Unusual olefin formation by PhSe-F trans-elimination

Article abstract of DOI:10.1080/15257770500230335

A new approach to the synthesis of 2′,3′-didehydro-2′, 3′-dideoxynucleosides was described in excellent yield through unusual olefin formation by PhSe-F trans-elimination. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/15257770500230335

This article was downloaded by: [University of Utah]
On: 09 October 2014, At: 20:59
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
Unusual Olefin Formation by PhSe-F trans-Elimination
Dr. Jinfa Du a , Junxing Shi a , Byoung-Kwon Chun a , Ann Hobbs a , Laurent Hollecker a &
Kyoichi A. Watanabe a
a Pharmasset, Inc. , 1860 Montreal Road, Tucker, Georgia, USA
Published online: 31 Aug 2006.
To cite this article: Dr. Jinfa Du , Junxing Shi , Byoung-Kwon Chun , Ann Hobbs , Laurent Hollecker & Kyoichi A. Watanabe
(2005) Unusual Olefin Formation by PhSe-F trans-Elimination, Nucleosides, Nucleotides and Nucleic Acids, 24:9, 1289-1292,
DOI: 10.1080/15257770500230335
To link to this article: http://dx.doi.org/10.1080/15257770500230335
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, 24 (9):1289–1292, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1080/15257770500230335
UNUSUAL OLEFIN FORMATION BY PhSe-F TRANS-ELIMINATION
Jinfa Du, Junxing Shi, Byoung-Kwon Chun, Ann Hobbs, Laurent Hollecker, and
5
Kyoichi A. Watanabe
Pharmasset, Inc., Tucker, Georgia, USA
5
A new approach to the synthesis of 2’,3’-didehydro-2’,3’-dideoxynucleosides was described in
excellent yield through unusual olefin formation by PhSe-F trans-elimination.
Keywords Nucleoside, HBV, HIV, Elimination
INTRODUCTION
Several 2’,3’-didehydro-2’,3’-dideoxynucleosides (d4-nucleosides) showed po-
tent activity against human immunodeficiency virus (HIV) in vitro.[1] D-2’,3’-
Didehydro-3’-deoxythymidine (d4T) has been approved by the FDA for clinical
treatment of HIV infection.[2] D-2’,3’-Didehydro-2’,3’-dideoxy-5-fluorocytidine
(d4FC) is currently in Phase II evaluation for the clinical treatment of HIV
infection, which is resistant to other nucleoside drugs, such as AZT and 3TC.[3]
Recently, L-2’,3’-didehydro-2’,3’-dideoxy-3’-fluorocytidine (L-3’-Fd4C) was reported
to show promising antiviral activity against HIV infection.[4] Due to the importance
of d4-nucleosides in antiviral chemotherapy, there are several methods developed
for the syntheses of d4-nucleosides.[5–9] Mattock’s bromide, 2-acetoxyisobutyryl
bromide, made the synthesis of d4-nucleosides from ribo-nucleosides practical.[9] d4-
Nucleosides can be prepared in excellent yields by the treatment of ribo-nucleosides
with Mattock’s bromide followed by reductive-elimination with Cu-Zn and
deprotection. We herein report a new approach to the synthesis of d4-nucleosides
in excellent yield by the treatment of 2,2’-anhydro-3’-fluorolyxofuranosyl nucleoside
with lithium phenylselenide (LiSePh).
In our ongoing drug development program, a sufficient amount of L-3’-Fd4C
was needed for in vivo evaluation. The original method from L-arabinose in 13
steps gave very low overall yield (3.88%).[4] Therefore, it was necessary for us to
develop a novel procedure scalable for its preparation in a large quantity. Huang
Received 13 January 2005, accepted 2 May 2005.
Address correspondence to Dr. Jinfa Du, Pharmasset, Inc., 1860 Montreal Road, Tucker, GA 30084, USA;
Fax: (678) 395-0030; E-mail: jdu@pharmasset.com
1289
Order reprints of this article at www.copyright.rightslink.com

1290
J. Du et al.
et al. reported that D-2’,3’-didehydro-3’-deoxy-2’-fluorothymidine (2’-Fd4T) was
synthesized from 2,3’-anhydro-2’-deoxy-2’-fluorolyxofuranosyl-5-methyluracil in
excellent overall yield by elimination catalyzed by t-BuOK in dimethylsulfoxide
(DMSO).[10] This strategy was utilized to explore the synthesis of L-3’-Fd4C through
the similar elimination of the key intermediate, 2,2’-anhydro-nucleoside 7.
RESULTS AND DISCUSSION
The exploration for the preparation of L-3’-Fd4C was illustrated in Scheme 1.
Compound 1 was prepared by Nomura’s method[11] for its D-isomer. Oxidation of
compound 1 with NaOCl catalyzed by 2,2,6,6-tetramethyl-1-piperidinyoxy
(TEMPO) followed by reduction of the resulting ketone with NaBH4 gave the
ribo-sugar 2 in excellent yield.[11,12] Treatment of 2 with (diethylamino)sulfur
trifluoride (DAST) in methylene chloride afforded the fluoro-sugar 3 in 80%
yield.[13] Acetolysis of compound 3 in Ac2O/AcOH in the presence of H2SO4
followed by coupling with silylated uracil in the presence of trimethylsilyl
trifluoromethanesulfonate (TMSOTf) provided b-nucleoside 5 in good yield.[14]
Deacetylation of 5 with Et3N in MeOH produced 1-(3’-deoxy-3’-fluoro-L-
xylofuranosyl)uracil derivative 6 in moderate yield. The key intermediate 3’-
*
deoxy-3’-fluoro-2,2’-anhydronucleoside 7 was obtained by reaction of compound
6 with mesyl chloride in the presence of Et3N followed by treatment with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) at reflux in methylene chloride. In contrast to
the preparation of 2’-F-d4T, complete decomposition was observed when
compound 7 was treated with t-BuOK in DMSO.[10] It was reported that d4-
nucleosides could be prepared by the treatment of 2,2’-anhydro-nucleosides with
phenylselenide ion followed by oxidative elimination of the resulting 2’-
phenylselenonyl intermediate with hydrogen peroxide.[15–17] In order to prepare
2’-phenylselenonyl intermediate 8, which could be further converted to inter-
mediate 10 for L-3’Fd4C by oxidative elimination with H2O2, compound 7 was
treated with lithium phenylselenide (LiSePh) in tetrahydrofuran (THF) at reflux
temperature. Instead of the expected 8, 5’-O-(p-chlorobenzoyl)-b-L-2’,3’-didehydro-
2’,3’-dideoxyuridine (9)y was obtained in 86% yield. The structures of 7 and 9 were
determined by high-resolution mass spectroscopy (HRMS) and comparison of
1H-NMR data with that reported in literature.[5]
1
*
Compound 7: H NMR (400 MHz, DMSO-d6) d 7.94 (d, J = 8.4 Hz, 2H, 2Bz-H), 7.90 (d, J = 7.2 Hz, 1H, H-
6), 7.62 (d, J = 8.4 Hz, 2H, 2Bz-H), 6.20 (d, J = 6.0 Hz, 1H, H-1’), 5.88 (d, J = 8.0 Hz, 1H, H-5), 5.72 (m, 1H, H-2’),
5.61 (dm, J = 56.0 Hz, 1H, H-3’), 4.65 (m, 1H, H-4’), 5.59 (dd, J = 4.4, 12.0 Hz, 1H, H-5’), 4.40 (dd, J = 8.0, 12.0 Hz,
1H, H-5’’). Anal Calcd for C16H12ClFN2O5: C, 52.40; H, 3.30; N, 7.64. Found: C, 52.19; H, 3.35; N, 7.65.
yCompound 9: 1H NMR (400 MHz, DMSO-d6) d 11.40 (s, 1H, D2O exchangeable, NH), 7.94 (d, J = 8.0 Hz,
2H, 2Bz-H), 7.64 (d, J = 6.8 Hz, 2H, 2Bz-H), 7.34 (d, J = 8.8 Hz, 1H, H-6), 6.82 (m, 1H, H-1’), 6.53 (d, J = 6.0 Hz,
1H, H-3’), 6.05 (d, J = 6.0 Hz, 1H, H-2’), 5.28 (d, J = 8.4 Hz, 1H, H-5), 5.12 (br s, 1H, H-4’), 4.55 (dd, J = 3.2,
12.0 Hz, 1H, H-5’), 4.45 (dd, J = 5.2, 12.0 Hz). Anal Calcd for C16H13ClN2O5ꢀ 1/4H2O: C, 54.35; H, 3.75; N, 7.92.
Found: C, 54.31; H, 3.81; N, 7.85.

Unusual Olefin Formation
1291
SCHEME 1 Reagents and conditions: a) i. TEMPO, NaOCl, H2O; ii. NaBH4; b) DAST, CH2Cl2; c) Ac2O,
AcOH, H2SO4; d) silylated uracil, TMSOTf, CH2Cl2; e) Et3N, MeOH; f) i. MsCl, Et3N, CH2Cl2; ii. DBU, CH2Cl2;
g) (PhSe)2, LiBH4, EtOH.
Possible mechanism of generation of compound 9 was also illustrated in
Scheme 1. Phenylselenide ion might attack the 2’-position of compound 7 to pro-
duce an intermediate 8, which could be converted to d4-nucleoside 9 by the direct
trans-elimination of F-Se or through intermediate 11. Our observation is unique
because fluorine is not considered a leaving group in the aliphatic system.[10,18]
In conclusion, a new approach to the synthesis of 2’,3’-didehydro-2’,3’-
dideoxynucleosides has been developed in excellent yield by the treatment of 2,2’-
anydro-3’-deoxy-3’-fluorolyxofuranosyl nucleoside with lithium phenylselenide
through a quite unusual mechanism.

1292
REFERENCES
J. Du et al.
1. Zemlicka, J. Enantioselectivity of the antiviral effects of nucleoside analogues. Pharmacol. Ther. 2000, 85,
251–266.
2. Lin, T.-S.; Schinazi, R.F.; Prusoff, W.H. Potent and selective in vitro activity of 3’-deoxythymidin-2’-ene (3’-
deoxy-2’,3’-didehydrothymidine) against human immunodeficiency virus. Biochem. Pharmacol. 1987, 36,
2713–2718.
3. Ma, L.; Hurwitz, S.J.; Shi, J.; McAree, J.J.; Liotta, D.C.; McClure, H.M.; Schinazi, R.F. Pharmacokinetics of
the antiviral agent b-D-2’,3’-didehydro-2’,3’-dideoxy-5-fluorocytidine in rhesus monkeys. Antimicrob. Agents
Chemother. 1999, 43, 381–384.
4. Chong, Y.; Gumina, G.; Mathew, J.S.; Schinazi, R.F.; Chu, C.K. L-2’,3’-Didehydro-2’,3’-dideoxy-3’-
fluoronucleosides: synthesis, anti-HIV activity, chemical and enzymatic stability, and mechanism of
resistance. J. Med. Chem. 2003, 46, 3245–3256.
5. Beach, J.W.; Kim, H.O.; Jeong, L.S.; Nampalli, S.; Islam, Q.; Ahn, S.K.; Babu, J.R.; Chu, C.K. A highly
stereoselective synthesis of anti-HIV 2’,3’-dideoxy- and 2’,3’-didehydro-2’,3’-dideoxynucleosides. J. Org.
Chem. 1992, 57, 3887–3894.
6. Ando, M.; Ohhara, H.; Takase, K. A mild and stereospecific conversion of vicinal diols into olefins via
2-methoxy-1,3-dioxolane. Chem. Lett. 1986, 879–882.
7. Clive, D.L.J.; Sgarbi, P.W.M.; Wickens, P.L. Synthesis of 2’,3’-didehydro-2’,3’-dideoxynucleosides by reaction
of 5’-O-protected nucleoside 2’,3’-dimesylates with lithium areneselenolates. J. Org. Chem. 1997, 62, 3751–
3753.
8. Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Zhu, Y.-L.; Gullen, E.; Dutschman, G.E.; Cheng, Y.-C. Design and synthesis
of 2’,3’-dideoxy-2’,3’-didehydro-b-L-cytidine (b-L-d4C) and 2’,3’-dideoxy-2’,3’-didehydro-b-L-5-fluorocytidine (b-
L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of
human immunodeficiency virus (HIV) in vitro. J. Med. Chem. 1996, 39, 1757–1759.
9. Greenberg, S.; Moffatt, J.G. Reactions of 2-acyloxyisobutyryl halides with nucleosides. I. Reactions of model
diols and of uridine. J. Am. Chem. Soc. 1973, 95, 4016–4024.
10. Huang, J.-Y.; Chen, L.-C.; Wang, L.; Kim, M.-H.; Warshaw, J.A.; Armstong, D.; Zhu, Q.-Y.; Chou, T.-C.;
Watanabe, K.A.; Matulic-Adamic, J.; Su, T.-L.; Fox, J.J.; Polsky, B.; Baron, P.A.; Gold, J.W.M.; Hardy, W.D.;
Zuckerman, E. Fluorinated sugar analogs of potential anti-HIV-1 nucleosides. J. Med. Chem. 1991, 34,
1640–1646.
11. Nomura, M.; Sato, T.; Washnosu, M.; Tanaka, M.; Asao, T.; Shuto, S.; Matsuda, A. Nucleosides and
nucleotides. Part 212: practical large-scale synthesis of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine
(ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the
Vorbruggen glycosylation reaction. Tetrahedron 2002, 58, 1279–1288.
12. Ma, T.; Pai, S.B.; Zhu, Y.L.; Lin, J.S.; Shanmuganathan, K.; Du, J.; Wang, C.; Kim, H.; Newton, G.M.; Cheng,
Y.-C.; Chu, C.K. Structure-activity relationships of 1-(2-deoxy-2-fluoro-b-L-arabinofuranosyl)pyrimidine
nucleosides as anti-hepatitis B virus agents. J. Med. Chem. 1996, 39, 2835–2843.
13. Gudmundsson, K.S.; Freeman, G.A.; Drach, J.C.; Townsend, L.B. Synthesis of fluorosugar analogues of 2,5,6-
trichloro-1-(b-D-ribofuranosyl)benzimidazole as antivirals with potentially increased glycosidic bond stability.
J. Med. Chem. 2000, 43, 2473–2478.
14. Du, J.; Surzhykov, S.; Lin, J.S.; Newton, M.G.; Cheng, Y.-C.; Schinazi, R.F.; Chu, C.K. Synthesis, anti-human
immunodeficiency virus and anti-hepatitis B virus activities of novel oxaselenolane nucleosides. J. Med.
Chem. 1997, 40, 2991–2993.
15. Haraguchi, K.; Tanaka, H.; Maeda, H.; Itoh, Y.; Saito, S.; Miyasaka, T. Selenoxide elimination for the
synthesis of unsaturated-sugar uracil nucleosides. J. Org. Chem. 1991, 56, 5401–5408.
16. Tong, W.; Xi, Z.; Gioeli, C.; Chattopadhyaya, J. Synthesis of new 2’,3’-modified uridine derivatives from 2’,3’-
ene-2’-phenylselenonyl uridine by michael addition reactions. Tetrahedron 1991, 47, 3431–3450.
17. Beach, J.W.; Kim, H.O.; Jeong, L.S.; Nampalli, S.; Islam, Q.; Ahn, S.K.; Babu, J.R.; Chu, C.K. A highly
stereoselective synthesis of anti-HIV 2’,3’-dideoxy- and 2’,3’-didehydro-2’,3’-dideoxynucleosides. J. Org.
Chem. 1992, 57, 3887–3894.
18. Siddiqui, M.A.; Driscoll, J.S.; Abushanab, E.; Kelley, J.A.; Barchi, J.J., Jr.; Marquez, V.E. The ‘‘b-fluorine
effect’’ in the non-metal hydride radical deoxygenation of fluorine-containing nucleoside xanthates.
Nucleosides Nucleotides Nucleic Acids 2000, 19, 1–12.