A convenient synthesis of 2′,3′-dideoxyinosine- 13C5and related 2′,3′-dideoxyadenosine- 13C5

Article abstract of DOI:10.1002/jlcr.1839

2′,3′-Dideoxyinosine-¹³C₅ (ddI- ¹³C₅) and the related 2′,3′-dideoxyadenosine- ¹³C₅ (ddA-¹³C₅) were prepared from (S)-5-[¹³C₅]2,3-dideoxyribonolac

Full text of DOI:10.1002/jlcr.1839

Research Article
Received 18 August 2010,
Revised 14 September 2010,
Accepted 15 September 2010
Published online 30 November 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1839
A convenient synthesis
of 20,30-dideoxyinosine-13C5
and related 20,30-dideoxyadenosine-13C5
Ã
I. Victor Ekhato, and Jay K. Rinehart
20,30-Dideoxyinosine-13C5 (ddI-13C5) and the related 20,30-dideoxyadenosine-13C5 (ddA-13C5) were prepared from (S)-5-
[
13C5]2,3-dideoxyribonolactone 1. From a batch of this starting material ddI-13C5 was made in 27% overall yield in seven
steps and ddA-13C5 in five steps and 14% overall yield. The known synthesis of ddI-13C5 from glucose-13C6 took 18-steps;
therefore the present work is a substantial improvement.
Keywords: HIV-AIDS; 20,30-dideoxyinosine (ddI); 20,30-dideoxyadenosine (ddA); HIV-AIDS; dideoxynucleosides (ddNu)
power of ꢀ5000. Capillary voltage and sample voltage were at 3
and 25 kV respectively. A desolvation temperature of 2501C and a
source temperature of 1201C were used for all HRMS experiments.
(S)-5-[13C5]2,3-Dideoxyribonolactone Lot ] PR-16144, Chemical
Purity 498%, GC/MS for Isotopic Enrichment 99.3%, was
purchased from Cambridge Isotope Laboratories, Inc., MA, USA.
Introduction
20,30-Dideoxyinosine (ddI) or VidexTM is among the nucleosides
and nucleoside analogs that have been approved by the FDA for
treating HIV-AIDS.1 It is currently being studied for clinical use in
pediatrics. We became interested in the carbon-13 labeled
version of ddI and the related 20,30-dideoxyadenosine (ddA),
Figure 1, because the bioassays in the study program required
labeled ddI for the quantitation of 2,3-dideoxyinosine and
related drug substances in biological samples. There is an earlier
synthesis of these 13C5-labeled purine nucleosides from
glucose-13C6 and it is quite lengthy.2 It was also not clear that
the product obtained by their sequence from glucose was free
of contamination with N7-isomer.
We conducted an initial study to resolve the pitfalls mentioned
above and from it3 the useful reactions have been put together to
make 13C5-labeled dideoxyinosine (ddI) and the related dideox-
yadenosine (ddA). Broadly described, we substituted (S)-5-[13C5]2,3-
dideoxyribonolactone for glucose-13C6 and used 6-chloropurine
instead of hypoxanthine to achieve a short, practical and high
yielding asymmetric synthesis of the titled labeled compounds.
(S)-5-½13C5ꢁ((tert-Butyldiphenylsilyloxy)methyl)dihydrofuran-
2(3H)-one 2
tert-Butylchlorodiphenylsilane (12.48 g, 45.40 mmol) was added to
a stirred solution of (S)-5-[13C5]2,3-dideoxyribonolactone 1 (5.0 g,
41.28 mmol) and imidazole (6.31 g, 92.68 mmol) in dry dimethyl-
formamide (DMF) (45 mL) under an atmosphere of argon. After 1 h
at room temperature, the reaction mixture was concentrated to a
residue under high vacuum, the residue was diluted with
chloroform (160 mL) and washed successively with water
(2 ꢂ 50 mL), brine (50 mL) and dried on MgSO4. The solvent was
evaporated to a residue and it was chromatographed (silica gel,
10–30% ether in pet ether). The pure fractions were combined,
evaporated and the solid material was crystallized from pet ether
1
to give 2 (12.3 g, 82%). H-NMR (400 MHz, CDCl3) d 7.65 (m, 4H),
7.41 (m, 6H), 4.79 and 4.10 (brs, 1H), 4.05 and 3.69 (m, 1H), 3.86 and
3.50 (m, 1H), 2.85 and 2.68 (m, 1H), 2.44 (brd, 2H), 2.09 (brm, 1H).
Experimental
All reactions were carried out under an atmosphere of argon
unless otherwise specified. Solvents were of commercial grade
and used without purification or drying. Flash chromatographic
separations were done with Biotage Flash System and pre-packed
(90 g) silica gel cartridges. TLC visualization reagents included
(10% iodine110% AcOH) in 40% aqueous KI. 1H NMR spectra were
recorded on a 300, 400 or 500 MHz Spectrometer. Chemical shifts
are given in ppm relative to tetramethylsilane (TMS). 13C-NMR
spectra were recorded at 100 MHz and chemical shifts given in
ppm with CDCl3 reference set at 77.0ppm. HPLC analyses were
completed using various columns, as specified in the experimental
section. HRMS data were acquired on an LCT-TOF spectrometer
(Micromass Ltd., Manchester, UK), in ESI mode, with a resolving
(3R,5S)-5-½13C5ꢁ((tert-Butyldiphenylsiloxy)methyl-3-phenyl-
selenyl)-dihydrofuran-2(3H)-one 3
Lithium bis(trimethylsilyl)amide (LHMDSi) (1.0 M solution in THF,
36.87 mL, 36.87 mmol) was added over 10 min to a solution of 2
Bristol-Myers Squibb Company, Department of Chemical Synthesis, Route 206
and Provinceline Road, Princeton, NJ 08543, USA
*Correspondence to: I. Victor Ekhato, Bristol-Myers Squibb Company, Depart-
ment of Chemical Synthesis, Route 206 and Provinceline Road, Princeton, NJ
08374, USA.
E-mail: ihoezo.ekhato@bms.com
J. Label Compd. Radiopharm 2011, 54 175–179
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I. V. Ekhato and J. K. Rinehart
residue. The solid was dissolved in 1,2-dichloroethane (35 mL)
and cooled to ꢃ251C (dry ice/acetonitrile) while stirring under
argon atmosphere. A solution of 5 (7.38 g, 13.2 mmol) in
1,2-dichloroethane (25 mL) was added in one portion. This was
followed by adding TMSOTf (3.5 mL, 19.40 mmol) slowly over
several minutes. The mixture was stirred at ꢃ201C (ice-salt) for
25 min and a further 30 min at room temperature and poured
with stirring onto ice-cold EtOAc-saturated NaHCO3 (80:50 v/v)
mixture. After 30 min the layers were separated, the organic
phase was washed with saturated NaHCO3 (2 ꢂ 50 mL), dried
over anhydrous sodium sulfate and evaporated to a cream.
Chromatography (silica gel 5–25% EtOAc in hexane) gave clear
creamy liquid. It was dissolved in minimum CH2Cl2, transferred
into hot pet-ether and stirred at room temperature to yield
white solid 6 (6.1g, 71%). HRMS (TOF MS ES1): [M1H]1 calcd.
Figure 1. Targeted labeled nucleosides.
(12.05 g, 33.52 mmol) in dry THF (120 mL) at ꢃ781C under argon
atmosphere. After stirring for 1 h chlorotrimethylsilane (5.32 mL,
41.90 mmol) was added slowly and the reaction mixture was
allowed to warm to room temperature for 30 min. It was cooled
to ꢃ781C and a solution of phenylselenyl bromide PhSeBr
(11.86 g, 50.28 mmol) in dry THF (60 mL) was added rapidly. The
reaction was diluted with 160 mL of ether after 25 min at ꢃ781C,
washed with water several times until the organic phase
became permanent light yellow. After the solvent was removed,
the crude cream was applied as a solution in dichloromethane
to a column of silica gel, and eluted with hexane to remove
excess PhSeBr. Further elution with 5–12% ether in hexane gave
3 (8.203 g). The b-isomer 4 was flushed from the column with
40% EtOAc in hexane and recycled by equilibration with DBU in
THF for 1 h followed by chromatography to give a total yield of
3 (12.30 g, 71.3%). 1H NMR (400 MHz, CDCl3) d 7.60–7.68 (m, 5H),
7.14–7.45 (m, 10H), 4.79 and 4.10 (brs, 1H), 4.05 and 3.69 (m, 1H),
3.86 and 3.50 (m, 1H), 2.85 and 2.68 (m, 1H), 2.44 (brd, 2H), 2.09
(brm, 1H).
1
for [13C5]C32H34ClN4O2SeSi, 654.1473; found, 654.1465. H-NMR
(400 MHz, CDCl3) d 8.58 (s, 1H), 8.19 (s, 1H), 7.61–7.65 (m, 5H),
7.32–7.45 (m, 10H), 7.01–7.19 (m, 10H), 6.01–6.64 (m, 1H),
4.15–4.60 (brm, 2H), 4.16–3.90 (m,. 1H), 3.55–3.93 (m, 1H),
2.36–2.86 (brm, 1H), 1.66–2.50 (brd, 1H), 1.07 (s, 9H). 13C NMR
(101 MHz, CDCl3)
d
ppm 32.86 (t, J = 32.80 Hz) 43.18
(t, J = 32.80 Hz) 65.25 (d, J = 43.35 Hz) 80.15 (dd, J = 43.49,
33.57 Hz) 91.32 (d, J = 37.4 Hz).
9-((2R,3R,5S)-5-((tert-Butyldiphenylsiloxy)methyl)-3-(phenyl-
selenyl)-tetrahydrofuran-2-yl)-9H-purin-6-amine11
Adenine (1.66 g, 12.30 mmol) was similarly converted to the silyl
derivative and reacted with 5 (4.88 g, 8.73 mmol, (see experi-
ment 6)) to give 11 (4.65 g, 84%) as a white solid after trituration
(3R,5S)-5-½13C5ꢁ((tert-Butyldiphenylsiloxy)methyl-3-phenyl-
selenyl)-tetrahydrofuran-2-yl acetate 5
1
with ether. H-NMR (400 MHz, CDCl3) d 8.41 (s, 1H), 7.95 (s, 1H),
7.59–7.16 (m, 20H), 6.31 (brs, –NH2), 6.03–5.60 (two d, 1H),
4.55–4.21 (two brs, 1H), 3.84–3.55 (two m, 1H), 2.99–2.64 (two
brs, 1H), 2.35–2.01 (two brs, 1H), 1.05 (s, 9H).
To a stirred solution of 3 (12.30 g, 23.9 mmol) in 80 mL of
anhydrous toluene at ꢃ781C was added DIBAL-H (1.0 M solution
in toluene, 38.0 mL, 38 mmol) over 15 min. After 2 h at ꢃ781C,
8.0 mL of methanol was added cautiously, and the temperature
was raised to ꢃ201C and the mixture was stirred for 30 min. The
mixture was diluted with ethyl acetate (200 mL) followed by
9-((2R,3R,5S)-5-½13C5ꢁ((tert-Butyldiphenysiloxy)methyl)-3-
(phenylselenyl)-tetrahydrofuran-2-yl)-1H-purin-6(9H)-one 7
potassium/sodium tartrate (100 mL) and allowed to warm to A solution of 6 (5.02 g, 7.68 mmol), 2-mercaptoethanol (1.68 mL,
room temperature. Celite was added to break up the slug and 21.56 mmol), sodium methoxide 0.5 M in methanol (45.36 mL,
the mixture was filtered. The cake was washed with ethyl 22.68 mmol) was refluxed for 4 h and cooled to room
acetate and the washings were combined with the filtrate. The temperature. The reaction mixture was acidified with acetic
aqueous phase was discarded and the organic portion was acid, diluted with water and extracted with ethyl acetate
further washed with water (200 mL), brine (200 mL), dried over (2 ꢂ 80 mL). The organic phase was washed with water
MgSO4 and filtered. It was evaporated and repeatedly co- (100 mL), dried over magnesium sulfate, filtered and concen-
evaporated with toluene to give the lactol (11.63 g). The material trated under reduced pressure. Column chromatography (silica
was dissolved in dry CH2Cl2 (60 mL) and cooled in ice bath. While gel), eluting first with 70% ethyl acetate in hexane, and finally
stirring under argon atmosphere catalytic DMAP (20 mg), with 5% MeOH in dichloromethane gave pure fractions that was
pyridine (14.70 mL, 144.75 mmol), and acetic anhydride evaporated to a foamy solid. The solid was taken up in hot
(5.50 mL, 57.8 mmol) were added. After stirring for 2 h at 01C, hexane aided with CH2Cl2 and cooled to room temperature to
the solvent was evaporated under reduced pressure and further give solid 7 (4.35 g, 89%). HRMS (TOF MS ES1): [M1H]1 calcd.
co-evaporated with toluene. The residue was dissolved in ether for [13C5]C32H34N4O3SeSi, 636.1811; found, 636.1811. 1H-NMR
(200 mL), washed with 80 mL of water, 80 mL of brine and dried. (400 MHz, CDCl3) d 12.58 (brs, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 6.36
Evaporation of solvent gave 5 (12.26 g, 92%).
and 5.94 (brd, 1H), 4.58 and 4.21 (brs 1H), 4.40 and 4.21 (brs, 1H),
4.14 and 3.77 (brm, 1H), 3.91 and 5.36 (brd, 1H0, 2.82 and 2.49
(brs, 1H ), 2.34 and 2.00 (brd, 1H) and 1.07 (s, 9H).
9-((2R,3R,5S)-5-((tert-Butyldiphenylsiloxy)methyl)-3-(phenyl-
selenyl)-tetrahydrofuran-yl)-6-chloro-9H-purine 6
9-((2R,5S)-5-½13C5ꢁ((tert-Butyldiphenysiloxy)methyl)-tetrahy-
drofuran-2-yl)-1H-purin-6(9H)-one 8
A mixture of 6-chloropurine (2.87 g, 18.61 mmol) and ammo-
nium sulfate (70 mg) in hexamethyldisilazane (45 mL) was
refluxed under argon atmosphere for 1.5 h during which a clear A mixture of 7 (2.4 g, 3.78 mmol), triethylborane, 1.0 M solution
solution was formed. After cooling to room temperature, the in hexanes (4.19 mL, 4.19 mmol), and tributyltin hydride 97%
solvent was removed under reduced pressure to give a solid (1.5 mL, 5.61 mmol) in anhydrous benzene 100 mL was stirred at
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 175–179

I. V. Ekhato and J. K. Rinehart
room temperature for 4 h. After evaporation of solvent the After column chromatography, the product was treated with
residue was dissolved in acetonitrile, washed with hexane TBAF (1.0 M solution in THF, 5 mL, 5 mmol) at room temperature
(3 ꢂ 20 mL) and evaporated to a residue. The material was for 3 h, purified by column chromatography on silica gel (5–20%
purified (silica gel, 5% MeOH in CH2Cl2), and crystallization from MeOH in CH2Cl2) to give 12 (401 mg, 31.6%) as white solid
hexane-CH2Cl2 gave a white solid 8 (1.71 g, 95%). 13C NMR following trituration with methanol–ether. Chemical Purity
(101 MHz, CDCl3)
d
ppm 25.70 (t, J = 32.04 Hz) 33.25 98.3%; Isotopic Distribution: [M15] 95.2%, [M10] not detected.
(t, J = 32.81 Hz) 65.13 (d, J = 44.25 Hz) 82.26 (dd, J = 43.49, HRMS (TOF MS ES1): [M1H]1 calcd. for [13C5]C10H13N5O2,
33.57 Hz) 85.63 (d, J = 35.86 Hz).
241.1315; found, 241.1315. 1H-NMR (400 MHz, CD3OD) 8.38
(s, 1H), 8.13 (s, 1H), 6.33 and 5.90 (two brs, 1H), 4.44 and 4.07
20,30-Dideoxyinosine-13C5((ddI), 9-((2R,5S)-5-Hyroxymethyl)- (two brs, 1H), 3.79 and 3.40 (two d, 1H), 3.58 and 3.21 (two d,
½
13C5ꢁ tetrahydrofuran-2-yl)-1H-purin-6(9H)-one 10
1H), 2.73 and 2.37 (two, brm, 1H), 2.59 and 2.16 (two brs, 1H),
2.26 and 1.81 (two brd, 2H).
To a solution of 8 (1.54 g, 3.21 mmol) in dry THF (20 mL) was
slowly added tetrabutylammonium fluoride (TBAF) (1.0 M
solution in THF 3.3 mL, 3.3 mmol), and stirred at room
temperature for 3 h. The solvent was evaporated to give a
residue that was applied in a solution of dichloromethane to a
column of silica gel. After first equilibrating with 0–6% MeOH in
CH2Cl2, the compound was eluted with 10% MeOH in CH2Cl2 to
give pure fractions. The fractions were evaporated to a white
solid, and trituration with CH2Cl2/acetone gave 10 (660 mg,
85.2%). Chemical Purity 99.2%; Isotopic Distribution: [M15]
94.3%, [M10] not detected. HRMS (TOF MS ES1): [M1H]1 calcd.
for [13C5]C10H12N4O3, 242.1155; found, 242.1164. 1H-NMR
(400 MHz, CD3OD) d 8.28 (s, 1H), 7.92 (s, 1H), 6.39 and 5.98
(brm,1H), 4.31 and 3.94 (brs, 1H), 3.88 and 3.73 (brm, 1H), 3.53
and 3.36 (brm, 1H), 2.53 and 2.24 (brm, 2H) 2.17 and 1.83 (brs,
2H). 13C NMR (101 MHz, CDCl3) d ppm 32.00 (t, J = 33.45 Hz)
43.37 (t, J = 35.50 Hz) 64.18 (d, J = 42.60 Hz) 79.01 (dd, J = 42.75,
32.40 Hz) 92.9 (d, J = 38.5 Hz).
Results and discussions
We required a synthesis of ddI and ddA that is shorter than that
had been achieved from glucose-13C6. (S)-5-[13C5]2,3-Dideoxyr-
ibonolactone 1 met our criteria as a starting compound. With 1
we would avoid the dehomologation reactions, protective
group manipulations and the de-oxygenation steps that
together comprised the 18-step sequence of the prior labeled
synthesis.2 The downside to our strategy is the requirement for a
group which would potentially steer a b-face glycosylation to
provide the b-anomer downstream in our transformation
sequence.4 Such useful synthon 5, bearing a-phenylselenyl
substitution in the ribonolactone, was synthesized from (S)-5-
[13C5]2,3-dideoxyribonolactone 1 as shown in Scheme 1. The
silyl ether 2, which formed by routine protocol, was reacted with
lithium bis(trimethylsilyl)amide to give an enolate that was
trapped as the trimethylsilyl enol-ether. Without isolation, the
silyl enol-ether was treated in situ with phenylselenyl bromide to
give a separable mixture of isomers 3 and 4. After chromato-
graphic separation, the (3S,5S)-isomer 4 was recycled by
equilibrating in a solution of THF containing DBU, leading to
71% total yield of desired (3R,5S)-isomer 3. To make 5 the
intermediate 3 was subjected to reduction with DIBAL-H at
20,30-Dideoxyadenosine-13C5,((2S,5R)-5-(6-amino-9H-purin-
9-yl)tetrahydrofuran-2-yl)methanol 12
A solution of 11 (3.32 g, 5.23 mmol), triethylborane (1.0 M
solution in hexane, 5.8 mmol), tributyltin (2.5 mL, 7.75 mmol) in
anhydrous benzene (80 mL) was reacted as in experiment 8.
Scheme 1.
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I. V. Ekhato and J. K. Rinehart
ꢃ781C and the resulting lactol was acylated to give 5 in 92% diphenysiloxy)methyl)-tetrahydrofuran-2-yl)-1H-purin-6(9H)-one 8
yield. It was now time to implement the glycosylation of in 95% isolated yield. It remained to remove the silyl protection to
6-chloropurine.
complete the synthesis of ddI-13C5. The desilylation was
By substituting 6-chloropurine for hypoxanthine we are able accomplished by the reaction of 8 in THF with TBAF at 231C
to obtain only the N9 inosine in a sequence of glycosylation and for 3 h. The crude material was filtered through a column of
chloride ion displacement. From 5 this strategy5 led to ddI-13C5 silica gel to furnish ddI-13C5 as a white solid in 85% yield. 20,30-
as illustrated in Scheme 2. A solution of 5 in 1,2-dichloroethane Dideoxyionsine-13C5 prepared in this manner did not contain
was added to a pre-generated6 silylated 6-chloropurine in a detectable amount3 of the N-7 isomer.
solution of 1,2-dichloroethane at ꢃ251C, and the reaction was
By a similar strategy depicted in Scheme 3 the related 20,30-
initiated by treatment with TMSOTf. Compound 6 was obtained dideoxyadenosine-13C5 12 was prepared from 5. In this instance,
as crystalline solid in 71% yield following chromatography and adenine was substituted for 6-chloropurine as the nucleobase,
crystallization. The inosine 7 was generated from 6 in 89% yield and the glycosylation reaction was conducted under identical
by treatment with 2-mercaptoethanol and sodium methoxide in reaction conditions, viz. addition of 5 to silylated adenine in
refluxing methanol. The 20,30-dideoxy ring structure was easily 1,2-dichloroethane at ꢃ251C followed by TMSOTf activation. The
restored by the reduction of 7 with (n-Bu3SnH/Et3B)7 to remove compound 11, obtained in 84% isolated yield, was sequentially
phenylselenyl group and provide 9-((2R,5S)-5-[13C5]((terytbutyl- subjected to reductive removal of the a-phenylselenyl group
Scheme 2.
Scheme 3.
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I. V. Ekhato and J. K. Rinehart
and desilylated to 20,30-dideoxyadenine-13C5 in 15% overall yield.
Proof of the structure of ddI-13C5 and ddA-13C5 were confirmed
Acknowledgements
1
by H-NMR spectroscopy and HPLC comparison with authentic
ddI and ddA respectively.
I. V. E. gratefully acknowledges the support of BMS Department
of Chemical Synthesis. The authors thank Richard E. Gedamke
for HRMS measurements.
Conclusion
20,30-Dideoxyinosine (ddI-13C5) and 20,30-dideoxyadenosine
(ddA-13C5) were made in overall yield of 28 and 15%. The
present preparation represents a significant improvement on
previously reported synthesis from glucose-13C6. By starting
from (S)-5-[13C5]2,3-dideoxyribonolactone instead of gluco-
se-13C6 we made ddI-13C5 in seven steps. Also, we eliminated
the formation of N7-nucleoside by using 6-chloropurine as
nucleobase instead of hypoxanthine to make the labeled ddI. A
b-face selectivity leading to these compounds was achieved
through the directional effect of a-phenylselenyl group sub-
stitution in the ribose moiety. The present method demon-
strates a useful solution to the vexing lengthy synthesis of ddI
from glucose and ensures high-quality grade material by
rigorous regio- and stereoselective control of the transforming
reactions.
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