Improved and Reliable Synthesis of 3′-Azido-2′,3′ -dideoxyguanosine Derivatives

Article abstract of DOI:10.1081/NCN-120027826

An improved synthesis of N²-protected-3′-azido-2′ ,3′-dideoxyguinosine 20 and 23 is described. Deoxygenation of 2′-O-alkyl (and/or aryl) sulfonyl-5′-dimethoxytritylguanosine coupled with [1,2]-hydride shift rearrangement gave protected 9-(2-deoxythreo-pentofuranosyl)guanines (10, 12 and 16). This rearrangement was accomplished in high yield with a high degree of stereoselectivity using lithium triisobutylborohydride (L-Selectride ^R). Compounds 10, 12 and 16 were transformed into 3′-O-mesylates (18 and 21), which can be used for 3′-substitution. The 3′-azido nucleosides were obtained by treatment of 18 and 21 with lithium azide. This procedure is reproducible with a good overall yield.

Full text of DOI:10.1081/NCN-120027826

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Improved and Reliable Synthesis of
3′‐Azido‐2′,3′‐dideoxyguanosine Derivatives
Victor A. Timoshchuk a , Richard I. Hogrefe a & Morteza M. Vaghefi a
a TriLink BioTechnologies Inc. , 9955 Mesa Rim Road, San Diego, California, 92121, USA
Published online: 01 Jun 2007.
To cite this article: Victor A. Timoshchuk , Richard I. Hogrefe & Morteza M. Vaghefi (2004) Improved and Reliable
Synthesis of 3′‐Azido‐2′,3′‐dideoxyguanosine Derivatives , Nucleosides, Nucleotides and Nucleic Acids, 23:1-2, 171-181,
DOI: 10.1081/NCN-120027826
To link to this article: http://dx.doi.org/10.1081/NCN-120027826
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, Nos. 1 & 2, pp. 171–181, 2004
Improved and Reliable Synthesis of
3’-Azido-2’,3’-dideoxyguanosine Derivativesy
*
Victor A. Timoshchuk, Richard I. Hogrefe, and Morteza M. Vaghefi
TriLink BioTechnologies Inc., San Diego, California, USA
ABSTRACT
An improved synthesis of N2-protected-3’-azido-2’,3’-dideoxyguanosine 20 and 23 is
described. Deoxygenation of 2’-O-alkyl (and/or aryl) sulfonyl-5’-dimethoxytritylgua-
nosine coupled with [1,2]-hydride shift rearrangement gave protected 9-(2-deoxy-
threo-pentofuranosyl)guanines (10, 12 and 16). This rearrangement was accomplished
in high yield with a high degree of stereoselectivity using lithium triisobutylborohy-
dride (L-Selectride1). Compounds 10, 12 and 16 were transformed into 3’-O-
mesylates (18 and 21), which can be used for 3’-substitution. The 3’-azido nucleosides
were obtained by treatment of 18 and 21 with lithium azide. This procedure is
reproducible with a good overall yield.
Key Words: Rearrangement; L-Selectride1; Reduction; Stereoselectivity; 3’-Azido-
2’; 3’-dideoxyguanosine.
Since the discovery of the human immunodeficiency virus (HIV), there has been
a growing interest in compounds that can block the replication of retroviruses. The
activity of 3’-azido-3’-deoxythymidine (AZT), an approved drug for the treatment of
AIDS patients, is partly attributed to an inhibition of the reverse transcriptase by the
5’-triphosphate metabolite of AZT.
yIn honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
*
Correspondence: Morteza M. Vaghefi, TriLink BioTechnologies Inc., 9955 Mesa Rim Road, San
Diego, CA 92121, USA; E-mail: mvaghefi@trilinkbiotech.com.
171
DOI: 10.1081/NCN-120027826
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

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Timoshchuk, Hogrefe, and Vaghefi
Because of the efficacy of AZT as an antiretroviral agent, the synthesis and
biological activity of other 3’-azido-2’,3’-dideoxynucleosides is of great interest. Most
of the efforts to date are focused on 3’-azido-2’,3’-dideoxypyrimidine nucleoside
derivatives for which a relatively convenient chemistry is well developed.
On the other hand, the methodology used to prepare the 3’-azido guanosine analog
is not as well developed.[1–6] Furthermore, in our hands the methods used to produce
the 3’-azido adenosine analogs did not work with guanosine. We wish to describe an
improved procedure that not only overcomes some of the difficulties encountered with
earlier methods, but also can be scaled-up without difficulty.
RESULTS
N2-Isobutyrylguanosine (2) was synthesized by treatment of guanosine (1) first
with an excess of trimethylsilyl chloride in pyridine, and then with isobutyryl chloride.
Silyl groups were then removed by treatment with water and dilute ammonia to yield 2.
Nucleoside 2 was converted to its 3’,5’-O-(1,1,3,3-tetraisopropyldisiloxan-1,3-diyl)
derivative 3 which was then tosylated to give fully protected compound 4. Mesylation
of 3 gave nucleoside 5. Removal of the silyl protective group from 4 and 5 with TBAF
in THF proceeded without difficulties to give N2-isobutyryl-2’-O-tosyl-guanosine 6 and
mesylate 7 in > 85% yield. Protection of the 5’-position with DMT-Cl in pyridine gave
nucleoside 8 and mesylate 9. The overall yield of 8 from compound 1 was 37%
(Scheme 1).
The next step in the synthesis of 3’-azido-2’,3’-dideoxyguanosine is the elimination
of the 2’-O-tosyl or mesyl group (6, 7, 8 and 9) coupled with hydride rearrangement[2]
to yield compounds 10 and 12 (Scheme 2). Attempts to use the route described for the
Scheme 1. Synthesis of the 2’-O-mesyl-and tosyl derivatives of guanosine.

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173
Scheme 2. [1,2]-Hydride shift rearrangement of 2’-O-mesyl and tosyl derivatives of guanosine
with Super-Hydride1 or L-Selectride1.
production of the threo analog of deoxyadenosine,[2] treatment with 10 eq. of lithium
triethylborohydride (Super-Hydride1) in THF, gave less than desirable results due to
the lack of selectivity. Equal amounts of both the desired (10 and 12) and undesired (11
and 13) isomers were formed from the tosyl derivatives (6 and 8) (Scheme 2), whereas
the mesyl analog (9) gave only traces of the desired compound (10).
The reactions were repeated without the protecting group (14 and 15) on the
exocyclic amine to see if the isobutyryl group affected selectivity. Selectivity was
improved somewhat (75% of 16 and 20% of 17) (Scheme 3) but we felt that there was
still considerable room for improvement.
We decided to investigate a bulkier lithium borohydride reagent (L-Selectride1;
lithium triisobutyl-borohydride), which has been reported to perform stereoselective
reductions. Originally L-Selectride1 was developed as a selective hydride donator, and
thus seemed to be a very practical choice for our purposes. The use of L-Selectride1 on
compounds 8 and 9 resulted in the formation of only the desired isomer, 10 (Scheme 2).
This conversion not only occurred with absolute selectivity, but also in near
quantitative yield.
The title compound, 20, was thus readily obtained from this intermediate first by
mesylation of the 3’-inverted hydroxyl. Subsequent treatment of 18 with lithium azide
Scheme 3. Rearrangement of 2’-O-mesyl and tosyl derivatives of guanosine without the
protecting group on the exocyclic amine.

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Timoshchuk, Hogrefe, and Vaghefi
Scheme 4. Conversion of N2-isobutyryl-9-(5-O-dimethoxytrityl-2-deoxy-b-D-threo-pentofurano-
syl)guanine into N2-isobutyryl-9-(3-azido-2,3-dideoxy-b-D-erythro-pentofuranosyl)guanine.
in DMF at 100°C for two hours gave 19, which was then deprotected with 80% AcOH/
H2O giving a 15% overall yield of 20 from compound 1 (Scheme 4).
Mesylation of the unprotected nucleosides 16 was also possible but side reactions
occurred. Although the N2-dimethylformamidine protection of 16 improved the
mesylation reaction (21), the overall yield of 3’-azido 22 and 23 were not improved
over the isobutyryl route (Scheme 5).
MATERIALS AND METHODS
Melting Points Are Uncorrected. 1H NMR spectra were obtained at 500 MHz.
Low-resolution ES mass spectra (LRMS) were recorded with an ionization voltage of
Scheme 5. Conversion of 9-(5-O-dimethoxytrityl-b-D-thereo-pentofuranosyl)guanine to N2-
(dimethylaminomethylene)-9-(3-azido-2,3-dideoxy,b-D-erythro-pentofuranosyl)guanine.

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175
90 eV. Reaction monitoring and compound purity determinations were performed with
Beckman HPLC (System Gold, 126 Solvent Module with Beckman 168 detector) using
mainly a reverse phase column. TLC was performed with Merck 60 F254 silica, and
flash column chromatography with Silica Gel 60 Geduran1 (40–63 mm, Merck).
Aldrich chemicals were used without purification. Solvents were purified, dried, and
distilled before use. Super-Hydride1 and L-Selectride1 were from Aldrich Chemicals
(Milwaukeee, WI).
N2-Isobutyryl-3’,5’-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanyl)guanosine (3). To
guanosine 1 (35 g, 124 mmol) dried by coevaporation with pyridine (2 ꢀ 200 mL) and
suspended in anhydrous pyridine (500 mL) was added over 5 min trimethylchlorosilane
(100 mL, 1075 mmol). This solution was stirred for 1 h at room temperature and then
mixed with isobutyryl chloride (26 mL, 248 mmol). After 20 h, water (50 mL) was
added, concentrated, and the residue was co-evaporated with water (2 ꢀ 50 mL). Crude
N2-isobutyrylguanosine (2) was dissolved in pyridine (100 mL) and ammonium
hydroxide (20 mL), and the solution was concentrated to dryness. The residue was
redissolved in pyridine (200 mL) and treated with 1,3-dichloro-1,1,3,3-tetraisopropyl-
disiloxane (38 mL, 132 mmol) overnight at room temperature. The volatiles were
evaporated and the residue was dissolved in DCM (300 mL), washed with water,
aqueous NaHCO3, dried (MgSO4) and evaporated to give crude product, which was
purified by column chromatography (2.0 L SiO2, in CH2Cl2:MeOH 98:2), to give 61 g
1
of product 3 (102 mmol, 83% yield). H NMR (500 MHz, Me2SO–d6): d 12.8 (s, 1H,
NH), 9.06 (s, 1H, NH), 7.90 (s, 1H, H-8), 5.86 (s, 1H, H-1’), 4.54 (dd, 1H, H-2’), 4.30
(d, 1H, H-3’, J = 5.0 Hz), 4.14 (dd, 1H, H-5’a), 4.09 (ddd, 1H, H-4’), 4.04 (dd, 1H,
H-5’b) 2.70 (m, 1H, HCMe2), 1.27–1.00 m, (34 H, TPDS, CMe2). C26H45N5O7Si2.
M = 595.84, LRMS m/z = 596 [100, M + H]+, 594 (100, M ꢁ H)ꢁ.
N2-Isobutyryl-2’-O-methanesulfonyl-3’,5’-O-(1,1,3,3-tetraisopropyl-1,3-disiloxa-
nyl)guanosine (5). Compound 3 (61 g, 102 mmol) was dissolved in anhydrous DCM
(400 mL) and treated with DMAP (15 g, 124 mmol) and mesyl chloride (10 mL,
136 mmol, 1.3 eq). The reaction mixture was stirred for 1 h at room temperature,
treated with MeOH (30 mL) and concentrated in vacuo. The residue was dissolved in
DCM (400 mL) washed with aq. NaHCO3, dried (MgSO4), evaporated and purified by
column chromatography (2.0 L SiO2, in CH2Cl2:MeOH 98:2) to give 43 g (64 mmol,
1
63%) of 5 as a foam. H NMR(500 MHz, CDCl3): d 12.07 (s, 1H, NH), 9.17 (s, 1H,
NH), 7.99 (s, 1H, H-8), 6.05(s, 1H, H-1’), 5.24(d, 1H, H-2’, J2’,3’ = 4.3 Hz), 4.58 (dd,
1H, H-3’, J3’,4’ = 9.4 Hz), 4.28 (dd, 1H, H-5’a), 4.10 (d, 1H, H-4’, J3’,4’ = 9.4 Hz), 4.01
(dd, 1H, H-5’b), 3.20 (s, 3H, SO2 CH3) 2.67(m, 1H, HC Me2), 1.24–1.04 (m, 34H,
TPDS, Cme2). C27H47N5O9SSi2. M = 673.86, LRMS m/z = 674 [100, M + H]+, 672
[100, M ꢁ H]ꢁ.
N2-Isobutyryl-2’-O-p-toluenesulfonyl-3’,5’-O-(1,1,3,3-tetraisopropyl-1,3-disiloxa-
nyl)guanosine (4). Compound 1 (35 g, 124 mmol) was coevaporated from pyridine
(2 ꢀ 200 mL), suspended in pyridine (600 mL) and treated with trimethylchlorosilane
(100 mL). After 1 h isobutyryl chloride (26 mL, 244 mmol, 2 eq) was added with
cooling and the reaction mixture was stirred at room temperature for 24 h. The volatiles
were evaporated and the residue was coevaporated with water (2 ꢀ 100 mL),

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Timoshchuk, Hogrefe, and Vaghefi
ammonium hydroxide (20 mL), and pyridine (2 ꢀ 300 mL). The residue was
redissolved in pyridine (600 mL) and treated with TPDS–Cl2 (38 mL, 1 eq). After
3 h the volatiles were evaporated, the residue dissolved in CH2Cl2 (500 mL) and
washed with water, aq. NaHCO3, dried (MgSO4) and evaporated to give the residue
which was dissolved in CH2Cl2 (500 mL) and treated with DMAP (30 g, 246 mmol,
2 eq) and tosyl chloride (30 g, 157 mmol, 1.5 eq). After 3 h the reaction mixture was
washed with 5% HCl, then with water, aq. NaHCO3, dried (MgSO4) and evaporated.
Crude product was purified by column chromatography (3.0 L SiO2, in CH2Cl2:MeOH
98:2) to afford 40 g of 5 (59 mmol, 48% from guanosine). 1H NMR (500 MHz,
CDCl3): d 12.07 (s, 1H, NH), 8.92 (s, 1H, NH), 7.85 (s, 1H, H-8), 7.74 (d, 2H, Ph,
J = 8.0 Hz), 7.26 (d, 2H, Ph) 6.03 (s, 1H, H-1’), (s, 1H, H-2’) J2’,3’ = 4.5 Hz), 4.58 (dd,
1H, H-3’, J3’,4’ = 9.0 Hz), 4.16 (d, 1H, H-5’a, J = 13.0 Hz) 4.05 (d, 1H, H-4’, J = 9.0
Hz), 3.95 (dd, 1H, H-5’b), 2.67 (m, 1H, HCMe2), 2.40 (s, 3H, PhCH3), 1.27–0.85 (m,
34H, TPDS, CMe2). C33H51N5O9SSi2. M = 749.95, LRMS m/z = 750 [100, M + H]+,
748 [100, M ꢁ H]ꢁ.
N2-Isobutyryl-2’-O-p-toluenesulfonylguanosine (6). Compound 4 (40.0 g,
53.3 mol) was dissolved in anhydrous THF (400 mL) and treated with TBAF (1 M
in THF, 110 mL) at room temperature for 2 h. The volatiles were evaporated to dryness
and the residue was purified by column chromatography (2.0 L SiO2, in CH2Cl2:MeOH
95:5) to give 23 g (45 mmol, 85%) of 6 as a white foam. 1H NMR (500 MHz,
Me2SO–d6): d 12.01 (s, 1H, NH), 11.53 (s, 1H, NH), 7.43 (d, 2H, Ph, J = 8.0 Hz), 6.02
(d, 1H, 3’-OH, J = 5.0 Hz), 5.94 (d, 1H, H-1’, J1’,2’ = 7.5 Hz), 5.39 (dd, 1H, H-2’,
J2’,3’ = 2.5 Hz), 5.20 (t, 1H, H-5’–OH, J = 5.0 Hz), 4.30 (m, 1H, H-3’), 4.00 (m, 1H, H-
4’), 3.64 (m, 1H, H-5’a), 3.55 (m, 1H, H-5’b), 2.79 (m, 1H, HCMe2), 2.26 (s, 3H, Ph
CH3), 1.17 (d, 6H, CMe2, J = 6.8 Hz). C21H25N5O8S. M = 507.44, LRMS m/z = 336
[100, loss of tosyl]ꢁ.
N2-Isobutyryl-2’-O-methanesulfonylguanosine (7). Nucleoside 5 (43 g,
64 mmol) was dissolved in THF (400 mL) and treated with TBAF (1M in THF,
128 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated in
vacuo and purified by column chromatography (2.0 L SiO2, in CH2Cl2:MeOH 95:5) to
1
afford 23.7 g (55 mmol, 86%) of 7 as a white foam. H NMR (500 MHz, Me2SO–d6):
d 12.10 (s, 1H, NH), 11.65 (s, 1H, NH), 8.27 (s, 1H, H-8), 6.10 (d, 1H, H-1’,
J1’,2’ = 5.9 Hz), 5.91 (d, 1H, 3’-OH, J = 5.0 Hz), 5.44 (t, 1H, 5’-OH, J = 5.0 Hz), 5.20
(t, 1H, H-2’, J = 5.0 Hz), 4.47 (dd, 1H, H-3’), 4.00 (m, 1H, H-4’,) 3.66 (m, 1H, H-5’a),
3.59 (m, 1H, H-5’b), 3.18 (s, 3H, SO2 CH3), 2.77 (m, 1H, HCMe2), 1.12 (d, 6H, CMe2.
J = 6.8 Hz). C15H21N5O8S. M = 431.36, LRMS m/z = 430 [100, M ꢁ H]ꢁ.
N2-Isobutyryl-2’-O-methanesulfonyl-5’-O-dimethoxytritylguanosine (9). Nu-
cleoside 7 (26.8 g, 62 mmol) was dissolved in pyridine then evaporated to dryness,
redissolved in pyridine (500 mL) and treated with DMTCl, (25 g, 1.2 eq., 73.8 mmol).
After 3 h the pyridine was evaporated together with toluene (500 mL), the residue was
dissolved in CH2Cl2 (500 mL), washed with saturated aq. NaHCO3, dried (Mg SO4),
evaporated and purified by column chromatography (2.0 L SiO2, in CH2Cl2:MeOH 97:3,
1
then 95:5) to yield compound 9 as a white foam (36 g, 49 mmol, 79%). H NMR (500
MHz, Me2SO–d6): d 12.12 (s, 1H, NH), 11.59 (s, 1H, NH), 8.16 (s, 1H, H-8), 7.33–6.80

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177
(m, 13h, Ph), 6.18 (d, 1H, H-1’ J1’,2’ = 4.3 Hz), 5.87 (d, 1H, 3’-OH, J = 6.0 Hz), 5.59 (dd,
1H, H-2’, J2’,3’ = 4.7 Hz), 4.60 (k, 1H, H-3’) 4.10 (m, 1H, H-4’), 3.72 (s, 6H, OMe), 3.35
(m, 1H, H-5’a), 3.22 (s, 3H, SO2CH3), 3.20 (m, 1H, H-5’b), 2.73 (m, 1H, HCMe2), 1.12
(2d, 6H, CMe2, J = 6.8 Hz). C36H39N5O10S. M = 733.7, LRMS m/z = 734 [100,
M + H]+, 732 [100, M ꢁ H]ꢁ.
N2-Isobutyryl-2’-O-p-toluenesulfonyl-5’-O-dimethoxytritylguanosine (8). Nu-
cleoside 6 (23 g, 45 mmol) was mixed with DMTCl (23 g, 68 mmol, 1.5 eq) in
anhydrous pyridine (300 mL) and stirred at room temperature for 3 h. The solution was
diluted with toluene (300 mL) and evaporated to dryness. The residue was treated with
EtOAc and saturated solution of NaHCO3; organic layer was washed with water, dried
(MgSO4) and evaporated to give a yellow foam. Crude 8 was purified by column
chromatography (2.0 L SiO2, in CH2Cl2:MeOH 95:5) to afford pure 8 (33 g, 40.8 mmol,
1
91%) as a yellow foam. H NMR (500 MHz, Me2SO–d6): d 11.99 (s, 1H, NH), 11.34
(s, 1H, NH), 7.93 (s, 1H, H-8) 7.22–6.79 (m, 17H, Ph), 5.99 (d, 1H, 3’-OH, J = 6.0 Hz),
5.97 (d, 1H, H-1, J1’,2’ = 6.4 Hz), 5.54 (t, 1H, H-2’, J2’,3’ = 6.0 Hz), 4.30 (dd, 1H, H-3’),
4.07 (m, 1H, H-4’), 3.71 (s, 6H, OMe), 3.34 (m, 1H, H-5’a), 3.15 (m, 1H, H-5’b), 2.73
(m, 1H, HCMe2), 2.26 (s, 3H, PhCH3) 1.15 (2d, 6H, CMe2, J = 6.8 Hz). C42H43N5O10S.
M = 809.76, LRMS m/z = 810 [100, M + H]+, 808 [100, M ꢁ H]ꢁ.
N2-Isobutyryl-9-(5-O-dimethoxytrityl-2-deoxy- -D-threo-pentofuranosyl)gua-
nine (10). To a solution of nucleoside 8 (4.2 g, 5 mmol) in anhydrous THF (50 mL),
cooled in an ice bath, was added lithium triethylborohydride (Super-Hydride1, 1M in
THF, 50 mL, 10 eq.). After 16 hours, water (10 mL) was added to the reaction mixture,
and the volatiles were evaporated. The residue was dissolved in DCM, washed with
water, dried and purified by column chromatography (400 mL of SiO2, CH2Cl2:MeOH
95:5). Compound 10 was obtained (0.87 g, 1.4 mmol, 26%) as white crystals with mp
1
178–183°C. H NMR (500 MHz, CDCl3) d12.08 (S, 1H, NH), 8.92 (s, 1H, NH), 7.93
(s, 1H, H-8), 7.42–6.79 (m, 13H, Ph), 6.07 (dd, 1H, H-1’, J = 2.0 Hz), 4.88 (d, 1H,
3’-OH, J = 5.5 Hz), 4.49 (1m, 1H, H-3’), 4.07 (m, 1H, H-4’), 3.54 (m, 1H, H-5’a,
J = 8.5 Hz), 3.45 (m, 1H, H-5’b), 2.72 (m, 1H, H-2’a), 2.58 (m, 1H, CH Me2), 2.50
(m, 1H, H-2’b), 1 22 (d, 3, HCMe, J = 6.8 Hz), 1.21 (d, 3H, HCMe, J = 6.8 Hz).
C35H37N5O7. M = 639.7, LRMS m/z = 640 [100, M + H]+ , 638 [100, M ꢁ H]ꢁ.
2’-O-Methanesulfonyl-5’-O-dimethoxytritylguanosine (15). Nucleoside 9 (31 g,
42 mmol) was dissolved in saturated solution of ammonia in methanol (300 mL) and
stirred at room temperature overnight. The volatiles were evaporated to give compound
1
15 (27 g, 40.7 mmol, 96%) as white crystals with mp 160–163°C (with decomp.). H
NMR (500 MHz, Me2SO–d6): d 8.60 (s, 1H, NH), 7.83 (s, 1H, H-8) 7.35–7.20 and
6.86–6.83 (m, 13H, Ph), 6.50 (s, 2H, NH2), 6.05 (d, 1H, H-1’, J1’,2’ = 4.0 Hz), 5.84 (s,
1H, 3’-OH), 5.53 (t, 1H, H-2’, J = 4.7 Hz), 4.57 (m, 1H, H-3’), 4.05 (m, 1H, H-4’), 3.73
(s, 6H, OMe), 3.33 (m, 1H, H-5’a), 3.24 (m, 1H, H-5’b), 3.24 (s, 3H, SO2Me).
C32H33N5O9S. M = 663.6, LRMS m/z = 664 [100, M + H]+, 662 [100, M ꢁ H]ꢁ.
2’-O-p-Toluenesulfonyl-5’-O-dimethoxytritylguanosine (14). Nucleoside 8 (3.3 g,
4 mmol) was dissolved in saturated solution of ammonia in methanol (20 mL) and
stirred overnight. The solution was evaporated to dryness, the crystalline residue was

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Timoshchuk, Hogrefe, and Vaghefi
diluted with methanol and filtered to give compound 14 (2.3 g, 3.1 mmol, 77%) as
1
white crystals, mp 198–202°C (with decomp.); H NMR (500 MHz, Me2SO–d6): d
10.61 (s, 1H, NH), 7.62 (s, 1H, H-8), 7.54–6.84 (m, 17H, Ph), 6.25 (s, 2 H, NH2), 5.90
(d, 1H, H-1’, J1’,2’ = 6.0 Hz), 5.84 (d, 1H, 3’-OH, J = 6.0 Hz), 4.32 (m, 1H, H-3’),
4.03–3.99 (m, 2H, H-4’, H-5’a), 3.73 (s, 6H, 2 OMe), 2.31 (s, 3H, Ph–Me).
C38H37N5O9S. M = 739.72, LRMS m/z = 740 [100, M + H]+, 738 [100, M ꢁ H]ꢁ.
9-(5-O-Dimethoxytrityl-2-deoxy- -D-threo-pentofuranosyl)guanine (16). Nu-
cleoside 15 (30 g, 45 mmol) was dissolved in hot THF (300 mL) and evaporated to
dryness. The residue again was dissolved in THF (500 mL) cooled to 5°C (ice-water
bath) and stirred under argon atmosphere for 30 min. L-Selectride1 (1 M in THF,
450 mL) was added dropwise over 30 min and the reaction mixture was stirred for 3 h.
The water (20 mL) was added very carefully and the solution was evaporated to
dryness. The residue was dissolved in CH2Cl2 (600 mL) and washed with sat. aq.
NaHCO3. During washing, 16 precipitated. The precipitate was filtered off, washed
with water and dried under vacuum to give compound 16 (23 g, 40.4 mmol, 90%), mp
1
178–183°C; H NMR (500 MHz, Me2SO–d6); d 10.61 (s, 1H, NH), 7.79 (s, 1H, H-8),
7.28–6.80 (m, 13H, Ph), 6.47 (s, 2H, NH2), 6.10 (dd, 1H, H-1’, J1’,2’ = 6.0 Hz), 5.38 (d,
1H, 3’-OH, J = 4.0 Hz), 4.30 (m, 1H, H-3’), 4.15 (m, 1H, H-4’), 3.32 (m, 1H, H-5’a),
3.18 (m, 1H, H-5’b), 2.66 (m, 1H, H-2’a), 2.17 (m, 1H, H-2’b). C31H31N5O6.
M = 569.5, LRMS m/z = 570 [100, M + H]+, 568 [100, M ꢁ H]ꢁ.
N2-[(Dimethylamino)methylene]-9-(3-O-methanesulfonyl-5-O-dimethoxytrityl-
2’-deoxy- -D-threo-pentofuranosyl)guanine (21). Nucleoside 16 (5.0 g, 8.8 mmol)
was dissolved in hot pyridine and evaporated to dryness. The residue was suspended in
pyridine (100 mL) and treated with N,N-dimethylformamide dimethyl acetal (3.0 mL,
28 mmol, 2 eq.) at room temperature overnight. The volatiles were evaporated in vacuo
and the residue was coevaporated from xylenes, then dissolved in pyridine (100 mL)
and cooled to 4°C (ice-water bath). Methanesulfonyl chloride (1.2 mL, 15.5 mmol, 1.5
eq.) in pyridine (2 mL) was added dropwise at stirring then DMAP (100 mg) was
added. After 20 h the volatiles were evaporated, the residue was dissolved in CH2Cl2,
washed with aq. NaHCO3, dried (MgSO4), evaporated and purified on the silica gel
(500 mL) column (CH2Cl2:MeOH 97:3) to give compound 21 (2.6 g, 3.7 mmol, 42%)
1
as a brown foam. H NMR (500 MHz, Me2SO–d6): d 11.36 (s, 1H, NH), 8.58 (s, 1H,
HC N), 7.71 (s, 1H, H-8), 7.40–6.84 (m, 13H, Ph), 6.30 (dd, 1H, H-1’), 5.43 (m, 1H,
H-3’), 4.40 (m, 1H, H-4’), 3.73 (s, 6H, OMe), 3.13 (s, 3H, SO2Me), 3.08 (s, 3H, NMe),
3.03 (s, 3H, NMe), 2.71 (m, 1H, H-2’a), 2.50 (m, 1H, H-2’b). C35H38N6O8S.
M = 702.69, LRMS m/z = 703 [100, M + H]+, 701 [100, M ꢁ H]ꢁ.
N2-[(Dimethylamino)methylene]-9-(3-azido-5-O-dimethoxytrityl-2,3-dideoxy- -
D-erythro-pentofuranosyl)guanine (22). Nucleoside 21 (2.6 g, 3.7 mmol) was
dissolved in DMF (50 mL) and treated with LiN3 (0.9 g, 18.5 mmol, 5 eq.) at room
temperature for 3 h. The volatiles were evaporated to dryness. The residue was
dissolved in CH2Cl2, washed with water and purified by column chromatography
1
(400 mL SiO2, in CH2Cl2:MeOH 98:2) to give compound 22 (1.8 g, 75%). H NMR
(500 MHz, Me2SO–d6): d 11.37 (s, 1H, NH), 8.53 (s, 1H, HC N), 8.02 (s, 1H, H-8),
7.31–6.80 (m, 13H, Ph) 6.23 (dd, 1H, H-1’, J1’,2’a = 7.0 Hz, J1’,2’b = 2.5 Hz), 4.73 (dd,

ORDER
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3’-Azido-2’,3’-dideoxyguanosine Derivatives
179
1H, H-3’), 3.89 (m, 1H, H-4’), 3.72 (s, 6H, 2 OMe), 3.10 (s, 3H, N Me), 3.02 (s, 3H, N
Me), 2.52 (m, 1H, H-2’a), other protons overlapped the signals associated with H2O and
N–me. C34H35N9O5. M = 649.68, LRMS m/z = 650 [100, M + H]+, 648 [50,
M ꢁ H]ꢁ.
N2-(Dimethylaminomethylene)-9-(3-azido-2,3-dideoxy- -D-erythro-pentofurano-
syl)guanine (23). Nucleoside 22 (1.8 g, 2.8 mmol) was dissolved in 80% AcOH/H2O
(50 mL) and stirred at room temperature for 1 h. The volatiles were evaporated and the
residue was purified by column chromatography (400 mL SiO2, in CH2Cl2:MeOH
95:5) to give compound 23 (0.63 g, 1.8 mmol, 66%) as white crystals, mp 193–195°C.
1H NMR (500 MHz), Me2SO–d6): d 11.35 (s, 1H, NH), 8.58 (s, 1H, HC N), 8.04 (s,
1H, H-8), 6.20 (t, 1H, H-1’, J = 6.6 Hz), 5.13 (m, 1H, 5’-OH), 4.62 (m, 1H, H-3’), 3.90
(m, 1H, H-4’), 3.58 (m, 2H, H-5’a, H-5’b), 3.16 (s, 3H, NMe), 3.03 (s, 3H, NMe), 2.85
(m, 1H, H-2’a), 2.46 (m, 1H, H-2’b). C13H17N9O3. M = 347.33, LRMS m/z = 348 [50,
M + H]+, 346 [100, M ꢁ H]ꢁ, HPLC purity: 99%.
N2-Isobutyryl-9-(5-O-dimethoxytrityl-2-deoxy- -D-threo-pentofuranosyl)gua-
nine (10). Nucleoside 8 (31.6 g, 39 mmol) in anhydrous THF (400 mL) was cooled to
5°C (ice-water bath) and stirred for 30 min under argon atmosphere. L-Selectride1 (1M
in THF, 390 mL, 10 eq.) was added dropwise and the reaction mixture was stirred for 2
h, then quenched with water (20 mL, dropwise). The volatiles were evaporated and the
residue was purified by column chromatography (2.0 L SiO2, in CH2Cl2:MeOH 95:5)
1
to give compound 10 (22.5 g, 35.2 mmol, 90%) as a light yellow foam. H NMR (500
MHz, Me2SO–d6): d 12.10 (s, 1H, NH), 11.74 (s, 1H, NH), 8.01 (s, 1H, H-8), 7.40–
6.79 (m, 13H, Ph), 6.21 (d, 1H, H-1’, J = 7.8 Hz), 5.29 (d, 1H, 3’-OH, J = 4.0 Hz), 4.33
(m, 1H, H-3’), 4.21 (m, 1H, H-4’), 3.72 (s, 6H, 2-OMe), 3.33 (m, 1H, H-5’a, overlapped
by H2O), 3.17 (m, 1H, H-5’b), 2.77 (m, 1H, H-2’a), 2.69 (m, 1H, HCMe2), 2.27 (m, 1H,
H-2’b), 1.12 (d, 3H, CH3, J = 6.8 Hz), 1.11 (d, 3H, CMe2, J = 6.8 Hz). C35H37N5O7.
M = 639.70, LRMS m/z = 640 [100, M + H]+, 638 [100, M ꢁ H]ꢁ.
N2-Isobutyryl-9-(3-O-methanesulfonyl-5-O-dimethoxytrityl-2-deoxy- -D-threo-
pentofuranosyl)guanine (18). Nucleoside 10 (0.32 g, 0.54 mmol) was evaporated
from anhydrous pyridine, then redissolved in pyridine (5 mL) and treated with
mesylchloride (80 ml, 1 mmol, 2 eq) at room temperature overnight. The volatiles were
evaporated to dryness and the residue was chromatographed on silica gel column
1
(80 mL, CH2Cl2:MeOH 98:2) to give compound 18 (0.284 g, 0.4 mmol, 73%). H
NMR (500 MHz, Me2SO–d6): d 12.12 (s, 1H, NH), 11.75 (S, 1H, NH), 7.83 (s, 1H, H-
8), 7.40–6.83 (m, 13H, Ph), 6.27 (dd, 1H, H-1’, J = 8.0 Hz, J = 2.0 Hz), 5.43 (t, 1H, H-
3’, J = 4.0 Hz), 4.44 (m, 1H, H-4’), 3.73 (s, 6H, 2-OMe), 3.35 (m, 1H, H-5’a), 3.21 (m,
1H, H-5’b), 3.07 (s, 3H, SO2Me), 3.02 (m, 1H, H-2’a), 2.79 (m, 1H, CHMe2), 2.71 (m,
1H, H-2’b), 1.12 (d, 3H, HCMe, J = 6.8 Hz), 1.11 (d, 3H, CMe2, J = 6.8 Hz).
C36H39N5O9S. M = 717.71, LRMS m/z = 718 [100, M + H]+, 716 [100, M ꢁ H]ꢁ.
N2-Isobutyryl-9-(3-azido-5-O-dimethoxytrityl-2,3-dideoxy- -D-erythro-pentofur-
anosyl)guanine (19). Nucleoside 18 (22.5 g, 31 mmol) was dissolved in pyridine
(200 mL) and concentrated, then redissolved in pyridine (400 mL) and treated with
mesylchloride (MsCl) (3.0 mL, 38 mmol, 1.1 eq) at room temperature for 4 h.

ORDER
REPRINTS
180
Timoshchuk, Hogrefe, and Vaghefi
Additional MsCl (3.0 m L, 1.1 eq) was added and reaction mixture was stirred
overnight. The dark solution was diluted with saturated solution of aq. NaHCO3 (1.0 L)
and extracted with CH2Cl2. The combined extracts (500 mL) were washed with water,
dried (MgSO4) and evaporated. LiN3 (45 mL, 20% in water, 5 eq) was evaporated three
times from dimethylformamide and redissolved in DMF (100 mL). This solution was
added to a solution of mesylate in DMF (150 mL) and the reaction mixture was heated
at 100°C for 2 h. The volatiles were evaporated and the residue was coevaporated from
xylenes and dissolved in CH2Cl2, washed with brine, dried (MgSO4) and the solvents
removed. The crude material was purified by column chromatography (2.0 L SiO2, in
CH2Cl2:MeOH 98:2) to give a compound 19 (16.7 g, 25 mmol, 81%). 1H NMR
(500 MHz, Me2SO–d6): d 12.08 (s, 1H, NH), 11.62 (s, 1H, NH), 8.23 (s, 1H, H-8),
7.29–6.77 (m, 13H, Ph), 6.22 (dd, 1H, H-1’, J = 7.0 Hz), 4.71 (m, 1H, H-3’) 3.95 (m,
1H, H-4’), 3.71 (s, 6H, 2 OMe), 3.17 (m, 2H, H-5’a, H-5’b), 2.98 (m, 1H, H-2’a), 2.77
(m, 1H, CHMe2), 2.56 (m, 1H, H-2’b), 1.12 (d, 3H, CMe2, J = 6.8 Hz), 1.11 (d, 3H,
CMe2 J = 6.8 Hz). C35H36N8O6. M = 664.71, LRMS m/z = 665 [100, M + H]+, 663
[100, M ꢁ H]ꢁ.
N2-Isobutyryl-9-(3-azido-2,3-dideoxy- -D-erythro-pentofuranosyl)guanine (20).
Nucleoside 19 (16.7 g, 25 mmol) was dissolved in 80% AcOH/H2O (200 mL) and
the reaction mixture was stirred at room temperature for 2 h. The volatiles were
evaporated to dryness and the residue was purified by column chromatography (2.0 L,
SiO2) (CH2Cl2:MeOH 97:3, then 95:5), to give compound 20 (6.4 g, 17.7 mmol, 70%)
1
as a white foam. H NMR (500 MHz, Me2SO–d6): d 12.08 (s, 1H, NH), 11.66 (s, 1H,
NH), 8.26 (s, 1H, H-8), 6.17 (t, 1H, H-1’, J = 6.5 Hz) 5.13 (t, 1H, 5’-OH, J = 5.5 Hz),
4.58 (m, 1H, H-3’) 3.91 (m, 1H, H-4’) 3.57 (m, 2H, H-5’a, H-5’b), 2.84 (m, 1H, H-2’a),
2.76 (m, 1H, H-2’b), 2.50 (m, 1H, CHMe2), 1.12 (d, 6H, CMe2, J = 6.8 Hz).
C14H18N8O4. M = 362.3, LRMS m/z = 363 [45, M + H]+, 361 [100, M ꢁ H]ꢁ. HPLC
purity: 98%.
CONCLUSION
Deoxygenative [1,2]-hydride shift rearrangement[2] of 2’-O-mesyl and 2’-O-tosyl-
guanosine derivatives was achieved in a stereoselective manner using lithiumtriisobu-
tylborohydride (L-Selectride1) in THF. The previously described lithium triethyl-
borohydride (Super-Hydride1) in a similar reaction[2] gives a mixture of erythro and threo
isomers. This improvement allows large scale preparation of 3’-azido-2’,3’-dideoxygua-
nosine in 15% overall yield. Optimization of each step is still being investigated.
REFERENCES
1. Imazawa, M.; Eckstein, F. Synthesis of 3’-Azido-2’,3’-dideoxyribofuranosylpurines.
J. Org. Chem. 1978, 43, 3044–3048.
2. Hansske, F.; Robins, M.J. A Deoxygenative [1,2]-Hydride Shift Rearrangement
Converting Cyclic cis-Diol Monotosylates to Inverted Secondary Alcohols. J. Am.
Chem. Soc. 1983, 106, 6736–6737.

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3’-Azido-2’,3’-dideoxyguanosine Derivatives
181
3. Herdewijn, P.A.M. Anchimeric Assistance of a 5’-O-Carbonyl Function for Inversion
of Configuration at the 3’-Carbon Atom of a 2’-Deoxyadenosine. Synthesis of 3’-
Azido-2’,3’-dideoxyadenosine and 3’-Azido-2’-3-dideoxyinosine. J. Org. Chem.
1988, 53, 5050–5053.
4. Herdewijn, P.A.M.; Balzarini, J.; De Clercq, E.; Pauwels, R.; Baba, M.; Broder, S.;
Vanderhaeghe, H. 3’-Substituted 2’,3’-dideoxynucleoside Analogues as Potential
Anti-HIV (HTLV-III/LAV) Agents. J. Med. Chem. 1987, 30, 1270–1278.
5. Robins, M.J.; Wood, S.G.; Dalley, N.K.; Herdewijn, P.A.M.; Balzarini, J.; De
Clercq, E. Nucleic Acid Related Compounds. 57. Synthesis, X-Ray Crystal Structure,
Lipophilic Partition Properties, and Antiretroviral Activities of Anomeric 3’-Azido-
2’,3’-dideoxy-2,6-diaminopurine Ribosides. J. Med. Chem. 1989, 32, 1763–1768.
6. Herdewijn, P.A.M.; Balzarini, J.; Baba, M.; Pauwels, R.; Van Aerschot, A.; Janssen,
G.; De Clercq, E. Synthesis and Anti-HIV Activity of Different Sugar-Modified
Pyrimidine and Purine Nucleosides. J. Med. Chem. 1988, 31, 2040–2048.
Received August 2, 2003
Accepted October 6, 2003

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