Scheme 1. Synthesis of Mono-, Di-, Tri-, and Tetraphosphitylating Reagents (1, 5, 9, and 12)
1
bonyldiimidazole (CDI). Furthermore, Np
4
N analogues have
polymer-bound N,N-diisopropylamino-1,3,2-oxathiophos-
2
3
been synthesized in modest yield by the reaction of a
nucleoside triphosphate with a nucleotide activated as the
morpholidate or imidazolate.1
pholane. The method was limited to the synthesis of NpN.
As part of our ongoing efforts to synthesize organophos-
3-15
24
Recently, Han and col-
phorus compounds and to minimize one or more of above-
leagues used protected triacetyl adenosine or guanosine and
trimetaphosphate chemistry to prepare dinucleoside tetra- and
described problems associated with the solution-phase meth-
ods, we synthesized polymer-bound phosphitylating reagents
for the synthesis of Np N (x ) 1-4) analogues. This strategy
x
offered several advantages. (i) A diverse number of com-
pounds were synthesized in a short period without the need
to use nucleoside phosphate precursors or protected nucleo-
sides. (ii) This method allowed the synthesis of four classes
1
6
pentaphosphates. Symmetrical dinucleoside monophos-
phates (NpN) have also been synthesized from 3′- or 5′-
protected nucleosides and phosphitylating or phosphoramidite
reagents.1
7,18
Some of the solution-phase strategies have been hampered
by one or more of the following difficulties. (i) The
nucleoside phosphate precursors, such as 5′-monophosphate,
of compounds (Np N, x ) 1-4) from the same polymer-
x
bound linker. (iii) Reactions using this strategy offered the
advantage of facile isolation of final products from the resin-
trapped linkers by filtration. (iv) Only one type of phos-
phodiester derivatives (i.e., 5′-5′-dinucleoside analogues) was
synthesized because of the presence of the phosphitylating
reagents on the solid support having a hindered structure,
thereby allowing for the regioselective reaction. The most
reactive hydroxyl group of unprotected nucleosides reacted
selectively with hindered polymer-bound reagents when an
excess of nucleoside was used. To the best of our knowledge,
5′-diphosphate, or 5′-triphosphate, need to be synthesized
first. (ii) Some strategies involve protection and deprotection
of nucleosides, thus are rather cumbersome. (iii) Extensive
purification of final products from the starting precursors
and other reagents are required.
Alternatively, enzymatic methods19,20 have been used for
x
the synthesis of Np N derivatives, such as the synthesis of
diinosine polyphosphates from the corresponding diadenosine
polyphosphates in the presence of 5′-adenylic acid deami-
nase.2 Enzymatic approaches have limitations in the scale
of products and use of natural nucleosides.
1,22
x
this is the first paper on the synthesis of Np N derivatives
using polymer-bound phosphitylating reagents.
At first, the trifunctional monophosphitylating (1), diphos-
phitylating (5), triphosphitylating (9), and tetraphosphitylating
We have previously reported the solid-phase synthesis of
dinucleoside phosphodiesters and phosphothiodiesters using
(
12) reagents were synthesized from phosphorus trichloride
(PCl ) (Scheme 1). Trifunctional phosphitylating reagents
contain one chlorine group (-Cl) and two diisopropylamino
groups (-N(iPr) ) that are replaced after the attachment of
(13) Pendergast, W.; Yerxa, B. R.; Douglass, J. G., III; Shaver, S. R.;
3
Dougherty, R. W.; Redick, C. C.; Sims, I. F.; Rideout, J. L. Bioorg. Med.
Chem. Lett. 2001, 11, 157.
(
14) Blackburn, G. M.; Taylor, G. E.; Thatcher, G. R. J.; Prescott, M.;
McLennan, A. G. Nucleic Acids Res. 1987, 15, 6991.
15) McLennan, A. G.; Taylor, G. E.; Prescott, M.; Blackburn, G. M.
Biochemistry 1989, 28, 3868.
2
the reagent to the polymer-bound linker and after coupling
reactions with two unprotected nucleosides, respectively.
(
(
(
16) Han, Q.; Gaffney, B. L.; Jones, R. A. Org. Lett. 2006, 8, 2075.
17) Dabkowski, W.; Michalski, J.; Qing, W. Angew. Chem., Int. Ed.
3 2
PCl (10 mmol) was reacted with diisopropylamine (iPr -
NH, 2 equiv) in the presence of N,N-diisopropylethylamine
(DIEA, 2 equiv) to yield bis(diisopropylamino)chloro-
Engl. 1990, 29, 522.
18) Donga, R. A.; Khaliq-Uz-Zaman, S. M.; Chan, T.-H.; Damha, M.
J. J. Org. Chem. 2006, 71, 7907.
19) Theoclitou, M. E.; El-Thaher, T. S. H.; Miller, A. D. J. J. Chem.
Soc., Chem. Commun. 1994, 5, 659.
20) Theoclitou, M. E.; Wittung, E. P. L.; Hindley, A. D.; El-Thaher, T.
S. H.; Miller, A. D. J. J. Chem. Soc., Perkin Trans. 1 1996, 16, 2009.
21) King, B. F.; Liu, M.; Pintor, J.; Gualix, J.; Mirs-Portugal, M. T.;
Burnstock, G. Brit. J. Phamacol. 1999, 128, 981.
22) Pintor, J.; Gualix, J.; Miras-Portugal, M. T. Mol. Pharmacol. 1997,
1, 277.
(
(
(23) Ahmadibeni, Y.; Parang, K. J. Org. Chem. 2006, 71, 6693.
(24) (a) Parang, K.; Fournier, E. J.-L.; Hindsgaul, O. Org. Lett. 2001, 3,
307. (b) Parang, K. Bioorg. Med. Chem. Lett. 2002, 12, 1863. (c)
Ahmadibeni, Y.; Parang, K. J. Org. Chem. 2005, 70, 1100. (d) Ahmadibeni,
Y.; Parang, K. Org. Lett. 2005, 7, 1955. (e) Ahmadibeni, Y.; Parang, K.
Org. Lett. 2005, 7, 5589. (f) Ahmadibeni, Y.; Parang, K. J. Org. Chem.
2006, 71, 5837. (g) Ahmadibeni, Y.; Parang, K. Angew. Chem., Int. Ed.
2007, 46, 4739.
(
(
(
5
4484
Org. Lett., Vol. 9, No. 22, 2007