Cyclopropyl and related analogs of the anti-HIV compound, isodideoxyadenosine

Article abstract of DOI:10.1081/NCN-120021424

Novel 3′-substituted isonucleoside analogs were designed on the basis of the similarities of their electrostatic potential with the active anti-HIV compound, (S, S)-isodideoxy-adenosine. The key synthetic step involved coupling between the dideoxygenated sugar derivatives, 10 and 14, and adenine under Mitsunobu conditions. Anti-HIV data are mentioned.

Full text of DOI:10.1081/NCN-120021424

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Cyclopropyl and Related Analogs of the Anti-HIV
Compound, Isodideoxyadenosine
Vasu Nair a b c , Travis Mickle b & Sanjib Bera b
a Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens,
Georgia, USA
b Department of Chemistry, University of Iowa, Iowa City, Iowa, USA
c Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Room 320A,
R.C. Wilson PH, Athens, GA, 30602, USA
Published online: 07 Feb 2007.
To cite this article: Vasu Nair , Travis Mickle & Sanjib Bera (2003) Cyclopropyl and Related Analogs of the Anti-HIV Compound,
Isodideoxyadenosine, Nucleosides, Nucleotides and Nucleic Acids, 22:3, 239-247, DOI: 10.1081/NCN-120021424
To link to this article: http://dx.doi.org/10.1081/NCN-120021424
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, No. 3, pp. 239–247, 2003
Cyclopropyl and Related Analogs of the Anti-HIV
Compound, Isodideoxyadenosine
2
2
Vasu Nair,1,2, Travis Mickle, and Sanjib Bera
*
1Department of Pharmaceutical and Biomedical Sciences, University of Georgia,
Athens, Georgia, USA
2Department of Chemistry, University of Iowa, Iowa City, Iowa, USA
ABSTRACT
Novel 30-substituted isonucleoside analogs were designed on the basis of the
similarities of their electrostatic potential with the active anti-HIV compound,
(S,S)-isodideoxy-adenosine. The key synthetic step involved coupling between
the dideoxygenated sugar derivatives, 10 and 14, and adenine under Mitsunobu
conditions. Anti-HIV data are mentioned.
Key Words: Isonucleosides; Electrostatic potential; Synthesis; Antiviral.
INTRODUCTION
The synthesis, enzymology and antiviral properties of various isomeric
nucleosides or isonucleosides have been the subject of intense investigation in our
laboratory for a number of years.[1] For example, 4(S)-(6-amino-9H-purin-9-yl)-
tetrahydro-1-(S)-furanmethanol (1, isoddA), an isomeric dideoxynucleoside synthe-
sized in our laboratory,[2] has potent anti-HIV activity against HIV-1 and HIV-2.[3]
*Correspondence: Vasu Nair, Department of Pharmaceutical and Biomedical Sciences,
University of Georgia, Room 320A, R.C. Wilson PH, Athens, GA 30602, USA; E-mail:
vnair@rx.uga.edu.
239
DOI: 10.1081/NCN-120021424
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

240
Nair, Mickle, and Bera
Figure 1.
Figure 2.
(S,S)-IsoddA is a substrate for human recombinant deoxycytidine kinase.[4] Its tri-
phosphate is one of the most potent inhibitors of HIV RT known (Ki ¼ 16 nM).[3]
Our interest in synthesizing new analogs of (S,S)-isoddA led us to a comprehensive
study of the correlation of antiviral activity with molecular conformation and electro-
static potential surfaces.[5] Close examination of the bioactivity diagram for the
isoddA series[5] has shown some possible areas for change including the addition of
an electropositive moiety at the 30-position of (S,S)-isoddA (normal nucleoside num-
bering). Examples of an electropositive modification of this area include the addition
of a spirocyclopropyl or methyl group (Fig. 1). Scrutiny of the steric interactions of
the bioactivity diagram[5] also showed that this region could allow for additional
steric bulk. Electrostatic potential surface analysis for 2 and 3 showed that both
new derivatives had similar electrostatic potential surfaces to (S,S)-isoddA with the
spirocyclopropyl analog exhibiting the closest match (see Fig. 2).
RESULTS AND DISCUSSION
The target spirocyclopropyl nucleoside 2 (or 11, R ¼ H) was synthesized starting
from the commercially available D-xylose derivative 4 and via the allylic alcohol 6 as
a key intermediate (Sch. 1). Selective benzoylation of the primary hydroxyl group of

Analogs of Isodideoxyadenosine
241
Scheme 1. Reaction conditions: (i) BF3.Et2O, Et3SiH, CH2Cl2; (ii) 2,5-bis-trifluoromethyl-
benzoyl chloride, pyridine, 0ꢁC; (iii) (a) CH2N2, CH2Cl2, ether, (b) hn, Ph2CO, benzene,
CH3CN; (iv) NaOMe, MeOH; (v) BzCl, pyridine, ꢂ10ꢁC; (vi) adenine, Ph3P, DEAD, dioxane;
(vii) NaOH, MeOH.
4, oxidation of the secondary hydroxyl group to the keto derivative followed by a
Wittig reaction of the keto compound[6,7] afforded compound 5 bearing the exocyclic
methylene group. One-step reductive deoxygenation[8] of the 1,2-O-isopropylidene
group of 5 by treatment with BF3ꢀEt2O and Et3SiH afforded the tetrahydrofuran
derivative 6[7] in 76% yield. For the successful introduction of the cyclopropyl group
onto 6, it was necessary to introduce a strong electron withdrawing (-I) protecting
group[9] on the secondary hydroxyl group adjacent to the exocyclic methylene
functionality. Thus, treatment of 6 with 2,5-bis-trifluoromethylbenzoyl chloride in
pyridine at 0ꢁC gave the dibenzoate 7 in 92% yield. Cycloaddition of 7 with diazo-
methane followed by photosensitized extrusion[9] of nitrogen from the diazo inter-
mediate afforded the spirocyclopropane compound 8 in 57% overall yield for the
two steps. Because of the difficulty of removing selectively the benzoyl protecting
group on the secondary hydroxyl group, deprotection of both benzoyl groups of 8
was carried out with NaOMe in MeOH to give diol 9 (50%). This was followed

242
Nair, Mickle, and Bera
Scheme 2. Reaction conditions: (i) H2, Pd=C, ethanol; (ii) MeOH, HCl; (iii) (a) TMSCl,
HMDS, (b) TMSOTf, Et3SiH; (iv) MsCl, pyridine; (v) adenine, K2CO3, 18-crown-6, DMF;
(vi) Ph3P, adenine, DEAD, THF; (vii) NaOMe, MeOH.
by selective protection of the primary hydroxyl group of 9 with benzoyl chloride in
pyridine at ꢂ10ꢁC to give 10 in 79% yield. Treatment of 10 with adenine under
Mitsunobu reaction conditions[7,10] afforded both the N-9 and N-3 coupled products
11a and 12a. Deprotection of the benzoyl group on treatment with NaOMe=MeOH
gave the free cyclopropyl nucleosides 11b and 12b in 31% overall yield. Their NMR
and HRMS data confirmed the structures of both isomers. Differentiation between
the isomers came from their UV spectral data. The UV spectrum of compound
11b showed a lmax at 261 nm indicative of the normal 9-substitution on the adenine
ring[2] whereas compound 12b exhibited a lmax at 275 nm, consistent with 3-substi-
tution.[11,12]
Synthesis of the 30-methylisoddA 3 also used the modified sugar 5 as the key syn-
thetic intermediate. Catalytic hydrogenation of 5 using H2 with Pd=C catalyst gave
the methyl derivative 13 with a-stereochemistry of the methyl group. The stereo-
chemistry obtained for the 3-methyl group is consistent with previous observations
of the approach of reducing agents to the b-face of a furanosyl ring bearing a 1,2-
O-isopropylidene group in the a-stereochemistry.[13,14] Acid-catalyzed methanolysis
of the acetonide group of 13 afforded the a- and b-methyl glycosides which were
reductively demethoxylated[2] to 14 by initial treatment with HMDS and TMSCl fol-
lowed by reaction with TMS-triflate and triethylsilane (82% yield). Conversion of 13
to 14 is also possible with BF3.Et2O, Et3SiH in CH2Cl2(see Sch. 1) but the yield was
lower than the two-step method. Protected isodideoxynucleoside 15 can be prepared
in very low yield (7%) by treatment of 14 with adenine under Mitsunobu conditions.
There was no evidence for the formation of the 3-substituted isomer in this case.
The inefficiency of the Mitsunobu reaction prompted the investigation of a less direct
method,[2] i.e., conversion of 14 to its mesyl derivative (77%) followed by treatment
of the mesylate with adenine in the presence of K2CO3, 18-crown-6 in DMF (28%).

Analogs of Isodideoxyadenosine
243
Deprotection of the resulting compound (15) by treatment with sodium methoxide
gave 3 in 66% yield.
The anti-HIV studies of the target compounds 2 (11b, R ¼ H), 12b (R ¼ H), and
3 showed that these compounds were devoid of any significant antiviral activity
(HIV-1, HSV, VZV, CMV). Correlation of this inactivity with electrostatic potential
surface data and the bioactivity diagram for the isoddA series[5] suggests that there
may be less tolerance for steric bulk at this position than previously suggested by our
bioactivity correlation.
EXPERIMENTAL
2(S)-(Benzoyloxymethyl)-4(R)-[O-(2,5-bis-trifluoromethyl)benzoyloxy]-3-spiro-
cyclo-propyltetrahydrofuran (8). To a solution of 5[7] (7.76 g, 26.8 mmol) in CH2Cl2
(150 mL) at 0ꢁC was added Et3SiH (42.6 ml, 268 mmol) followed immediately by
BF3ꢃEt2O (34.0 mL, 268 mmol). The solution was stirred at room temperature for
2 h followed by neutralization with saturated aqueous NaHCO3. Extraction with
CH2Cl2 (3 ꢄ 100 mL) and evaporation of the combined organic layers gave the crude
product which was purified over silica gel to give 6 (4.79 g, 76%) as a gum which soli-
dified on standing, m.p. 66–67ꢁC. To a solution of 6 (2.61 g, 11.1 mmol) in pyridine
(100 mL) at 0ꢁC was added 2,5-bis-trifluoromethylbenzoyl chloride (4.04 mL,
22.2 mmol). The reaction solution was stirred at 0ꢁC for 15 min. The reaction was
quenched with saturated aqueous NaHCO3 and the solvent was evaporated to dry-
ness and the residue was purified over silica gel to give the dibenzoyl derivative 7
(4.82 g, 92% yield) as yellow oil. To a solution of 7 (9.70 g, 20.5 mmol) in CH2Cl2
(25 mL) was added diazomethane (excess) in diethyl ether (250 mL). The resulting
solution was allowed to stir at ambient temperature for 48 h. Excess solvent was
removed by evaporation. The crude product was purified over silica gel (60% ethyl
acetate: hexanes) to give the spiropyrazoline derivative (10.04 g, 19.5 mmol, 95%
yield). To a solution of the pyrazoline derivative in 1:1 benzene: acetonitrile solution
(250 mL) was added benzophenone (1.83 g, 9.75 mmol). The solution was then irra-
˚
diated at 3000 A for 2 h. Excess solvent was removed and the crude product was pur-
ified over silica gel (0–10% ethyl acetate: hexanes) to give 8 (4.60 g, 11.5 mmol, 59%
1
yield) as a pale yellow amorphous powder: H NMR (CDCl3) d 0.77 (m, 1H, spiro-
cyclopropyl), 0.90 (m, 1H, spirocyclopropyl), 1.03 (m, 1H), 1.61 (m, 1H), 4.11–4.21
(m, 3H), 4.43 (dd, 1H), 4.53 (m, 1H), 5.19 (d, 1H), 7.44 (t, 2H), 7.57 (t, 1H), 7.92 (d,
2H), 8.05 (d, 3H); 13C NMR (CDCl3) d 5.30, 9.64, 28.23, 64.45, 72.20, 77.48, 83.94,
127.50, 127.54, 127.72, 127.76, 129.69, 129.78, 133.21, 165.44, 166.33; HRMS (FAB):
(MþH)þ calcd for C23H19F6O5 489.1136, found 489.1129.
2(S)-(Benzoyloxymethyl)-4(R)-hydroxy-3-spirocyclopropyltetrahydrofuran (10).
To a solution of 8 (0.8 g, 3.2 mmol) in MeOH (40 mL), was added 1N aqueous NaOH
(5 mL). After the addition, the reaction mixture was stirred at room temperature for
1.5h. The solution was neutralized with 0.5M HCl and evaporated to dryness.
The residue was purified over silica gel to give 9 (0.23 g, 50%) as a colorless oil. To a solu-
tion of 9 (0.21 g, 1.45 mmol) in pyridine (40 mL) was added benzoyl chloride (0.18 mL,
1.6 mmol) in pyridine (5 mL) slowly over a period of 1 h at ꢂ10ꢁC. The reaction mixture

244
Nair, Mickle, and Bera
was stirred for an additional 1h at ꢂ10ꢁC, then quenched with water and evaporated to
dryness. The residue was partitioned between saturated aqueous NaHCO3 (60 mL) and
CHCl3 (50 mL) and the aqueous part was further extracted with CHCl3 (50 mL). The
combined CHCl3 layers were dried over Na2SO4, evaporated to dryness and purified
1
over silica gel to give 10 (0.28 g, 78%) as a gum: H NMR (CDCl3) d 0.63 (m, 2H),
0.87 (m, 1H), 1.06 (m, 1H), 3.90 (m, 2H), 4.08–4.22 (m, 3H), 4.46 (dd, 1H), 7.42 (t,
2H), 7.55 (t, 1H), 8.02 (d, 2H); 13C NMR (CDCl3) d 3.78, 25.18, 60.01, 69.46, 72.74,
73.05, 123.49, 124.73, 128.23, 161.56; HRMS (FAB): (M þ H)þ calcd for C14H17O4
249.1126, found 249.1130.
4(S)-(6-Amino-9H-purin-9-yl)-3-spirocyclopropyltetrahydro-2(S)-furanmethanol
(11b) and 4(S)-(6-Amino-3H-purin-3-yl)-3-spirocyclopropyltetrahydro-2(S)-furan-
methanol (12b). To a suspension of 10 (0.15 g, 0.6 mmol), adenine (0.12g, 0.9 mmol),
Ph3P (0.24 g, 0.9 mmol) in dioxane (20 mL) was added DEAD (0.2 mL). After the
addition, the reaction mixture was stirred at room temperature for 2 days. The solvent
was then evaporated to dryness and the residue was purified over silica gel to give 11a
and 12a. To a solution of 11a in MeOH (12 mL) was added 1N NaOH (1 mL) and the
solution was stirred at room temperature for 1.5 h, then neutralized with 0.5 M HCl
and the solvent was evaporated to dryness. The residue was purified over silica gel to
give 11b (0.027 g, 17% from 10) as a white solid. Compound 12a was deprotected
following the same method to give 12b (0.22 g, 14% from 10) as a white solid.
1
Compound 11b: m.p: 180–181ꢁC; UV (MeOH) lmax 261 (13,800); H-NMR
(MeOH-d4) d 8.55 (s, 1H), 8.15 (s, 1H), 4.84 (s, 1H), 4.26 (m, 2H), 3.92 (m, 1H),
3.70 (dd, J ¼ 3.4, 12.2 Hz, 1H), 3.47 (dd, J ¼ 4.2, 12.2 Hz), 1.21 (m, 1H), 0.93 (m,
1H), 0.73 (m, 1H), 0.38 (m, 1H); 13C-NMR (MeOH-d4) d 157.2, 153.6, 150.7,
141.7, 119.3, 84.5, 73.7, 63.5, 62.1, 29.8, 14.3, 8.8; HRMS (FAB): (MþH)þ calcd
for C12H16N5O2 262.1304, found 262.1304.
Compound 12b: mp 244ꢁC; UV (MeOH) lmax 275 (12,600); 1H-NMR (d4-
MeOH): 8.95 (s, 1H), 7.85 (s, 1H), 5.12 (m, 1H), 4.31 (m, 2H), 4.94 (m, 1H), 3.78
(dd, J ¼ 3.2, 12.5 Hz), 3.46 (dd, J ¼ 3.3, 13.4 Hz), 1.32 (m, 1H), 1.04 (m, 1H), 0.79
(m, 1H), 0.46 (m, 1H); 13C-NMR (d4-MeOH): 156.5, 152.9, 150.9, 144.7, 120.5,
84.6, 73.7, 68.4, 61.3, 29.2, 14.9, 9.8. HRMS (FAB): (MþH)þ calcd for
C12H16N5O2 262.1304, found 262.1316.
5-O-Benzoyl-1,2-O-isopropylidene-3(R)-methyl-a-D-xylofuranose (13). To
a
solution of 5 (3.85 g, 13.3 mmol) in ethanol (150 mL) was added Pd=C (1.00 g).
The suspension was stirred under 25 psi of H2 for 24 h and filtered. The filtrate
was evaporated and the residue was purified over silica gel to give 13 (3.84 g, 99%)
1
as an oil: H NMR (CDCl3) d 1.15 (d, 3H), 1.35 (s, 3H), 1.54 (s, 3H), 2.04 (m,
1H), 4.11 (m, 1H), 4.38 (m, 1H), 4.58 (m, 2H), 5.85 (d, 1H), 7.44 (t, 2H), 7.57 (t,
1H), 8.03 (d, 2H); 13C NMR (CDCl3) d 9.35, 26.12, 26.31, 40.16, 64.30, 82.59,
105.05, 111.59, 128.36, 129.76, 133.10, 166.42; HRMS (FAB): (MþNa)þ calcd for
C16H20NaO5 315.1208, found 315.1212.
2(S)-(Benzoyloxymethyl)-3(S)-methyltetrahydrofuran-4(R)-ol (14). Hydrogen
chloride (0.03 g, 0.75 mmol) was bubbled through a solution of 13 (3.85 g,

Analogs of Isodideoxyadenosine
245
13.3 mmol) in MeOH (75 mL) and the resulting solution was stirred overnight at
room temperature. Excess acid was neutralized with saturated aqueous NaHCO3
solution and the solvent was then removed under reduced pressure and the residue
was purified over silica gel to give the anomeric mixture of methyl glycosides
(3.13 g, 89%) as a clear oil. To a solution of the methyl glycosides (3.13 g, 11.8 mmol)
in HMDS (150 mL) was added chlorotrimethylsilane (5 mL) and the mixture was
heated under reflux for 20 h and excess HMDS was then removed under reduced
pressure. The residue was dissolved in anhydrous dichloroethane (125 mL) and this
was followed by the addition of triethylsilane (5.64 mL, 35.4 mmol) and then slow
addition of TMS-triflate (6.40 mL, 35.4 mmol). After stirring at room temperature
for 17 h, the reaction mixture was quenched by the addition of water (100 mL).
The solution was allowed to stir for an additional 2 h, neutralized with aqueous
NaHCO3 and excess solvent was removed. The residue was purified over silica gel
1
to give 14 (2.56 g, 10.8 mmol, 92%) as a light yellow low melting solid: H NMR
(CDCl3) d 1.85 (d, 3H), 2.12 (m, 1H), 3.87 (d, 1H), 4.09 (m, 2H), 4.36 (m, 2H),
4.55 (dd, 1H), 7.42 (t, 2H), 7.58 (t, 1H), 8.08 (d, 2H); HRMS (FAB): (MþH)þ calcd
for C13H17O4 237.1127, found 237.1128.
4(S)-(6-Amino-9H-purin-9-yl)-3(S)-methyltetrahydro-2(S)-furanmethanol (3).
To a solution of 14 (2.56 g, 10.8 mmol) in pyridine (120 mL) was added methanesul-
fonyl chloride (4.18 mL, 54.0 mmol) at 0ꢁC and the mixture was stirred at room tem-
perature for 2 h. The reaction was quenched with water (5 mL), the excess solvent
was removed and the residue was coevaporated with toluene (2 ꢄ 25 mL). The crude
product was purified over silica gel to give the mesylate of 14 (2.60 g, 8.28 mmol,
1
77%) as a yellow oil: H NMR (CDCl3) d 1.22 (d, 3H), 2.30 (m, 1H), 3.08 (s, 3H),
4.03 (m, 1H), 4.16 (m, 1H), 4.26–4.58 (m, 3H), 5.22 (bs, 1H), 7.44 (t, 2H), 7.56 (t,
1H), 8.02 (d, 2H); 13C NMR (CDCl3) d 10.33, 38.62, 39.93, 64.78, 73.16, 81.49,
83.56, 128.45, 129.68, 133.22, 166.39. Adenine (0.238 g, 1.91 mmol), 18-crown-6
(0.252 g, 0.955 mmol), and K2CO3 (0.264 g, 1.91 mmol) were suspended in DMF
(25 mL) and heated at 100ꢁC for 2 h. A solution of the mesylate of 14 (0.300 g,
0.955 mmol) in DMF (5 mL) was then added and the mixture was stirred at 100ꢁC
for 20 h. Excess DMF was then removed and the crude product was purified over
1
silica gel to give 15 (0.095 g, 28%): H NMR (acetone-d6) d 1.24 (d, 3H), 2.04 (m,
1H), 4.05 (m, 1H), 4.22 (t, 1H), 4.28 (m, 1H), 4.48–4.62 (m, 2H), 4.93 (q, 1H),
6.79 (d, 2H), 7.52 (t, 2H), 7.63 (t, 1H), 8.06 (d, 2H), 8.15 (s, 1H), 8.19 (s, 1H); 13C
NMR (CDCl3) d 16.14, 43.45, 61.94, 64.85, 71.47, 84.19, 128.73, 129.90, 133.53,
153.30, 156.10, 166.70. [Compound 15 was also prepared by the Mitsunobu reaction.
To a solution of 14 (0.203 g, 0.86 mmol) in THF (10 mL) was added Ph3P (0.338 g,
1.29 mmol), adenine (0.174 g, 1.29 mmol), and DEAD (0.27 mL, 1.72 mmol). The
reaction mixture was stirred at room temperature for 5 days. Excess solvent was
removed and the crude product was purified over silica gel to yield 15 (0.022 g,
0.06 mmol, 7%)]. To a solution of 15 (0.095 g, 0.27 mmol) in MeOH (10 mL) was
added NaOMe (0.01 g, 0.18 mmol) and the mixture was stirred for 6 h at room tem-
perature. The solution was neutralized with HOAc, the solvent was then removed
and the crude product was purified over silica gel to give 16 (0.044 g, 66%) as a white
1
solid: m.p. 174–176ꢁC; H NMR (MeOH-d4) d 1.19 (d, 3H), 2.58 (m, 1H), 3.34 (m,
1H), 3.67 (m, 2H), 3.82 (m, 1H), 4.16 (m, 2H), 8.20 (s, 1H), 8.32 (s, 1H); UV (MeOH)

246
Nair, Mickle, and Bera
lmax 260 nm (e 12800); HRMS (FAB): (MþH)þ calcd for C11H16N5O2 250.1304,
found 250.1303.
ACKNOWLEDGMENTS
The project described was supported by Grant Number AI 32851 from the
National Institutes of Health. Its contents are solely the responsibility of the authors
and do not necessarily represent the official views of the NIH. We thank Drs. Erik
De Clercq and Jan Balzarini for the antiviral evaluations.
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Received September 16, 2002
Accepted December 26, 2002