Direct mono-phosphorylation of 1,3-diols. A synthesis of FTY720-phosphate

Article abstract of DOI:10.1016/j.tetlet.2005.05.127

A novel method for selective and direct phosphorylation of various 1,3-diols using silver(I) oxide, tetrabenzyl pyrophosphate (TBPP), and tetrahexylammonium iodide affording mono-phosphates was developed. We applied the present method to the synthesis of

Full text of DOI:10.1016/j.tetlet.2005.05.127

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5169–5172
Direct mono-phosphorylation of 1,3-diols. A synthesis
of FTY720-phosphate
Shuzo Takeda,* Masao Chino, Masatoshi Kiuchi and Kunitomo Adachi
Research Laboratory III (Immunology), Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama,
Kanagawa 227-0033, Japan
Received 27 April 2005; revised 25 May 2005; accepted 27 May 2005
Available online 17 June 2005
Abstract—A novel method for selective and direct phosphorylation of various 1,3-diols using silver(I) oxide, tetrabenzyl pyrophos-
phate (TBPP), and tetrahexylammonium iodide affording mono-phosphates was developed. We applied the present method to the
synthesis of FTY720-phosphate.
Ó 2005 Elsevier Ltd. All rights reserved.
FTY7201 (1, Fig. 1) is a novel immunosuppressive com-
pound, which is currently undergoing clinical phase III
trials for prevention of kidney graft rejection. Unlike
other standard immunosuppressants (e.g., Cyclosporin
A or FK506), 1 possesses an inhibitory action on migra-
tion of T- and B-lymphocytes from the thymus and sec-
ondary lymphoid tissues.2 Recently, it was revealed that
1 is rapidly mono-phosphorylated in vivo to form
FTY720-phosphate (2, Fig. 1), which is an agonist for
for each S1P receptor will be valuable tools to ascertain
the mechanism of immunosuppressive action of 1, and
provide further information to researchers. For this
purpose, it is important to develop a convenient method
for mono-phosphorylation of 1 and to synthesize
various analogs of 2.
Compound 1 has a propan-1,3-diol moiety. Because 1 has
the two hydroxyls in it, to properly protect one of the
hydroxyls has been needed before the phosphorylation
of the other. Indeed, we and other groups3,5,6 reported
the synthesis of 2; however, the protection to prevent
the formation of the bisphosphorylated byproduct com-
plicated their syntheses. Accordingly, it will be valuable
to develop a synthetic method for direct mono-phosphor-
ylation of diols without protecting one of the hydroxyls.
We required a selective and convenient method of phos-
phorylation with wide adaptability for several kinds of
substrates having the propane-1,3-diol moiety.
four sphingosine-1-phosphate (S1P) receptors (S1P1,3,4,5)
out of five (S1P1–5) and responsible for the biological
activity of 1.3,4 We believe that complementary agonists
There have been numerous reports7,8 on the phosphoryl-
ation of alcohols for the syntheses of nucleotides, phos-
phorylated inositols, etc. The use of phosphoramidite,7a–d
one of frequently used reagents, on N-protected
FTY720 (3) gave no mono-phosphate but a cyclic phos-
phate.9 Other highly useful reagents, the pyrophos-
phate7e–h or the chlorophosphate,7i–l require strong
bases such as butyl lithium and sodium hydride, and
the bases make their reactivity too high. A method for
selective mono-phosphorylation of inositol derivatives
using dibutyltin oxide and pyrophosphate7h has been
Figure 1. FTY720 (1), FTY720-phosphate (2), and N-protected
FTY720 (3).
Keywords: FTY720; Mono-phosphorylation; 1,3-diol; Silver(I) oxide;
Tetrabenzyl pyrophosphate (TBPP); Tetrahexylammonium iodide.
*
Corresponding author. Tel.: +81 459634479; fax: +81 459633529;
e-mail: Takeda.Shuzo@mh.m-pharma.co.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.127

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S. Takeda et al. / Tetrahedron Letters 46 (2005) 5169–5172
reported; however, the method failed to give an interme-
diate for 2. Under a similar condition described in the
literature, compound 3 was converted into an oxazolid-
inone formed by cyclization of the carbamate moiety
and one of the hydroxyls. As described above, tradi-
tional phosphorylation methods using phosphoramidite
or pyrophosphate were ineffective for mono-phosphoryl-
ation of 3.
tives in 69–76% yields (entry 1–3). When 1.1 equiv of
the phosphorylating reagent was used, the desired
mono-phosphate was obtained in a slightly low yield
(entry 4). Although the phosphorylations of secondary
alcohol (entry 5) and mono-ol (entry 6), which has a
similar structure to the diol in entry 2 except lacking
the other hydroxyl, proceeded in a slightly low yield,
1-methylpropan-1,3-diol including both a primary and
a secondary alcohol was selectively mono-phosphoryl-
ated at the primary alcohol in a good yield (entry 7).
These results suggested that steric requirement for the
chelation between silver(I) oxide and two hydroxyls
would have a crucial role for the smooth reaction. As ex-
pected, 2,2-dimethyl-1-propanol (entry 8), which is a
model compound of a hindered alcohol and lacks an
internal chelatable hydroxyl, had no reactivity for
phosphorylation.
On the other hand, Bouzide and Sauve10 reported a
method for mono-protection and mono-tosylation of
symmetrical diols utilizing chelation and Lewis acidity
of silver(I) oxide.11 We leveraged this intermolecular
chelating system between silver(I) oxide and diol for
mono-phosphorylation of propane-1,3-diols with tetra-
benzyl pyrophosphate12 (TBPP) as a phosphatic donor.
In this communication, we describe a concise procedure
to obtain mono-phosphates from various non-protected
diols without any oxidative reagents or strong bases
under a mild condition, and the application of the pres-
ent method to provide 2.
Next we examined the reaction on other 1,n-diols and a
substrate having a competing phenol group (Table 2).
Although ethylene glycol (entry 1) gave little phosphor-
ylated product, 1,4-butanediols (entry 2) was efficiently
phosphorylated in a similar yield to that of 1,3-propane-
diol (Table 1, entry 1). As for a series of 1,n-diols,
increasing the number of the carbon atoms between
the two hydroxyls resulted in a decrease of the yields
for the reaction; the treatment of 1,10-decanediol (entry
5) failed to give the corresponding mono-phosphate,
suggesting that the present method was applicable to
mono-phosphorylation of 1,n-diols (n = 3–6). The phe-
nolic hydroxyl of 3-(4-hydroxyphenyl)-1-propanol (en-
try 6) was selectively phosphorylated over the aliphatic
hydroxyl in an excellent yield. This selectivity to the phe-
nolic hydroxyl could be attributed to its higher acidity;
therefore, the method would be useful for the selective
phosphorylation on the phenol moiety without any
protection of aliphatic hydroxyls.
In our initial investigation, reactivity and selectivity of
our method were evaluated in the phosphorylation of
simple diols. The present procedure13 is as follows. To
a solution of a diol, TBPP and silver(I) oxide in dichlo-
romethane was added tetrahexylammonium iodide.14
The mixture was stirred at ambient temperature. After
purification, the corresponding mono-phosphate was
obtained. Although 2 equiv of the phosphorylating re-
agent was used, bisphosphorylated byproducts of simple
diols were not detected. The results are summarized in
Table 1.
Propane-1,3-diols underwent smooth conversion to the
corresponding mono-phosphorylated alcohol deriva-
Table 1. Direct mono-phosphorylation of 1,3-diols
On the basis of the result on the simple alcohols, we ap-
plied the method to the synthesis of 2 as shown in
Scheme 1. We examined the phosphorylation of
Entrya
Substrate
Productb
Yieldc,d
69
1
2
74
Table 2. Direct mono-phosphorylation of diols
Entrya
Substrate
Productb
Yieldc,d
Trace
3
4e
76
55
1
5
6
7
8
44f
2
3
4
5
71
43
43
31
76
N.R.g
Trace
a Conditions: TBPP (2 equiv), Ag2O (2 equiv), tetrahexylammonium
iodide (2 equiv) in DCM at room temperature for 20 h.
b P = P(O)(OBn)2.
6
97
a Conditions: TBPP (2 equiv), Ag2O (2 equiv), tetrahexylammonium
iodide (2 equiv) in DCM at room temperature for 20 h.
b P = P(O)(OBn)2.
c Isolated yield.
d No bisphosphorylated byproduct was observed.
c Isolated yield.
d No bisphosphorylated byproduct was observed.
e 1.1 equiv of all reagents was used.
f
No diastereoselectivity was observed.
g No reaction.

S. Takeda et al. / Tetrahedron Letters 46 (2005) 5169–5172
5171
Scheme 1.
compound 36 whose N-benzyloxycarbonyl group can be
cleaved easily along with the benzyl groups of the resul-
tant phosphate ester of 4. Compound 3 was successfully
converted to the corresponding mono-phosphate 4 in
60% yield. In this case, however, bisphosphate (5,
22%) generated by the extra phosphorylation of 4 and
oxazolidinone15 (6, 12%) were obtained as the major
byproducts. This lower selectivity compared with that
of simple diols might be due to the carbamate moiety,
which could chelate to silver(I) oxide and increase its Le-
wis acidity. The resulting product 4 was converted into
FTY720-phosphate (2) by hydrogenolysis in 90% yield.
This phosphorylating method of 1,3-diol enabled by
the present procedure was simple and shorter than the
previous methods by omitting the protecting step; there-
fore, the method has considerable potential to be a facile
and effective tool to synthesize various analogs of 2.
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In summary, the present procedure using silver(I) oxide,
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and practical method for conversion of diols into the
corresponding mono-phosphates without any strong
bases and oxidative reagents. As for the selectivity, we
revealed that the primary alcohol and phenolic hydroxyl
were preferred to the secondary and aliphatic hydroxyl,
respectively. Our successful application to prepare
FTY720-phosphate (2) suggested that using the present
method for phosphorylation makes it possible to mono-
phosphorylate multi-functional and biologically active
compounds.
Supplementary data
Supplementary data associated with this article can
be found, in the online version at doi:10.1016/j.tetlet.
2005.05.127.
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