineering, Hangzhou Normal
UniVersity, Hangzhou 310036, P. R. China
wmxu@zju.edu.cn
Received August 10, 2010
ABSTRACT
A site-selective modification of a vitamin D analogue (Deltanoid) through a two-step 2,3-sigmatropic rearrangement of organoselenium resin
to prepare the key intermediate of calcipotriol has been developed. The polystyrene-supported selenium resins used here not only facilitate
separation of product but also assist the crucial 2,3-sigmatropic rearrangement to introduce an important functional group (1r-hydroxyl) with
high stereo- and regioselectivity.
Medicinal chemistry relies on the efficient generation of
analogues of lead compounds. Natural products represent a
special class of leads since they have survived eons of natural
selection and generally evolved to perform a specific
function.1 As an effective approach, the application of solid-
phase organic synthesis (SPOS) in the field of natural
product-like synthesis2 is of considerable significance in the
discovery and development of new drug compounds. One
of the key challenges in SPOS involves immobilizing the
substrates onto the solid support, thus driving the demand
for the development of new and innovative linkers.3 Toward
this end, there has been particular interest in developing
linking strategies, whereby the loading and cleavage steps
contribute to the complexity of the target structure rather
than merely constituting extraneous manipulations.3
Since the discovery of the active hormone 1R,25-dihy-
droxyvitamin D3 [1,25(OH)2D3, calcitriol], synthetic organic
chemists have altered the structure of 1,25(OH)2D3 in various
ways with the goal of preparing vitamin D analogues as
sensitive molecular biology probes and as new drugs having
a favorable therapeutic index (i.e., high efficacy and low
toxicity).4 Considerable success has been achieved in the
development of new deltanoid drugs. Among those currently
in use as drugs for chemotheraphy of various human diseases
and those currently in human clinical trials, most of the
(3) (a) Guilliier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091.
(b) Sharma, P.; Moses, J. E. Org. Lett. 2010, 12, 2860. (c) Huang, X.; Xu,
W. M. Org. Lett. 2003, 5, 4649. (d) Taihades, J.; Gidel, M.-A.; Grossi, B.;
Lecaillon, J.; Brunel, L.; Subra, G.; Martinez, J.; Amblard, M. Angew.
Chem., Int. Ed. 2010, 49, 117.
(1) Clardy, J.; Walsh, C. Nature 2004, 432, 829.
(2) (a) Doi, T.; Hijikuro, I.; Takahashi, T. J. Am. Chem. Soc. 1999, 121,
6749. (b) Nicolaou, K. C.; Pastor, J.; Winssinger, N.; Murphy, F. J. Am.
Chem. Soc. 1998, 120, 5132. (c) Hirose, T.; Sunazuka, T.; Sugawara, T.;
Noguchi, Y.; Tanaka, T.; Iguchi, K.; Yamamoto, Y.; Gouda, H.; Shiomi,
K.; Omura, S. J. Antibiot. 2009, 62, 495. (d) Tannert, R.; Hu, T. S.; Arndt,
H. D.; Waldman, H. J. Chem. Soc., Chem. Commun. 2009, 1493. (e)
Nicoletti, D.; Mourino, A.; Torneiro, M. J. Org. Chem. 2009, 74, 4782.
(4) (a) Bouillon, R.; Okamula, W. H.; Norman, A. W. Endocr. ReV.
1995, 16, 200. (b) Zhu, G. D.; Okamura, W. H. Chem. ReV. 1995, 95, 1877.
(c) Feldman, D., Glorieux, F., Pike, J. W., Eds.;Vitamin D; Academic Press:
San Diego, 1997.
10.1021/ol101879k  2010 American Chemical Society
Published on Web 09/09/2010

analogues used thus far are modified in the side chain along
with a new 1R-hydroxyl compared with vitamin D2.5
The major advantage of preparing new deltanoids from
almost whole steroid precursors is that most of the deltanoid
skeleton, including its absolute stereochemistry, is available
without needing costly and time-consuming multistep syn-
theses.6 Yet, natural products are difficult to modify ef-
ficiently by chemical methods because of their complexity
and multifunctional nature.7
As part of our research program on the study of orga-
noselenium resin,8 we wish to report here a site-selective
modification of modified vitamin D2 through a two-step 2,3-
sigmatropic rearrangement9 to prepare the key intermediate
of calcipotriol with evident advantages of easy operation for
its odorlessness and high stereo- and regioselectivity of the
product. Compared with the reported literature (during the
allylic hydroxylation reaction, the ratio of two isomers was
constant 6:1),10 the high diastereomeric excess (de) values
of 1R-hydroxyl in our reaction were proposed to be due to
the steric course of organoselenium11 and the intramolecular
interaction between selenium and oxygen.12
Aldehyde 5 was then treated with polystyrene-supported
selenenyl bromide 6 (Br: 0.68 mmol/g, dark red resin,
prepared as described in refs 3c and 8) to give the
corresponding pale-green resin 7, which was followed by
elimination to give polystyrene-supported aldehyde 8 almost
quantitatively. The characteristic IR -CHO stretch (1724
cm-1) of resin 8 provides a convenient mode to monitor the
progress of resin loading. Resin 8 reacted smoothly with
cyclopropylcarbonylmethylenetriphenyl phosphorane to fur-
nish resin 9, and in this process the Wittig reaction was
followed also using IR spectroscopy, which showed disap-
pearance of the distinctive -CHO stretch and appearance
of the distinctive -CdO stretches at 1686 and 1666 cm-1.
Upon further investigation, we found that it was necessary
to keep the reaction temperature between 110 and 115 °C
to ensure an adequate reaction rate and an acceptable product
yield and purity of the final product (Scheme 2).
Scheme 2. Preparation of Resin 9
We began our efforts from vitamin D2, which was
converted to its SO2-adducts, without further purification,
directly followed by silylation with tert-butylchlorodimeth-
ylsilane (TBDMSCl) and ozonation with O3. After flash
chromatography, cheletropic extrusion of SO2 in refluxing
ethanol containing suspended NaHCO3 gave substituted
aldehyde 513 (Scheme 1).
Scheme 1. Preparation of Substituted Aldehyde 5
In the field of synthetic organoselenium chemistry, 2,3-
sigmatropic rearrangements of allylic selenides are one of
the most fundamental reactions. Since the first 2,3-sigmat-
ropic rearrangement of allylic selenide was reported in
1972,14 the method has been widely studied due to this 1,3-
allylic alcohol transposition which proceeds under very mild
conditions.15
With resin 9 in hand, we first followed the conditions that
Back and McPhee had devised16 in the preparation of a
natural product. Although the same strategy using organose-
lenium resin for 2,3-sigmatropic rearrangement to introduce
a hydroxyl group on a different nature product can also be
found,17 an inseparable mixture was obtained in our reaction
(5) (a) Laverny, G.; Penna, G.; Uskokovic, M.; Marczak, S.; Maehr,
H.; Jankowski, P.; Ceailles, C.; Vouros, P.; Smith, B.; Robinson, M.; Reddy,
G. S.; Adorini, L. J. Med. Chem. 2009, 52, 2204. (b) Posner, G. H.;
Kahraman, M. Eur. J. Org. Chem. 2003, 3889. (c) Kubodera, N. Molecules
2009, 14, 3869.
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Org. Lett., Vol. 12, No. 19, 2010

whether 3-chloroperoxybenzoic acid (mCPBA) or H2O2 is
used as an oxidant (Scheme 3). Further investigation
Scheme 4
.
Two-Step 2,3-Sigmatropic Rearrangement to Prepare
the Key Intermediate of Calcipotriol
Scheme 3
.
General 2,3-Sigmatropic Rearrangement to Prepare
the Key Intermediate of Calcipotriol
indicated that the assumed product (intermediate of calci-
potriol) 10 could not stably exist in our oxidized system.
To solve this problem, we developed here a two-step 2,3-
sigmatropic rearrangement: a typical 2,3-sigmatropic rear-
rangement involves an oxidation of selenides and a transfer
of oxygen from the selenium atom to the carbon atom of an
allylic selenoxide, then an allylic alcohol after hydrolysis.
In our procedure, the intermediate selenoxide resin 11 was
separated through filtration from the reaction mixture, which
was then followed by hydrolysis and protection of the 1R-
hydroxyl group with tert-butylchlorodimethylsilane (TB-
DMSCl) simultaneously (Scheme 4). To our surprise, key
product 12 was obtained with 86% purity of the crude
product and 64.5% of isolated yield according to resin 5.18
From the literature,5 key product 12 can be smoothly
followed by selective reduction, clean photoisomerization,
and deprotection to give calcipotriol as a Psoriasis drug.
It is noteworthy that in our procedure the organoseleno
species used here not only facilitate separation of the
procedure but also assist the crucial 2,3-sigmatropic rear-
rangement to introduce an important functional group (1R-
hydroxyl) with high stereo- and regioselectivity, which shows
a wide range of activities, including cell-differentiating and
antiproliferative activities among the hormonally active form
of vitamin D3. Furthermore, an efficient route, starting from
vitamin D2, to different kinds of vitamin D analogues is
developed.
In conclusion, we have developed a site-selective modi-
fication of vitamin D analogue (Deltanoid) through a two-
step 2,3-sigmatropic rearrangement of organoselenium resin
to prepare the key intermediate of calcipotriol. Further
detailed studies and application will be disclosed in due
course.
(6) (a) Westermann, J.; Schneider, M.; Platzek, J.; Petrov, O. Org.
Process Res. DeV. 2007, 11, 200. (b) Sabroe, T. P.; Pederson, H.; Binderup,
E. Org. Process Res. DeV. 2004, 8, 133. (c) Gomez-Reino, C.; Vitale, C.;
Maestro, M.; Mourino, A. Org. Lett. 2005, 7, 5885.
(7) Ortholand, J. Y.; Ganesan, A. Curr. Opin. Chem. Biol. 2004, 8, 271.
(8) (a) Xu, W. M.; Huang, X.; Tang, E. J. Comb. Chem. 2005, 7, 726.
(b) Wang, Y. G.; Xu, W. M.; Huang, X. J. Comb. Chem. 2007, 9, 513. (c)
Huang, X.; Tang, E.; Xu, W. M.; Cao, J. J. Comb. Chem. 2005, 7, 802.
(9) (a) Liotta, D. Organoselenium Chemistry; Wiley-Interscience: New
York, 1987. (b) Back, T. G. Organoselenium Chemistry; Oxford University
Press: Oxford, 1999.
(10) Calverley, M. J. Tetrahedron 1987, 43, 4609.
Acknowledgment. Dedicated to the memory of Prof. Xian
Huang. We are also grateful to the National Natural Science
Foundation of China (20602029) and Hangzhou Normal
University (HSKQ0023) for financial support.
(11) Hess, L. C.; Posner, G. H. Org. Lett. 2010, 12, 2120.
(12) Mukherjee, A. J.; Zade, S. S.; Singh, H. B.; Sunoj, R. B. Chem.
ReV. 2010, 110, 4357.
(13) In accordance with ref 10, aldehyde 5 (C-20 epimers as starting
material) for the following Wittig reaction was equal to that in the final
product 12.
(14) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 7154.
(15) (a) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95,
2697. (b) Reich, H. J.; Wollowitz, S. J. Am. Chem. Soc. 1982, 104, 7051.
(16) Back, T. G.; McPhee, D. J. J. Org. Chem. 1984, 49, 3842.
(17) Shintani, K.; Hanzawa, S. Jpn. Kokai Tokkyo Koho 1991, Heisei.
(18) For the detailed processes, please see Supporting Information.
Supporting Information Available: Experimental pro-
cedures and IR, HPLC, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
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