Synthetic utility of an isolable nucleoside phosphonium salt

Article abstract of DOI:10.1021/ol8006106

(Chemical Equation Presented) The reaction of O⁶-benzyl- 3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyxanthosine with 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) yielded the nucleoside C-2 tris(dimethylamino)phosphonium hexafluorophosphate salt as a stable, isolable species. This is in contrast to reactions of inosine nucleosides with BOP, where the in situ formed phosphonium salts undergo subsequent reaction to yield O⁶-(benzotriazol-1-yl)inosine derivatives. The phosphonium salt obtained from the 2′-deoxyxanthosine derivative can be effectively used to synthesize N²-modified 2′-deoxyguanosine analogues. Using this salt, a new synthesis of an acrolein-2′-deoxyguanosine adduct has also been accomplished.

Full text of DOI:10.1021/ol8006106

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2203-2206
Synthetic Utility of an Isolable
Nucleoside Phosphonium Salt
Suyeal Bae and Mahesh K. Lakshman*
Department of Chemistry, The City College and The City UniVersity of New York,
160 ConVent AVenue, New York, New York 10031-9198
lakshman@sci.ccny.cuny.edu
Received March 16, 2008
ABSTRACT
The reaction of O6-benzyl-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyxanthosine with 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (BOP) yielded the nucleoside C-2 tris(dimethylamino)phosphonium hexafluorophosphate salt as a stable, isolable species.
This is in contrast to reactions of inosine nucleosides with BOP, where the in situ formed phosphonium salts undergo subsequent reaction
to yield O6-(benzotriazol-1-yl)inosine derivatives. The phosphonium salt obtained from the 2′-deoxyxanthosine derivative can be effectively
used to synthesize N2-modified 2′-deoxyguanosine analogues. Using this salt, a new synthesis of an acrolein-2′-deoxyguanosine adduct has
also been accomplished.
The ability to modify natural nucleosides translates to novel
applications in biochemistry, biology, and medicine.1
In this context, we demonstrated that in reactions of
hypoxanthine nucleosides with BOP, the inosine-derived
phosphonium salts undergo reaction with BtO- that is
released. This results in the formation of O6-(benzotriazol-
1-yl)inosine derivatives.9 More recently, we demonstrated
that the inosine-derived phoshonium salt formed via reaction
with Ph3P·I2 can also be converted to O6-(benzotriazol-1-
yl)inosine derivatives in good yields.7 These new O6-
(benzotriazol-1-yl)inosine derivatives possess excellent re-
activity for a variety of transformations, leading to modification
at the C-6 position of the purine (Scheme 1).7,9
A
classical method for nucleoside modification is via displace-
ment chemistry. For modification at the C-2 position various
protected or unproteced 2-halo-2′-deoxyinosines, namely
fluoro,2 bromo,3 and chloro4 derivatives, have been used. In
addition, use of triflate5 and tosylate4a derivatives have also
been reported.
Phosphonium salts have been proposed as intermediates
in the reactions of inosine nucleosides with Ph3P·I26,7 or with
1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (BOP).8,9 These salts can be converted
to adenine derivatives via reaction with various amines.6,8
On the basis of our prior work on inosine nucleosides,
we became interested in studying the reaction of O6-
protected 2′-deoxyxanthosine with BOP. This paper describes
our preliminary results on the reaction of O6-benzyl-3′,5′-
bis-O-(tert-butyldimethylsilyl)-2′-deoxyxanthosine with BOP.
In the course of these studies we have identified the
nucleoside C-2 phosphonium salt as an isolable compound
that can be readily utilized for SNAr displacement chemistry
with a broad range of amines. Finally, the C-2 phosphonium
(1) (a) Nucleic Acids in Chemistry and Biology, 3rd ed.; Blackburn,
G. M., Gait, M. J., Loakes, D., Williams, D. M., Eds.; RSC Publishing:
Cambridge, UK, 2006. (b) Simons, C. Nucleoside Mimetics: Their Chemistry
and Biological Properties; Gordon and Breach: Amsterdam, 2001. (c)
PerspectiVes in Nucleoside and Nucleic Acid Chemistry; Kisaku¨rek, M. V.,
Rosemeyer, H., Eds.; Verlag Helvetica Chimica Acta: Zu¨rich and Wiley-
VCH: Weinheim, 2000. (d) Suhadolnik, R. J. Nucleosides as Biological
Probes; Wiley: New York, 1979.
10.1021/ol8006106 CCC: $40.75
Published on Web 05/13/2008
2008 American Chemical Society

Scheme 1
.
Synthesis of O6-(Benzotriazol-1-yl) Derivatives of
Scheme 2.
Synthesis of O6-Benzyl-
3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyxanthosine
Inosine and 2′-Deoxyinosine via Reaction with BOP or
Ph3P/I2/HOBt
reaction was observed (4-5 h at room temperature) with
the predominant formation of a new material that was isolated
by chromatography on silica gel.
Analysis of this new product indicated that it was the
phosphonium salt 3 and not the benzotriazol-1-yl compound
4. From this reaction, two noteworthy points emerged: (a)
the greater difficulty in SNAr displacement of HMPA by
BtO- from the C-2 position, in contrast to reactions at the
C-6 of purines9 and (b) the relative stability of phosphonium
salt 3, which could be readily obtained by chromatographic
purification.
salt has been utilized in a new synthesis of an acrolein adduct
with 2′-deoxyguanosine.
O6-Benzyl-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deox-
yguanosine (1) can be readily synthesized on the multigram
scale via a Mitsunobu etherification of 3′,5′-bis-O-(tert-
butyldimethylsilyl)-2′-deoxyguanosine.2b,3a,10 Diazotization-
hydrolysis of 1 as described4a,11 yielded O6-benzyl-3′,5′-bis-
O-(tert-butyldimethylsilyl)-2′-deoxyxanthosine (2 in Scheme
2, 64% yield).
Scheme 3.
Reaction of O6-Benzyl-
3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyxanthosine with
BOP
Under conditions similar to those we have described
previously,9 (2 molar equiv of BOP/1.5-2.0 molar equiv
(i-Pr)2NEt, anhydrous CH2Cl2, room temperature), the reac-
tion of 2 with BOP was evaluated (Scheme 3). A fairly rapid
(2) Some examples for the synthesis of 2-fluoro-2′-deoxyinosine deriva-
tives: (a) Woo, J.; Sigurdsson, S. T.; Hopkins, P. B. J. Am. Chem. Soc.
1993, 115, 3407–3415. (b) Zajc, B.; Lakshman, M. K.; Sayer, J. M.; Jerina,
D. M. Tetrahedron Lett. 1992, 33, 3409–3412. (c) Kim, S. J.; Stone, M. P.;
Harris, C. M.; Harris, T. M. J. Am. Chem. Soc. 1992, 114, 5480–5481
.
(3) Some examples for the synthesis of O6-protected and unprotected
2-bromo-2′-deoxyinosine derivatives: (a) Harwood, E. A.; Sigurdsson, S. T.;
Edfeldt, N. B. F.; Reid, B. R.; Hopkins, P. B. J. Am. Chem. Soc. 1999,
121, 5081–5082. (b) Jhingan, A. K.; Meehan, T. Synth. Commun. 1992,
1
The H NMR spectrum of 3 (CDCl3) showed a charac-
22, 3129–3135
.
teristic doublet at δ 2.83 ppm for the NMe2 resonance (JP-H
) 10.7 Hz). The 31P NMR of 3 (CDCl3) showed a singlet at
δ 34.11 ppm as well as a septet centered at δ -143.27 ppm
(JP-F ) 712.7 Hz) for the PF6 anion. The synthesis of
phosphonium salt 3 is reproducible and scalable, usually
returning product yields of 88-92%.12
(4) Some examples for the synthesis of 2-chloro-2′-deoxyinosine deriva-
tives: (a) Pottabathini, N.; Bae, S.; Pradhan, P.; Hahn, H.-G.; Mah, H.;
Lakshman, M. K. J. Org. Chem. 2005, 70, 7188–7195. (b) Ramasamy, K. S.;
Zounes, M.; Gonzalez, C.; Freier, S. M.; Lesnik, E. A.; Cummins, L. L.;
Griffey, R. H.; Monia, B. P.; Cook, P. D. Tetrahedron Lett. 1994, 35, 215–
218
.
(5) Some examples of an O6-protected C-2 triflate: (a) Edwards, C.;
Boche, G.; Steinbrecher, T.; Scheer, S. J. Chem. Soc., Perkin Trans. 1 1997,
1887–1893. (b) Steinbrecher, T.; Wameling, C.; Oesch, F.; Seidel, A. Angew.
Given the high isolated yield of phosphonium salt 3 and
the relative simplicity of its synthesis, we were interested in
evaluating its utility in displacement reactions with amines.
Such reactions would involve HMPA as a neutral leaving
group, and this would lead to a simple approach to N-
modified 2′-deoxyguanosine analogues. A variety of amines
were selected for this purpose (Table 1).
Chem., Int. Ed. Engl. 1993, 32, 404–406
(6) Lin, X.; Robins, M. J. Org. Lett. 2000, 2, 3497–3499
(7) Bae, S.; Lakshman, M. K. J. Org. Chem. 2008, 73, 1311–1319
.
.
.
(8) Wan, Z.-K.; Binnun, E.; Wilson, D. P.; Lee, J. Org. Lett. 2005, 7,
5877–5880
.
(9) Bae, S.; Lakshman, M. K. J. Am. Chem. Soc. 2007, 129, 782–789
.
(10) Himmelsbach, F.; Schulz, B S.; Trichtinger, T.; Charubala, R.;
Pfleiderer, W. Tetrahedron 1984, 40, 59–72
.
(11) (a) Jurczyk, S. C.; Horlacher, J.; Devined, K. G.; Benner, S. A.;
The displacement reactions on 3 were conducted in 1,2-
dimethoxyethane (DME) at room temperature or at 85 °C
Battersby, T. R. HelV. Chim. Acta 2000, 83, 1517–1524. (b) Kodra, J. T.;
Benner, S. A. Synlett 1997, 939–940
.
2204
Org. Lett., Vol. 10, No. 11, 2008

rivatives.14,15 However, this fluoro nucleoside requires a
multistep synthesis and involves the use of HF-pyridine in
the diazotization-fluorination step. In comparison, 3 offers
significant advantages.
Table 1. Synthesis of N2-Modified 2′-Deoxyguanosine
Analogues from 3
For our synthesis, we reasoned that ready access to the
acrolein adduct with 2′-deoxyguanosine could be attained
from commercially available 3-amino-1-propanol and 3.
Initial experiments were therefore directed toward displace-
ment of HMPA from 3 by 3-amino-1-propanol (Scheme 4).
However, the yield of 6 via this approach was low (ca. 30%).
Scheme 4
.
Approaches to 3′,5′-Bis-O-(tert-butyldimethylsilyl)-
N-(3-hydroxypropyl)-2′-deoxyguanosine
a Reaction using 5.7 molar equiv of amine, 2.0 molar equiv of Cs2CO3,
DME, room temperature. b Reaction using 4 molar equiv of amine, DME,
room temperature. c Reaction using 4 molar equiv of amine, DME, room
temperature and then 85 °C. d Reaction using 7.5 molar equiv of amine,
DME, room temperature and then 85 °C. e Debenzylation was performed
using H2 (1 atm)/10% Pd-C, 1:1 THF-MeOH, room temperature.
f Debenzylation was accompanied by nitro group reduction, no attempt was
made at finding selective debenzylation conditions.
By analysis of the byproducts formed in the synthesis of 6,
protection of the hydroxyl group in 3-amino-1-propanol was
deemed necessary to suppress the undesired side reactions.
when reactions were slow or incomplete at room temperature.
Subsequent to the displacement, the O6-benzyl group was
removed by catalytic hydrogenolysis at room temperature.
The fact that the O6-protected derivative 3 could be used in
these reactions makes 3 a substrate for SNAr displacement.
This is different in comparison to the displacement reactions
on 2-chloro-2′-deoxyinosine which were addition-elimination-
type processes on a conjugated system.4a Also, no degrada-
tion of 3 was observed with the primary amine (entry 7)
and this contrasts to what has been reported in the reaction
of O6-benzyl-3′,5′-bis-O-(tert-butyldimethylsilyl)-2-bromo-
2′-deoxyinosine.13 All of these features bode well for the
utility of 3 in SNAr displacement reactions.
With the simple displacement reactions completed, we then
considered the use of 3 for the synthesis of a more complex,
biologically relevant compound. Of several possibilites, we
chose to evaluate the synthesis of the 2′-deoxyguanosine-
acrolein adduct. This compound has been important in studies
aimed at understanding the structure and biological implica-
tions of acrolein-induced DNA damage.
(12) Synthesis of O6-Benzyl-3′,5′-bis-O-(tert-butyldimethylsilyl)-O2-
tris(dimethylamino)phosphonium-2′-deoxyxanthosine hexafluorophos-
phate (3). In a clean, dry flask equipped with stirring bar were placed O6-
benzyl-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyxanthosine (2) (0.588
g, 1.00 mmol) and BOP (0.885 g, 2.00 mmol). CH2Cl2 (10.0 mL) and (i-
Pr)2NEt (0.35 mL, 2.01 mmol) were added. The mixture was flushed with
nitrogen gas and allowed to stir at room temperature. After 5 h, the reaction
was complete and the mixture was concentrated. Chromatographic purifica-
tion (SiO2, eluted with 50% EtOAc in hexanes followed by 30% acetone
in CH2Cl2) afforded 0.785 g (88% yield) of compound 3 as a beige foam.
Rf (5% MeOH in CH2Cl2) ) 0.40. 1H NMR (500 MHz, CDCl3): δ 8.36 (s,
1H, H-8), 7.46 (d, 2H, Ar-H, J ) 6.8), 7.38-7.31 (m, 3H, Ar-H), 6.38 (t,
1H, H-1′, J ) 6.4), 5.67 (s, 2H, OCH2), 4.58 (app q, 1H, H-3′, J ∼ 4.2),
4.02 (br q, 1H, H-4′, J ) 2.9), 3.85 (dd, 1H, H-5′, J ) 11.7, 3.2), 3.78 (dd,
1H, H-5′, J ) 11.7, 2.4), 2.83 (d, 18H, NCH3, JH-P ) 10.7), 2.44 (t, 2H,
H-2′, J ) 5.9), 0.91 (s, 18H, t-Bu), 0.10 (br s, 12H, SiCH3). 13C NMR
(125 MHz, CDCl3): δ 161.9, 152.7, 152.6, 141.5, 135.3, 128.6, 128.5, 127.8,
120.2, 88.0, 84.0, 71.6, 69.7, 62.6, 41.9, 37.0 (d, JC-P ) 4.5), 26.0, 25.7,
18.4, 17.9, -4.7, -4.8, -5.4, -5.5. 31P{1H} NMR (202 MHz, CDCl3): δ
34.11 (s, P[N(CH3)2]3), -143.27 (septet, PF6, JP-F ) 712.7). ESI HRMS:
+
calcd for C35H63N7O5PSi2 748.4161, found 748.4151.
(13) Harwood, E. A.; Hopkins, P. B.; Sigurdsson, S. T. J. Org. Chem.
2000, 65, 2959–2964.
(14) Acrolein: (a) Khullar, S.; Varaprasad, C. V.; Johnson, F. J. Med.
Chem. 1999, 42, 947–950. (b) Nechev, L. V.; Harris, C. M.; Harris, T. M.
Chem. Res. Toxicol. 2000, 13, 421–429.
Typically compounds of this type have been synthesized
by fluoride displacement from 2-fluoro-2′-deoxyinosine de-
(15) Cinnamaldehyde: Rezaei, M.; Harris, T. M.; Rizzo, C. M. Tetra-
hedron Lett. 2003, 44, 7513–7516.
Org. Lett., Vol. 10, No. 11, 2008
2205

Based upon a literature procedure,16 3-amino-1-propanol was
selectively converted to the O-benzyl ether. The reaction of 3
with this benzyl-protected 3-amino-1-propanol (Scheme 4)
proceeded smoothly at 85 °C in DME to provide the bis-benzyl
ether protected nucleoside 7 in 82% yield.
Table 2. Conditions Tested for the Oxidative Cyclization of 8
as Well as the Yields of 9 in These Reactions
At this stage, removal of the two benzyl protecting groups
in 7 followed by mild oxidation of the primary hydroxyl should
result in the requisite cyclized acrolein-2′-deoxyguanine adduct
as its bis-TBDMS ether. Along these lines, exposure of 7 to 1
atm H2 and 10% Pd-C in 1:1 THF-MeOH resulted in the
debenzylated product 8 (89% yield). Upon monitoring this
reduction carefully, it was observed that the nucleoside benzyl
ether underwent rapid deprotection (within 4 h), whereas the
alkyl benzyl ether required prolonged exposure to the reductive
conditions (23 h).
With 8 in hand, the final oxidative cyclization to 9 was
explored. This proved to be nontrivial and both TPAP/
NMO17,18 as well as PCC19,20 gave modest to low yields of
9 (Table 2). In the presence of silica gel, 4-acetylamino-
2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluorobo-
rate has been shown to be an excellent mild oxidant.21,22
Application of this reagent resulted in successful synthesis
of the desired 9 in 69% yield.
entry
1
conditions
resulta
TPAP (0.16 molar equiv), NMO
(1.9 molar equiv), 4 Å molecular sieves,
CH2Cl2, room temperature, 8 h
PCC (3.0 molar equiv),
4 Å molecular sieves, CH2Cl2,
room temperature, 16 h
4-acetylamino-2,2,6,6-tetramethylpiperidine- 69% yield
1-oxoammonium tetrafluoroborate
(1.2 molar equiv), silica gel, CH2Cl2,
room temperature, 16 h
Incomplete
reaction,
41% yield
23% yield
2
3
a Yield of isolated, purified product.
The in situ formation of phosphonium salts in the reactions
of peptide coupling agents with amide and urea functional-
ities have been reported.23 However, in this letter we have
shown that the C-2 tris(dimethylamino)phosphonium hexaflu-
orophosphate salt 3 is formed in a high-yield reaction of O6-
benzyl-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyxan-
thosine (2) with BOP, and is a readily isolated species. This
reactivity contrasts to that of inosine nucleosides with BOP,
where the final products are the O6-(benzotriazol-1-yl)
derivatives.9
Salt 3 is a good substrate for SNAr displacement reactions
with primary and secondary amines, providing a facile
approach to N2-modified 2′-deoxyguanosine analogues. As
demonstrated with the synthesis of the acrolein-2′-deoxygua-
nosine adduct 9, it appears that 3 can be used for the synthesis
of other biologically important compounds. Thus, these C-2
nucleoside phosphonium salts can be considered as a new
family of reactive nucleosides. Given the simplicity in
synthesis, a variety of O6 protecting groups can be readily
utilized in order to accommodate for a wide range of
reactions. Other reactions of the C-2 tris(dimethyl)phospho-
nium hexafluorophosphate salt 3 and related compounds are
currently under investigation in our laboratories.
Acknowledgment. Support of this work by NSF Grant No.
CHE-0640417 and a PSC CUNY-38 award are gratefully
acknowledged. Acquisition of a mass spectrometer was funded
by NSF Grant No. CHE-0520963. Infrastructural support at
CCNY was provided by NIH RCMI Grant No. G12 RR03060.
We thank Prof. James. M. Bobbitt (University of Connecticut)
for a generous sample of 4-acetylamino-2,2,6,6-tetramethylpi-
peridine-1-oxoammonium tetrafluoroborate.
Note Added after ASAP Publication. In the version
published May 29, 2008 the compound named O6-Benzyl-
2′,3′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyxanthosine was
changed to O6-Benzyl-3′,5′-bis-O-(tert-butyldimethylsilyl)-
2′-deoxyxanthosine in three places.
(16) Hu, X. E.; Cassady, J. M. Synth. Commun. 1995, 25, 907–913.
(17) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13–19
.
(18) Manaviazar, S.; Frigerio, M.; Bhatia, G. S.; Hummersone, M. G.;
Aliev, A. E.; Hale, K. J. Org. Lett. 2006, 8, 4477–4480
.
(19) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647–2650
.
(20) Su, Q.; Panek, J. S. Angew. Chem., Int. Ed. 2005, 44, 1223–1225
.
(21) (a) Zakrzewski, J.; Grodner, J.; Bobbitt, J. M.; Karpin´ska, M.
Synthesis 2007, 2491–2494. (b) Bobbitt, J. M.; Merbouh, N. Org. Synth.
Supporting Information Available: Experimental pro-
cedures, 1H and 13C NMR spectra of 3, 4a-g, and 7-9. 1H
NMR spectra of 5a-d,f,g and 31P{1H} NMR spectrum of
3. This material is available free of charge via the Internet
at http://pubs.acs.org.
2005, 82, 80–86
.
(22) For a mechanism, see: (a) Bailey, W. F.; Bobbitt, J. M.; Wiberg,
K. B. J. Org. Chem. 2007, 72, 4504–4509. (b) Bobbitt, J. M. J. Org. Chem.
1998, 63, 9367–9374
.
(23) For examples, see: (a) Wan, Z.-K.; Wacharasindhu, S.; Levins,
C. G.; Lin, M.; Tabei, K.; Mansour, T. S. J. Org. Chem. 2007, 72, 10194–
10210. (b) Kang, F.-A.; Kodah, J.; Guan, Q.; Li, X.; Murray, W. V. J.
Org. Chem. 2005, 70, 1957–1960
.
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