Synthesis of 9-fluorenemethyl boranophosphonodiphosphate via an H-phosphonate approach

Article abstract of DOI:10.1080/15257770701542413

9-Fluorenemethyl boranophosphonate 6 and its boranophosphonodiphosphate 7 were synthesized via an H-phosphonate approach. The method is efficient for the synthesis of acyclic compounds 6 & 7, and can be explored for the synthesis of nucleoside 5′-deoxy boranophosphonodiphosphate. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701542413

This article was downloaded by: [Cambridge University Library]
On: 10 August 2015, At: 23:41
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: 5 Howick Place, London, SW1P 1WG
Nucleosides, Nucleotides and Nucleic
Acids
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lncn20
Synthesis of 9-Fluorenemethyl
Boranophosphonodiphosphate Via an H-
Phosphonate Approach
Hongyan Liu a , Syed N. Hashmi a & Barbara Ramsay Shaw a
a Department of Chemistry , Duke University , Durham, North
Carolina, USA
Published online: 05 Dec 2007.
To cite this article: Hongyan Liu , Syed N. Hashmi & Barbara Ramsay Shaw (2007) Synthesis of
9-Fluorenemethyl Boranophosphonodiphosphate Via an H-Phosphonate Approach, Nucleosides,
Nucleotides and Nucleic Acids, 26:10-12, 1455-1457, DOI: 10.1080/15257770701542413
To link to this article: http://dx.doi.org/10.1080/15257770701542413
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Nucleosides, Nucleotides, and Nucleic Acids, 26:1455–1457, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701542413
SYNTHESIS OF 9-FLUORENEMETHYL BORANOPHOSPHONO-
DIPHOSPHATE VIA AN H-PHOSPHONATE APPROACH
Hongyan Liu, Syed N. Hashmi, and Barbara Ramsay Shaw
Department of
2
Chemistry, Duke University, Durham, North Carolina, USA
9-Fluorenemethyl boranophosphonate 6 and its boranophosphonodiphosphate 7 were synthesized
2
via an H-phosphonate approach. The method is efficient for the synthesis of acyclic compounds 6 &
7, and can be explored for the synthesis of nucleoside 5ꢁ-deoxy boranophosphonodiphosphate.
Keywords Boranophosphonate;
boranophosphonodiphosphate;
antiviral;
H-
phosphonate; triphosphate analogues
INTRODUCTION
Phosphonate nucleoside analogues were first synthesized by A.
Burger.[1] Since then, numerous synthetic approaches and biological
applications have been reported for various nucleoside phosphonates.
Potent antiviral activity (HSV, CMV, HBV, HIV) has been associated with
phosphonoalkylnucleobases, e.g., 9-[3-hydroxy-2-(phosphonylmethoxy)-
propyl]adenine (HPMPA) and 9-[2-(phosphonylmethoxy)ethyl]adenine
(PMEA).[2] The acyclic analogues possess a broad-spectrum anti-HSV
activity and a potent anti-HIV activity, respectively. More recently, borane
substitution of one of the non-bridging oxygens in a phosphate diester link-
age has been shown to improve substrate properties, increase lipophilicity,
and increase nuclease resistance compared to normal nucleotide diesters.[3]
Studies show that the presence of a BH3 group at the α-phosphate position
of di- and triphosphates of clinically relevant dideoxy compounds, such as
AZT, d4T, and ddA, improves both phosphorylation by nucleoside diphos-
phate kinase and incorporation by wild-type and mutant HIV-1 reverse
transcriptase (RT).[4] Moreover, after a boranophosphate is incorporated
into a DNA chain, repair of the blocked DNA chains by pyrophosphorolysis
is reduced significantly with mutant RT enzymes from drug-resistant viruses.
This research was supported by NIH grant GM-57693 to B.R.S. We thank Dr. Ping Li and Dr. Shoeb
I. Khan for helpful discussion.
Address correspondence to Barbara Ramsay Shaw, Department of Chemistry, Duke University,
Durham, NC 27708, USA. E-mail: brshaw@chem.duke.edu
1455

1456
H. Liu et al.
It, thus, is worthwhile to combine the borane with the phosphonate modi-
fication to study their antiviral properties. To our knowledge, no method
has been reported for synthesis of a boranophosphonodiphosphate.
Here we present the synthesis of a model compound, 9-fluorenemethyl
boranophosphonodiphosphate 7, via a modified H-phosphonate approach
(Scheme 1).
As shown in Scheme 1, the commercially available 9-fluorenemethanol
was reacted with methyltriphenoxyphosphonium iodide in the presence
of 2,6-lutidine to give 9-fluorenemethyl iodide 2 in 90% yield. The iodide
was then treated with bis(trimethylsilyl)phosphonite (BTSP) 3[5](prepared
by refluxing the mixture of ammonium phosphinate and hexamethyl-
disilazane under argon) to obtain 9-fluorenemethyl H-phosphonate 4
in 85% yield. Subsequent silylation, boronation, and hydrolysis gave 9-
fluorenemethyl boranophosphonate 6 in quantitative yield.[6] In the pres-
ence of trifluoroacetic anhydride and N -methylimidazole, 9-fluorenemethyl
boranophosphonate 6 was further phosphorylated by tributylammonium
pyrophosphate to give 9-fluorenemethyl boranophosphonodiphosphate 7
in 30% yield.[7]
SCHEME 1 Synthesis of 9-fluorenemethyl boranophosphonate 6 and boranophosphonodiphosphate 7.

Synthesis of 9-Fluorenemethyl Boranophosphono-Diphosphate
1457
In conclusion, a modified H-phosphonate approach was applied to
synthesize the first fluorescent-labeled boranophosphonate compound, 6,
in good yield. It was further pyrophosphorylated to 9-fluorenemethyl bo-
ranophosphonodiphosphate 7. This method is being explored to make
cyclic and acyclic nucleoside boranophosphonodiphosphate compounds as
triphosphate analogues.
REFERENCES
1. Parikh, J.R.; Wolff, M.E.; Burger, A. Analogs of nucleotides. II. phosphonate esters of ribose and
glucopyranosyl purine derivatives. J. Am. Chem. Soc. 1957, 79, 2778–2781.
2. De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P.C. A novel selective broad-
spectrum anti-DNA virus agent. Nature 1986, 323, 464–467.
3. Shaw, B.R.; Sergueev, D.; He, K.; Porter; K., Summers, J.; Sergueeva, Z.; Rait, V. Boranophosphate
backbone: a mimic of phosphodiesters, phosphorothioates, and methylphosphonates. Methods in En-
zymology: Antisense Technology 1999, 313, 226–257.
4. Meyer, P.; Schneider, B.; Sarfati, S.; Deville-Bonne, D.; Guerreiro, C.; Boretto, J.; Janin, J.; Veron, M.;
Canard, B. Structural basis for activation of alpha-boranophosphate nucleotide analogues targeting
drug-resistant reverse transcriptase. EMBO J. 2000, 19, 3520–3529.
5. An, H.; Wang, T.; Maier, M.A.; Manoharan, M.; Ross, B.S.; Cook, P.D.. Synthesis of novel 3ꢁ-C-
methylene thymidine and 5-methyluridine/cytidine H-phosphonates and phosphonamidites for new
backbone modification of oligonucleotides. J. Org. Chem. 2001, 66, 2789–2801.
6. Compound 6: 1H NMR (D2O) δ 7.65–7.23 (m, 8H, Ph), 4.12 (m, 1H, H-9), 1.96 (m, 2H, CH2),
(+)0.62-(−)0.03 (br, 3H, BH3); 31P NMR (D2O) δ 100.60 (br, 1P); LC-MS m/z 257.0, calcd for
C
14H14BO2P− (M−): 257.09.
7. Compound 7: 31P NMR (D2O) δ 115.60 (br, 1P, P-α), -9.95 (s, 1P, P-γ ), -20.23 (s, 1P, P-β); LC-MS m/z
416.6, calcd for C14H17BO8P−3 (M−): 417.02.