New telluride-mediated elimination for novel synthesis of 2′,3′-didehydro-2′,3′-dideoxynucleosides

Article abstract of DOI:10.1021/jo7025806

(Chemical Equation Presented) Several 2′,3′-dideoxynucleosides (ddNs) and 2′,3′-didehydro-2′,3′-dideoxynucleosides (d4Ns) are FDA-approved anti-HIV drugs. Via conveniently synthesized 2,2′-anhydronucleosides, we have developed a novel synthesis of d4Ns by discovering and applying a new telluride-mediated elimination reaction. Our experiment results show that after substitution of 2,2′-anhydronucleosides with a telluride monoanion, a telluride intermediate is formed, and its elimination leads to formation of the olefin products (d4Ns). Our mechanistic study indicates that this telluride-assisted reaction consists of two steps: substitution (or addition) and elimination. By using dimethyl ditelluride (0.1 equiv) as the reagent, d4Ns can be synthesized with yields up to 90% via this telluride-mediated elimination. Our novel strategy has great potential to simplify synthesis of these drugs and to further reduce cost of AIDS treatment and will also facilitate development of novel d4N and ddN analogues.

Full text of DOI:10.1021/jo7025806

New Telluride-Mediated Elimination for Novel Synthesis of
2′,3′-Didehydro-2′,3′-dideoxynucleosides
Jia Sheng, Abdalla E. A. Hassan, and Zhen Huang*
Department of Chemistry, Georgia State UniVersity, Atlanta, Georgia 30303
huang@gsu.edu
ReceiVed December 4, 2007
Several 2′,3′-dideoxynucleosides (ddNs) and 2′,3′-didehydro-2′,3′-dideoxynucleosides (d4Ns) are FDA-
approved anti-HIV drugs. Via conveniently synthesized 2,2′-anhydronucleosides, we have developed a
novel synthesis of d4Ns by discovering and applying a new telluride-mediated elimination reaction. Our
experiment results show that after substitution of 2,2′-anhydronucleosides with a telluride monoanion, a
telluride intermediate is formed, and its elimination leads to formation of the olefin products (d4Ns). Our
mechanistic study indicates that this telluride-assisted reaction consists of two steps: substitution (or
addition) and elimination. By using dimethyl ditelluride (0.1 equiv) as the reagent, d4Ns can be synthesized
with yields up to 90% via this telluride-mediated elimination. Our novel strategy has great potential to
simplify synthesis of these drugs and to further reduce cost of AIDS treatment and will also facilitate
development of novel d4N and ddN analogues.
Introduction
well-developed strategies, including Corey-Winter reaction
through the cyclic thionocarbonates,5 Eastwood olefination
through the cyclic orthoformates,6 Mattocks reaction through
the bromoacetates,7 and olefin metathesis via the ring-closure
reaction.8 In addition, 2′,3′-anhydro-2′-deoxyuridine and -thy-
midine can be converted to d4Ns via base-catalyzed elimina-
tion.9 Furthermore, syntheses of d4Ns via oxidative elimination
2′,3′-Dideoxynucleosides (ddNs) and 2′,3′-didehydro-2′,3′-
dideoxynucleosides (d4Ns) are an important type of antiviral
compounds, which terminate viral DNA polymerization after
their incorporation by reverse transcriptase.1 Several of them
(Figure 1), including 2′,3′-dideoxycytidine (ddC, 1), 2′,3′-
didehydro-3′-deoxythymidine (d4T, Stavudine, 2), 3′-azido-3′-
deoxythymidine (AZT, 3), ddI (2′,3′-dideoxyinosine, 4), 3TC
(ꢀ-3′-deoxy-3′-thiocytidine, 5), ABC (Abacavir, 6), and FTC
(Emtricitabine, 7), have been approved and permitted for
marketing by the FDA as potent anti-HIV therapeutics.2 Since
the finding of the ddNs and d4Ns with high efficacy against
HIV, tremendous attention has been directed toward the
development of new chemistry for synthesizing these com-
pounds as well as exploring novel analogues in order to reduce
cost and better treat AIDS, one of the most deadly diseases
caused by HIV.3
(3) (a) Ogilvie, K. K.; Iwacha, D. J. Can. J. Chem. 1974, 52, 1787. (b) Saito,
Y.; Zevaco, T. A; Agrofoglio, L. A. Tetrahedron 2002, 58, 9593. (c) Wiley,
C. A.; Grafe, M.; Kennedy, C.; Nelson, J. A. Acta Neuropathol. (Berlin) 1988,
76, 338. (d) Kikyoya, T. Jpn. Kokai Tokkyo Koho 1988, JP 63241356-A-
19881006. (e) Luzzio, F. A.; Menes, M. E. J. Org. Chem. 1994, 59, 7267.
(4) Huryn, D. M.; Okabe, M. Chem. ReV. 1992, 92, 1745.
(5) (a) Dudycz, L. W. Nucleosides Nucleotides 1989, 8, 35. (b) Chu, C. K.;
Bhadti, V. S.; Doboszewski, B.; Gu, Z. P.; Kosugi, Y.; Pullaiah, K. C.; Van
Roey, P. V. J. Org. Chem. 1989, 54, 2217.
(6) (a) Josan, J. S.; Eastwood, F. W. Aust. J. Chem. 1968, 21, 2013. (b)
Crank, G.; Eastwood, F. W. Aust. J. Chem. 1964, 17, 1392.
(7) (a) Robins, M. J.; Wilson, J. S.; Madej, D.; Low, N. H.; Hansske, F.;
Wnuk, S. F. J. Org. Chem. 1995, 60, 7902. (b) Mansuri, M. M.; Starrett, J. E.;
Wos, J. A.; Tortolani, D. R.; Brodfuehrer, P. R.; Howell, H. G.; Martin, J. C. J.
Org. Chem. 1989, 54, 4780. (c) Robins, M. J.; Hansske, F.; Low, N. H.; Park,
J. I. Tetrahedron Lett. 1984, 25, 367.
Extensive research has been conducted in this area, and the
field has been reviewed.4 In general, the ddNs can be synthesized
from hydrogenation of d4Ns, and d4Ns are synthesized from
(8) (a) Gillaizeau, I.; Lagoja, I. M.; Nolan, S. P.; Aucagne, V.; Rozenski,
J.; Herdewijn, P; Agrofoglio, L. A. Eur. J. Org. Chem. 2003, 666. (b) Ewing,
D.; Glacon, V.; Mackenzie, G.; Postel, D.; Len, C. Tetrahedron Lett. 2002,
43, 3503.
(1) For a review, see: Chu, C. K., Baker, D. C., Eds. Nucleosides and
Nucleotides as Antitumor and AntiViral Agents; Plenum Press: New York, 1993.
(2) (a) De Clercq, E. J. Med. Chem. 1995, 38, 2491. (b) Doong, S. L.; Tsai,
C. H.; Schinazi, R. F.; Liotta, D. C.; Cheng, Y. C. Proc. Natl. Acad. Sci. U.S.A.
1991, 88, 8495. (c) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17.
(9) Horwitz, J. P.; Chua, J.; Rooge, M. A. D.; Noel, R.; Klundt, I. L. J. Org.
Chem. 1966, 31, 205.
10.1021/jo7025806 CCC: $40.75
Published on Web 04/15/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3725–3729 3725

Sheng et al.
SCHEME 1. Synthesis of 2′-Se-nucleosides
SCHEME 2. Telluride-Mediated Elimination of Nucleosides
FIGURE 1. Structure of FDA-approved anti-HIV drugs.
of nucleoside R-phenyl selenoxides10 and via substitution of
nucleoside dimesylates by selenide and telluride dianions11 were
reported.
Despite enormous efforts in developing synthetic routes for
these d4Ns and ddNs, new methodology development will lead
to disease treatment cost reduction as well as novel analogue/
drug discovery. In our chemogenetic research of nucleic acid
structure and function using atomic probes, we have pioneered
atom-specific replacement of oxygen with selenium.12 Selenium
functionality can be successfully introduced to the R-2′-position
via reacting sodium methyl selenide (reduced from dimethyl
diselenide with NaBH4) with 2,2′-anhydronucleosides, which
gives the 2′-SeMe-nucleosides (Scheme 1).12a,g Surprisingly,
when the corresponding telluride was used (Scheme 2), instead
of the expected 2′-Te-nucleosides (11), we observed the formation
of eliminated 2′,3′- and 1′,2′-olefin products (12 and 13).
Interestingly, by tailoring the SN2 leaving ability of the
3′-moieties (such as acetylation), we are able to steer the
telluride-mediated elimination to the 2′,3′-olefins (or d4Ns, 12)
exclusively. We report here the new telluride-mediated elimina-
tion reaction, its mechanistic study, and our novel methodology
for d4N synthesis.
available ribonucleosides,12a,g,13 followed by protection of the
5′- and 3′-hydroxyl groups using conventional methodologies.
On the basis of our observation of the telluride-mediated
elimination, we hypothesized a two-step mechanism: substitution
(or addition) and elimination. In this reaction, dimethyl ditel-
luride is first reduced to methyl telluride monoanion. Via a SN2
reaction, this strong telluride nucleophile attacks the R-2′-
position of 2,2′-anhydronucleosides by substituting the 2-oxide
as the intramolecular leaving group, which leads to formation
of a substitution (or addition) intermediate (11). This intermedi-
ate undergoes elimination to give 2′,3′-olefin (12, d4N) and 1′,2′-
olefin (13). This hypothesis has guided our investigation. When
dimethyl ditelluride (Me2Te2) was used as the reagent, however,
the expected intermediate 11 could not be isolated. The
instability of the intermediate was probably caused by the highly
reactive alkyl telluride. Thus, we reasoned that a less reactive
aryl telluride might allow us to isolate the intermediate for a
mechanistic study.
Results and Discussion
Compound 8 was conveniently prepared via the well-
established 2,2′-anhydronucleoside synthesis from the readily
(10) (a) Diaz, Y.; El-Laghdach, A.; Matheu, M. I.; Castillon, S. J. Org. Chem.
1997, 62, 1501. (b) Beach, J. W.; Kim, H. O.; Jeong, L. S.; Nampalli, S.; Islam,
Q.; Ahn, S. K.; Babu, J. R.; Chu, C. K J. Org. Chem. 1992, 57, 3887. (c)
Haraguchi, K.; Tanaka, H.; Maeda, H.; Itoh, Y.; Saito, S.; Miyasaka, T. J. Org.
Chem. 1991, 56, 5401.
As expected, when diphenyl ditelluride was used as the
reagent, we were indeed able to successfully isolate the telluride
intermediate. Due to the 3′-deacetylation under basic conditions
in ethanol, however, intermediate 15 with the 2′-Ph-Te func-
tionality was isolated instead of the 3′-Ac intermediate (14,
Scheme 3). Similar to oxidative elimination of the nucleoside
phenylselenides,9,10a phenyltelluride 15 can also undergo oxida-
(11) Clive, D. L. J.; Wickens, P. L.; Sgarbi, P. W. M. J. Org. Chem. 1996,
61, 7426.
(12) (a) Sheng, J.; Jiang, J.; Salon, J.; Huang, Z. Org. Lett. 2007, 9, 749. (b)
Salon, J.; Sheng, J.; Jiang, J.; Chen, G.; Caton, W, J.; Huang, Z. J. Am. Chem.
Soc. 2007, 129, 4862. (c) Jiang, J.; Sheng, J.; Carrasco, N.; Huang, Z. Nucleic
Acids Res. 2007, 35, 477. (d) Carrasco, N.; Caton-Williams, J.; Brandt, G.; Wang,
S.; Huang, Z. Ang. Chem., Int. Ed. 2006, 45, 94. (e) Salon, J; Chen, G.; Portilla,
Y.; Germann, M. W.; Huang, Z. Org. Lett. 2005, 7, 5645. (f) Carrasco, N.; Huang,
Z. J. Am. Chem. Soc. 2004, 126, 448. (g) Carrasco, N.; Buzin, Y.; Tyson, E.;
Halpert, E.; Huang, Z. Nucleic Acids Res. 2004, 32, 1638. (h) Du, Q.; Carrasco,
N.; Teplova, M.; Wilds, C. J.; Egli, M.; Huang, Z. J. Am. Chem. Soc. 2002,
124, 24. (i) Carrasco, N.; Ginsburg, D.; Du, Q.; Huang, Z. Nucleosides
Nucleotides Nucleic Acids 2001, 20, 1723.
(13) (a) Ogilvie, K. K.; Iwacha, D. J. Can. J. Chem. 1974, 52, 1787. (b) Shi,
J.; Du, J.; Ma, T.; Pankiewicz, K. W.; Patterson, S. E.; Tharnish, P. M.; McBrayer,
T. R.; Stuyver, L. J.; Otto, M. J.; Chu, C. K.; Schinazi, R. F.; Watanabe, K. A.
Bioorg. Med. Chem. 2005, 13, 1641.
3726 J. Org. Chem. Vol. 73, No. 10, 2008

Te-Mediated Nucleoside Elimination for d4N Synthesis
SCHEME 3. Mechanism of d4N Synthesis Assisted by the
Telluride Elimination
SCHEME 5. Telluride-Mediated Synthesis of d4Ns
SCHEME 4. Mechanism of the Telluride-Mediated
Elimination
TABLE 1. Synthesis of d4Ns via Te-Assisted Elimination (for
Scheme 5
substrates
R1
R2
R3
products
yield (%)
8a
8b
17a
17b
17c
H
CH3
H
H
H
Ac
Ac
Ac
Bz
DMTra
DMTr
Ac
Bz
DMTr
12a
12b
18a
18b
None
90
85
80
69
DMTr
a DMTr: dimethoxytrityl.
ditelluride reagent was not used in this reaction, only deacylated
products were observed instead of the eliminated products.
Moreover, no chemical reactions were observed in the absence
of NaBH4. Apparently, the telluride nucleophile may work as a
catalyst in this elimination reaction. The telluride nucleophile
(R-TeNa or R-TeH) is first generated by NaBH4 reduction of
the ditelluride reagent (RTe-TeR) and regenerated by reductive
elimination of the telluride intermediate, such as 15. Since
the methyl-telluro group at the 2′-position is more reactive than
the phenyl-telluro group and offers high yield, it is better to
use MeTe-TeMe for the elimination reaction, where longer
reaction time and the Te-intermediate isolation are not necessary.
In addition, we have incorporated a bulky DMTr group to
the 3′-position of 17c (Scheme 5). Probably due to the steric
hindrance of this protecting group, which prevents the attack
of the bulky telluride at the 2′-R-position, no elimination reaction
was observed (Table 1). Furthermore, when the 3′-OH of 8c
was not activated, 13 was formed via 1′, 2′-elimination (Scheme
2). Moreover, when both the 3′- and 5′-positions of 17 were
protected with the same acyl group for convenient synthesis
(e.g., Ac- or Bz-), satisfactory elimination yields of d4Ns were
also obtained. Thus, our experimental results reveal that a
moderate leaving group at the 3′-positions can provide sufficient
regioselectivity for the d4N synthesis, and that the 5′-position
is not involved in the Te-assisted substitution-elimination
reaction. Our experimental results suggest that this Te-mediated
elimination consists of a two-stage mechanism: substitution and
elimination.
tive elimination when treated with iodine/water (Scheme 4).
Furthermore, the cis-2′,3′-elimination of 15 can also happen
when it is treated with NaBH4, which explains the formation
of a significant amount of 12 formed during the synthesis of
phenyltelluride nucleoside 15. Under the oxidative condition,
this cis-elimination is probably caused by convenient transfer
of the 3′-OH to the tellurium functionality in the same face.
Under the NaBH4 reduction, the telluride is probably reduced
first by hydride, thereby generating a carbanion at the 2′-position
and followed by elimination via an E1cb mechanism. Moreover,
it is worth mentioning that, to the best of our knowledge, this
is the first synthesis and isolation of tellurium-modified
nucleosides.
To further explore the elimination mechanism and synthesis,
the d4N formation has been further investigated with dimethyl
ditelluride (Scheme 5). The advantages of using Me2Te2 are
that (i) the substitution-elimination reaction is fast and (ii) we
are able to control the exclusive formation of the 2′,3′-
elimination products (d4Ns) without isolation of the telluride
intermediate. In addition, by placing acyl groups on the
3′-positions of 8 and 17, we are able to form 12 and 18 (5′-
protected d4Ns) exclusively with reaction yield up to 90%, when
Me2Te2 (0.1 equiv) is used (Table 1). Further lower amounts
of Me2Te2 did not work well, presumably due to the consump-
tion of MeTeH by minor side reactions. Furthermore, when a
Conclusions
We have successfully developed a novel synthetic strategy
for d4Ns via a new telluride-mediated elimination reaction.
J. Org. Chem. Vol. 73, No. 10, 2008 3727

Sheng et al.
14
1
17a: H NMR (CDCl3, identical to literature) δ 2.03 (s, 3H),
2.19 (s, 3H), 4.03-4.07 (dd, 1H, J1 ) 3.6 Hz, J2 ) 12.4 Hz),
4.33-4.37 (dd, 1H, J1 ) 3.6 Hz, J2 ) 12.4 Hz), 4.52-4.54 (m,
1H), 5.41-5.42 (m, 1H), 5.44-5.45 (m, 1H), 6.09 (d, J ) 7.2 Hz,
1H), 6.30 (d, J ) 6.4 Hz, 1H), 7.37 (d, J ) 7.2 Hz, 1H); ESI-TOF
m/z calcd for C13H15N2O7 (M + H)+ 311.0879, found 311.0883.
17b: 1H NMR (DMSO-d6, identical to literature)15 δ 4.34-4.39
(m, 2H), 4.89 (m, 1H), 5.72 (m, 1H), 5.75-5.78 (m, 1H), 5.90 (d,
1H, J ) 7.2 Hz), 6.49 (d, 1H, J ) 5.6 Hz), 7.49-8.07 (m, 11H);
ESI-TOF m/z calcd for C23H19N2O7 (M + H)+ 435.1192, found
435.1177.
Substitution of 2,2′-anhydronucleosides with a telluride monoan-
ion leads to formation of a telluride intermediate. When the
3′-OH of the 2, 2′-anhydronucleosides is acylated, this Te-
intermediate is eliminated to give d4Ns exclusively. The
synthesis of d4Ns can reach up to 90% yield when dimethyl
ditelluride (0.1 eq) is used. Furthermore, our mechanistic studies
suggest that this telluride-mediated elimination reaction consists
of two steps: the substitution (or addition) and elimination.
17c: 1H NMR (CDCl3, identical to literature)16 δ 2.79-2.92 (m,
2H), 3.74 (s, 3H), 3.78 (s, 3H), 3.84 (s, 12H), 3.94-3.96 (m, 1H),
4.32 (m, 1H), 4.77-4.81 (m, 1H), 5.90 (d, J ) 7.2 Hz, 1H), 5.95
(d, J ) 5.6 Hz, 1H), 6.78-6.85 (m, 8H), 7.13-7.42 (m, 19H);
ESI-TOF m/z calcd for C51H47N2O9 (M + H)+ 831.3282, found
831.3277.
(R)-5-(4,4′-Dimethoxytrityloxymethyl)-2,3-dihydrofuran-4-
ol (13). To a stirred suspension of NaBH4 (12 mg) in anhydrous
THF (5 mL), under argon, was added dimethyl ditelluride (50 µL,
0.3 mmol), followed by several drops of dry ethanol until bubbles
formed. The suspension was heated to 50 °C, and then the THF
solution of starting material 8c (0.32 g, 0.6 mmol) was added
dropwise. The mixture was heated for 3 h at this temperature under
argon. The solvent was evaporated under reduced pressure, and
the residue was then dissolved in CH2Cl2 (20 mL). The solution
was washed with water (3 × 20 mL). The CH2Cl2 layer was dried
over MgSO4(s) and evaporated under reduced pressure, and the
residue was purified by silica gel column chromatography with pure
CH2Cl2 to give compound 13 as a white solid (230 mg, 92% yield).
13: 1H NMR (CDCl3) δ 3.18-3.22 (m, 2H), 3.81 (s, 6H),
4.44-4.49 (m, 1H), 4.79-4.81 (m, 1H), 5.20-5.21 (m, 1H),
6.62-6.63 (m, 1H), 6.84-6.86 (m, 4H), 7.23-7.46 (m, 9H,), 7.85
(d, J ) 7.6 Hz, 1H); 13C NMR (CDCl3) δ 55.2, 63.7, 76.2, 86.0,
88.3, 103.3, 113.1, 126.8, 127.8, 128.1, 130.1, 136.0, 144.8, 150.3,
158.5; ESI-TOF m/z calcd for C26H25O5 (M - H)- 417.1702, found
417.1708; mp 142.4-143.7 °C.
5′-O-(4,4′-Dimethoxytrityl)-2′-phenyltelluro-2′-deoxyuridine
(15a) or -thymidine (15b). To a stirred suspension of NaBH4 (6.2
mg) in anhydrous THF (5 mL), under argon at 0 °C, was added
the THF solution of diphenylditelluride (0.2 g, 0.5 mmol in 5 mL),
followed by several drops of dry ethanol until bubbles formed and
the solution turned colorless. To this solution was added the starting
material 8a (0.285 g, 0.5 mmol, dissolved in 5 mL of THF), and
the reaction was slowly warmed to room temperature and allowed
to progress for 3 h at 50 °C, monitored by TLC. The solvent was
then evaporated under reduced pressure. The residue was dissolved
in CH2Cl2 (20 mL) and washed with water (3 × 20 mL). The
CH2Cl2 solution was dried over MgSO4(s), and evaporated under
reduced pressure. The crude product was purified by silica gel
column chromatography (gradient, 0-3% methanol in CH2Cl2) to
give compound 15a as slight yellow solid (163 mg, 42% yield).
Compound 15b was synthesized analogously to 15a.
Experimental Section
5-Methyluridine or ribothymidine (16b). was synthesized from
thymine and the acylated ribose via glycosidation by following
minor modifications of the literatures.7c,12a
2,2′-Anhydro-1-[2′-deoxy-3′-acetyl-5′-O-(4,4-dimethoxytrityl)-
ꢀ-D-arabinofuranosyl]uracil (8a) or -5-methyluracil (8b). 2,2′-
Anhydrouridine3a,b,12g and 2,2′-anhydro-5-methyuridine12a,13 were
first synthesized by following slight modifications of the literatures.
Then, to a suspension of 2,2′-anhydrouridine or 2,2′-anhydrothy-
midine (2.85 or 3.02 g, 12.6 mmol) in dry pyridine (25 mL) was
added dimethoxytrityl chloride (DMT-Cl, 2.36 g, 6.95 mmol), and
the mixture was stirred at room temperature. One hour later,
additional DMT-Cl (2.36 g, 6.95 mmol) was added, and the mixture
was stirred for another 1 h (the 5′- and 3′-ditritylated products can
be isolated as 8c or 8d). Acetic anhydride (1.89 mL, 20 mmol)
was then added, and the mixture was stirred for 20 min at room
temperature. The reaction was quenched by the addition of methanol
(4 mL), and the solvents were removed under reduced pressure.
The residue was dissolved in CH2Cl2 (40 mL), and the suspension
was washed with sodium bicarbonate (sat., 2 × 15 mL) and
saturated brine (2 × 15 mL). The organic layer was dried over
MgSO4(s) and concentrated under reduced pressure, and the
resulting residue was subjected to silica gel chromatography (0-5%
MeOH in CH2Cl2) which gave pure 8a (5.8 g, 87% yield) and 8b
(5.9 g, 85% yield) as white solids.
1
8a: H NMR (CDCl3) δ 2.14 (s, 3H), 2.99-3.06 (m, 2H), 3.81
(s, 6H), 4.45 (m, 1H), 5.30-5.32 (m, 1H), 5.40 (m, 1H), 5.86 (d,
J ) 7.6 Hz, 1H), 6.27 (d, J ) 5.6 Hz, 1H), 6.80-6.83 (m, 4H),
7.21-7.35 (m, 10H); 13C NMR (CDCl3) δ 20.7, 55.3, 62.6, 77.0,
85.8, 86.3, 86.6, 90.4, 110.2, 113.3, 127.1, 128.0, 129.8, 135.2,
144.1, 158.6, 134.5, 159.1, 169.4, 171.2; ESI-TOF m/z calcd for
C32H31N2O7 (M+H)+ 571.2080,found571.2080;mp126.1-127.2°C.
1
8b: H NMR (CDCl3) δ 1.86 (s, 3H), 2.23 (s, 3H), 2.94-3.04
(m, 2H), 3.80 (s, 6H), 4.42-4.45 (m, 1H), 5.27-5.28 (m, 1H),
5.38 (m, 1H), 6.22 (d, J ) 5.6 Hz, 1H), 6.76-6.81 (m, 4H),
7.12-7.35 (m, 10H); 13C NMR (CDCl3) δ 14.1, 20.7, 55.2, 62.8,
77.1, 85.8, 86.0, 86.6, 90.3, 119.0, 113.2, 127.9, 128.2, 129.8, 135.1,
144.1, 157.1, 130.0, 158.7, 169.6, 171.8; ESI-TOF m/z calcd for
C33H33N2O7 (M+H)+ 585.2237,found585.2255;mp130.5-131.3°C.
2,2′-Anhydro-1-(2′-deoxy-3′,5′-di-O-acety-ꢀ-D-arabinofuran-
osyl)uracil (17a), 2,2′-Anhydro-1-(2′-deoxy-3′,5′-di-O-benzoyl-
ꢀ-D-arabinofuranosyl)uracil (17b), and 2,2′-Anhydro-1-[2′-deoxy-
3′,5′-di-(4,4-dimethoxytrityl)-ꢀ-D-arabinofuranosyl]uracil (17c).
To the pyridine suspension (10 mL) of 2,2′-anhydrouridine (0.62
g, 2.75 mmol) at room temperature was added acetic anhydride
(for 17a, 0.8 mL, 8.25 mmol), benzoyl chloride (for 17b, 0.95 mL,
8.25 mmol), or the pyridine solution of dimethoxytrityl chloride
(for 17c, 1.86 g, 5.5 mmol). The reactions were stirred overnight
before quenching with methanol (5 mL) and water (5 mL). The
solvents were evaporated under reduced pressure, and the residue
of 17a, 17b, or 17c was dissolved in dichloromethane and washed
with saturated sodium dicarbonate, brine, and water. The organic
layers were combined, dried over MgSO4(s), and evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (gradient, 0-3% of methanol in CH2Cl2). The
yields were generally high (88-95%) for the synthesis of 17a-c.
15a: 1H NMR (CDCl3) δ 3.45-3.46 (m, 2H), 3.82 (s, 6H),
3.92-3.95 (m, 1H), 4.24 (m, 1H), 4.54-4.57 (m, 1H), 5.12 (d, J
) 8 Hz, 1H), 6.63 (d, J ) 9.2 Hz, 1H), 6.81-6.86 (m, 4H),
7.19-7.37 (m, 12H), 7.45 (d, J ) 8 Hz, 1H), 7.82 (m, 2H); 13C
NMR (CDCl3) δ 36.9, 55.3, 63.9, 75.1, 85.5, 87.2, 91.6, 102.5,
109.6, 113.3, 127.2, 127.8, 128.0, 128.1, 128.7, 129.5, 130.1, 135.2,
140.2, 144.2, 150.2, 158.7, 162.7; ESI-TOF m/z calcd for C36
-
H34N2O7TeNa(M+Na)+759.1326,found759.1316;mp135.2-136.3°C.
15b: 1H NMR (CDCl3) δ 1.21 (s, 3H), 2.71-2.83 (m, 1H), 3.36
and 3.51 (2xd, J ) 10 and 10 Hz, 2H), 3.81 (s, 6H), 3.95-4.06
(14) Logue, M. W.; Han, B, H. J. Org. Chem. 1980, 45, 5000.
(15) Sasaki, T.; Minamoto, K.; Sugiura, T.; Niwa, M. J. Org. Chem. 1976,
41, 3138.
(16) Dunkel, M.; Cook, P. D.; Acevedo, O. L. J. Heterocycl.Chem. 1993,
30, 1421.
3728 J. Org. Chem. Vol. 73, No. 10, 2008

Te-Mediated Nucleoside Elimination for d4N Synthesis
(m, 1H), 4.21-4.27 (m, 1H), 4.54-4.62 (m, 1H), 6.70 (d, J ) 10
Hz, 1H), 6.81-6.86 (m, 4H), 7.19-7.41 (m, 12H), 7.84 (m, 2H),
8.18 (s, 1H); 13C NMR (CDCl3) δ 11.47, 36.8, 55.3, 63.9, 75.4,
85.2, 87.2, 91.0, 109.5, 111.3, 113.3, 127.2, 128.0, 128.1, 128.6,
129.5, 129.6, 130.1, 135.0, 135.1, 140.3, 144.2, 150.4, 158.8, 163.1;
ESI-TOF m/z calcd for C37H36N2O7TeNa (M + Na)+ 773.1477,
found 773.1475; mp 138.3-140.0 °C.
(m, 1 H), 6.51 (m, 1 H), 7.02 (m, 1 H), 7.67 (d, J ) 8.6 Hz, 1H);
ESI-TOF m/z calcd for C11H11N2O5 (M - H)- 251.0668, found
251.0670.
18b: 1H NMR (DMSO-d6, identical to literature)18 δ 4.43-4.51
(m, 2H), 5.15 (m, 1H), 5.18 (d, J ) 7.6 Hz, 1H), 6.02 (m, 1H),
6.51 (m, 1 H), 6.89 (m, 1 H), 7.25-7.85 (m, 5H), 7.92 (d, J ) 7.6
Hz, 1H). ESI-TOF m/z calcd for C16H13N2O5 (M-H)- 313.0824,
found 313.0825.
5′-O-(4,4-Dimethoxytrityl)-2′,3′-didehydro-2′,3′-dideoxyuri-
dine (12a), 5′-O-(4,4-dimethoxytrityl)-2′,3′-didehydro-2′,3′-did-
eoxy-5-methyluridine (12b), 5′-O-acetyl-2′,3′-didehydro-2′,3′-
dideoxyuridine (18a), and 5′-O-benzoyl-2′,3′-didehydro-2′,3′-
dideoxyuridine (18b). To a stirred suspension of NaBH4 (12 mg)
in anhydrous THF (5 mL), under argon, was added dimethyl
ditelluride (50 µL, 0.3 mmol), followed by several drops of dry
ethanol until bubbles were formed. The suspension was heated to
50 °C, and then the THF solution or suspension (5 mL) of the
starting material (anhydronucleosides 8a, 8b, 17a, 17b, or 17c, 3
mmol) was added. These reactions completed in 3-5 h, which was
monitored by TLC. All of the solvents were evaporated under
reduced pressure. The residues were then dissolved in CH2Cl2 and
washed with water. Each CH2Cl2 solution was dried over MgSO4
(s) and evaporated under reduced pressure. Each crude product was
purified individually by silica gel column chromatography (gradient,
0-3% methanol in CH2Cl2) to give 69-90% yields of 12a, 12b,
18a, or 18b (Table 1).
1-(2,3-Dideoxy-ꢀ-D-glycero-pent-2-enofuranosyl)uracil (19a,
d4U) and 1-(2,3-Dideoxy-ꢀ-D-glycero-pent-2-enofuranosyl)thy-
mine (2, d4T). From 12a and 12b: Activated Dowex 50 w (H+
form, 100 mg) was added to a methanol solution (3 mL) of 12a or
12b (0.1 mmol), and the mixture was stirred for 10 min. The
insoluble solid was filtered out and washed with methanol several
times. The organic solution was evaporated to a small volume under
reduced pressure and the residue was precipitated with pentane.
The precipitate was collected by filtration and washed with ether
to give pure d4U and d4T in 90% yield.
From 18a and 18b: Ammonia solution (conc, 0.5 mL) was added
to a methanol solution (3 mL) of 18a or 18b (0.1 mmol). The
reaction was stirred for 1 h to complete the deprotection. The solvent
was evaporated under reduced pressure. The crude product d4U or
d4T was purified by silica gel column chromatography (gradient:
5-10% methanol in CH2Cl2) to offer a satisfactory yield (80-90%).
10b
1
19a (d4U): H NMR (DMSO-d6, identical to literature)
δ
3.58-3.60 (m, 2H), 4.79-4.80 (m, 1H), 4.98 (m, 1H), 5.59 (d, J
) 8.0 Hz, 1H), 5.93-5.94 (m, 1 H), 6.40-6.42 (m, 1H), 6.81 (m,
1H), 7.75 (d, J ) 8.0 Hz, 1H), 11.3 (m, 1H); ESI-TOF m/z calcd
for C9H9N2O4 (M-H)- 209.0562, found 209.0563.
3d
1
12a: H NMR (CDCl3) δ 3.47-3.48 (m, 2H), 3.82 (s, 6H),
4.97-4.98 (m, 1H), 5.06 (d, 1H, J ) 7.6 Hz), 5.89-5.91 (m, 1H),
6.35-6.37 (m, 1H), 6.84-6.86 (m, 4H), 7.05 (d, J ) 2.0 Hz, 1H),
7.27-7.38 (m, 9H), 7.85 (d, J ) 7.6 Hz, 1H); 13C NMR (CDCl3)
δ 55.4, 64.2, 86.1, 86.9, 89.6, 102.2, 113.2, 127.1, 127.8, 127.4,
129.1, 130.20, 150.6, 127.1, 134.6, 141.4, 150.6, 158.6, 163.2; ESI-
TOF m/z calcd for C30H27N2O6 (M - H)- 512.1869, found
511.1861.
7c
1
2 (d4T): H NMR (DMSO-d6, identical to literature) δ 1.72
(s, 3H), 3.60-3.61 (m, 2H), 4.76-4.78 (m, 1H), 4.98 (br, 1H),
5.91-5.92 (m, 1H), 6.39-6.41 (m, 1H), 6.82 (m, 1H), 7.65 (s,
1H), 11.3 (m, 1H); ESI-TOF C10H11N2O4, (M-H)- 223.0719, found
223.0721.
17
1
12b: H NMR (CDCl3, identical to literature) δ 1.34 (s, 3H),
3.36-3.48 (m, 2H), 3.81 (s, 6H), 5.00 (m, 1H), 5.91-5.93 (m,
1H), 6.38-6.40 (m, 1H), 6.83-6.85 (m, 4H), 7.06 (m, 1H),
7.26-7.41 (m, 9H), 7.50 (s, 1H); 13C NMR (CDCl3) δ 14.1, 55.3,
64.6, 85.8, 86.4, 89.7, 111.8, 113.2, 127.1, 127.7, 127.4, 129.2,
130.2, 150.6, 133.1, 134.6, 141.4, 150.5, 158.7, 163.4; ESI-TOF
m/z calcd for C31H29N2O6 (M - H)- 525.2026, found 525.2048.
Acknowledgment. We thank Dr. Jozef Salon and Dr. Junfeng
Wang for their discussions. This work was supported by the
GSU research program and the NSF (MCB-0517092).
Note Added after ASAP Publication. Footnote 3e was
added in the version published May 9, 2008.
7b
1
18a: H NMR (CDCl3, identical to literature) δ 2.01 (s, 3H),
4.13-4.38 (m, 2H), 5.04 (m, 1H), 5.74 (d, J ) 7.6 Hz, 1H), 5.91
Supporting Information Available: 1H and 13C NMR
spectra for compound 8, 12, 13, 15, and 17-19 and the HRMS
spectra for compound 15a and 15b. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Chambert, S.; Gautier-Luneau, I.; Fontecave, M.; Decout, J. L. J. Org.
Chem. 2000, 65, 249.
(18) Palomino, E.; Meltsner, B, R.; Kessel, D.; Horwitz, J. P. J. Med. Chem.
1990, 33, 258.
JO7025806
J. Org. Chem. Vol. 73, No. 10, 2008 3729