Design and synthesis of some new α-phenyl cinnamoyl derivatives for selective protection of purine nucleosides

Article abstract of DOI:10.1080/00397910500278867

Three new α-phenylcinnamic acid derivatives [4-methoxy-α- phenylcinnamic acid, α-(4-methoxyphenyl)-cinnamic acid, and 4,4′-bismethoxy-α-phenylcinnamic acid] were synthesized, characterized, and selectively used for protecting the exocyclic amino function of purine nucleosides (2′-deoxyadenosine and 2′-deoxyguanosine) via active ester generation. The acids were first activated using p -nitrophenol, and these activated esters were used subsequently for the selective protection of amino groups. The N -protected derivatives of 2′-deoxyguanosine and 2′-deoxyadenosine have been found to be sufficiently stable toward acids, thus minimizing depurination under oligodeoxyribonucleotide synthesis protocol. The ease of syntheses of N -protected purine nucleosides, their stability under an acidic environment, and mild deprotection conditions are the key advantages of the new protecting groups. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500278867

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Design and Synthesis
of Some New α‐Phenyl
Cinnamoyl Derivatives for
Selective Protection of Purine
Nucleosides
Snehlata Tripathi a , Krishna Misra a & Yogesh S.
Sanghvi b
a Nucleic Acids Research Laboratory, Department
of Chemistry , University of Allahabad , Allahabad,
India
b Rasayan Incorporation , Encinitas , California, USA
Published online: 21 Aug 2006.
To cite this article: Snehlata Tripathi , Krishna Misra & Yogesh S. Sanghvi (2005)
Design and Synthesis of Some New α‐Phenyl Cinnamoyl Derivatives for Selective
Protection of Purine Nucleosides, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 35:23, 3069-3081
To link to this article: http://dx.doi.org/10.1080/00397910500278867
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Synthetic Communicationsw, 35: 3069–3081, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500278867
Design and Synthesis of Some New a-Phenyl
Cinnamoyl Derivatives for Selective
Protection of Purine Nucleosides
Snehlata Tripathi and Krishna Misra
Nucleic Acids Research Laboratory, Department of Chemistry,
University of Allahabad, Allahabad, India
Yogesh S. Sanghvi
Rasayan Incorporation, Encinitas, California, USA
Abstract: Three new a-phenylcinnamic acid derivatives [4-methoxy-a-phenylcinnamic
acid, a-(4-methoxyphenyl)-cinnamic acid, and 4,40-bismethoxy-a-phenylcinnamic acid]
were synthesized, characterized, and selectively used for protecting the exocyclic amino
function of purine nucleosides (20-deoxyadenosine and 20-deoxyguanosine) via active
ester generation. The acids were first activated using p-nitrophenol, and these
activated esters were used subsequently for the selective protection of amino groups.
The N-protected derivatives of 20-deoxyguanosine and 20-deoxyadenosine have been
found to be sufficiently stable toward acids, thus minimizing depurination under
oligodeoxyribonucleotide synthesis protocol. The ease of syntheses of N-protected
purine nucleosides, their stability under an acidic environment, and mild deprotection
conditions are the key advantages of the new protecting groups.
Keywords: acylation, antisense, a-phenylcinnamoyl, depurination resistant
Received in the USA June 30, 2005
Address correspondence to Snehlata Tripathi, Center for Emerging and Re-emerging
Pathogens, Department of Biochemistry and Molecular Biology, UMDNJ—New Jersey
Medical School, 185 South Orange Avenue, Newark, New Jersey 07103, USA (present
address). Tel.: 1-973-972-5322; Fax: 1-973-972-8657; E-mail: tripatsn@umdnj.edu;
snehlatatripathi@yahoo.com
3069

3070
S. Tripathi, K. Misra, and Y. S. Sanghvi
INTRODUCTION
Chemically synthesized oligodeoxyribonucleotides (ODNs) have become
extremely important tools for the study of the life sciences. More than two
dozen oligonucleotide drugs are undergoing human clinical trials for the
treatment of viral infections, cancers, and a range of inflammatory disorders.
In addition, use of antisense gene expression modulation to produce well-
defined pharmacological effects is now a routine procedure.[1] The need for
very large quantities of therapeutically useful antisense ODNs can be easily
anticipated by their growing demand in therapeutics.[2,3] However, a series
of problems hampers the current methodology of automated solid-phase
synthetic approaches on controlled pore-glass supports, specifically, the
problem of depurination, which occurs because of the repeated acid
treatment used for the removal of the 50-O-4,40-dimethoxytrityl (DMTr) pro-
tecting group during synthesis of ODNs.[4] Acylation of amino function in
purine nucleosides facilitates the protonation at N7,[5] which makes the
glycosyl bond more prone to hydrolysis under acidic conditions.[6,7]
Depurination is the most common problem faced while using the most
commonly used groups, the benzoyl, anisoyl, and isobutyryl groups. The
phthaloyl group[8] for adenosine has been suggested to be depurination
resistant, but because of its instability problem, it could not be used successfully
in large-scale synthesis. The depurination is facilitated under acidic conditions
required for removal of DMTr group during automated synthesis of ODNs.
Because the growing chain of ODNs is frequently subjected to acid treatment,
the risk of depurination involves protonation or deprotonation of the purine
residues followed by cleavage of the glycosidic linkage, generating undesirable
apurinic sites.[9,10] Depurination in the case of N6-protected 20-deoxyadenosine
is facilitated because of the protonation at the N7 position. In the case of partially
depurinated oligomer, chain cleavage takes place at the site of depurination
by double b-elimination, thus generating truncated sequences.[10] In the
case of guanosine, the site of protonation is N7, but the tendency of N2-
isobutyryl deoxyguanosine to depurinate is lower than that of N6-benzoyl-20-
deoxyadenosine.[11] To block N7 protonation, we had successfully used several
groups earlier, namely 3-methoxy-4-phenoxy benzoyl,[12] phenoxyacetyl,[13]
naphthaloyl,[14] and a-phenyl-cinnamoyl,[15] in ODN synthesis.
In continuation of our efforts toward development of new protecting
groups that would resist depurination, three new derivatives of a-phenyl
cinnamic acid have been synthesized by introducing a methoxy group at the
para position of either or both benzene rings. The main purpose for the intro-
duction of the methoxy group in these three derivatives was to decrease the
t1/2 for the deprotection step using ammonia and also to check N-protonation,
thereby further reducing the depurination problem. More emphasis was also
given to the crystallization of the protected nucleosides, which may eliminate
the expensive chromatographic purification of raw materials, an important
aspect in the scaling of ODN synthesis.

New a-Phenyl Cinnamoyl Derivatives
3071
The conventionally used acylation reagents for amino protection are either
in acid chloride or anhydride form. In the present work, the installation of the pro-
tecting group has been done by a new method. For example, instead of using
corrosive and hazardous acid chloride, we utilized the safe and cheaper acid
forms that have been activated via p-nitrophenol esters. The activated ester
strategy is an established protocol in the peptide chemistry where dicyclohexyl-
carbodiimide is used as a coupling agent to furnish the –CO–NH– bond. To the
best of our knowledge, use of the active ester approach for the N-protection of
purine residue is not reported in the literature. Herein, the N-acylation of
purine residue was accomplished with excellent selectivity and high yield.
MATERIALS AND METHODS
All the deoxynucleosides and 4,40-dimethoxytrityl chloride were purchased from
Aldrich Chem. Co. Phenylacetic acid, 4-methoxy phenyl acetic acid, benzal-
dehyde, and 4-methoxy benzaldehyde were purchased from Merck-Schudardt,
Germany. Solvents were duly purified and dried before use. Pyridine was
refluxed with ninhydrin and distilled over KOH. Silica-gel G (Merck) plates
were used for TLC. Plates were sprayed with sulphuric acid to ascertain the
nucleoside spots. UV absorption was measured on a Hitachi 220S spectro-
photometer. Elemental analyses were carried out using a Carlo Erba 1106
analyser.
a-Phenylcinnamic acid derivatives (Scheme 1) were prepared by the
Perkin reaction involving phenylacetic acid, 4-methoxyphenylacetic acid,
benzaldehyde, 4-methoxybenzaldehyde, and acetic acid in the presence of
triethylamine as catalyst.[16]
Synthesis of 4-Methoxy a-Phenylcinnamic Acid (a)
p-Methoxy phenylacetic acid (8.3 g, 0.05 mol), benzaldehyde (5 mL,
0.05 mol), acetic anhydride (10.58 mL, 0.10 mol), and triethylamine (5 mL)
were taken in a three-necked round-bottomed flask (100 mL) fitted with a
Scheme 1. Synthesis of different methoxy derivatives of a-phenylcinnamic acid.

3072
S. Tripathi, K. Misra, and Y. S. Sanghvi
reflux condenser and a CaCl2 drying tube. The reaction mixture was refluxed
for 5 h. Steam distillation was done directly from the reaction flask until the
distillate passing over was no longer cloudy. This process was used to
remove the excess of acetic acid, which is formed as a by-product in the
reaction. The distillate was discarded. The solid deposited in the flask was
dissolved in minimum quantity of hot ethanol followed by quick filtration
over pump. The resulting solution was cooled down to get the product in
crystallized form. Yield 94% (8.5g), mp150–1528C, lmax 272 nm. Elemental
analysis C16H13O2: calc. C, 75.88%; H, 5.13%, Found C, 75.86%; H, 5.13%.
Synthesis of a-(4-Methoxyphenyl)-cinnamic Acid (b)
p-Methoxy benzaldehyde (6.8 mL, 0.05 mol), acetic anhydride (10.2 mL,
0.10 mol), and triethylamine (5 mL) were added to the equimolar amount of
phenylacetic acid (6.8 g, 0.05 mol)in a three-necked flask and the reaction
was carried out as previously described. Yield 88% (5.2g), mp 168–1708C,
lmax 275 nm. Elemental analysis C16H13O2: calc. C, 75.88%; H, 5.13%,
Found C, 75.80%; H, 5.14%.
Synthesis of 4,40-Bis Methoxy-a-phenylcinnamic Acid (c)
Synthesis of this acid was carried out using the previously mentioned protocol
using 4-methoxy phenylacetic acid and p-methoxy benzaldehyde in the respect-
ive molar ratio. Yield 88% (5.2 g), mp 160–1638C, lmax 29nm. Elemental
analysis C17H15O4: calc. C, 72.12%; H, 5.3%, Found C, 72.11%; H, 5.5%.
General Method for Preparation of N6-Protected-20-dA
and N2-Protected-20-dG (Scheme 2)
Activation of the Respective Acids to Esters
A solution of p-nitrophenol (0.0048 mol) in 1,4-dioxane (5 mL) was added to a
stirred solution of the appropriate acids (a, b, c; 0.004 mol) in dry 1,4-dioxane
(5 mL) at room temperature. The reaction media was made basic by the
addition of pyridine (0.5 mL) and triethylamine (0.5 mL). After stirring for
10 min dicyclohexylcarbodiimide (0.005 mol) was added and the stirring
continued for 2 h. (Caution! Protection from moisture was necessary.) After
completion of the reaction (monitored by TLC) the mixture was cooled to 08C.
Protection Step
Anhydrous 20-deoxynucleoside (0.004mol) was dissolved in dry pyridine
(5mL) and added to the activated ester solution at 08C. After 10min of

New a-Phenyl Cinnamoyl Derivatives
3073
Scheme 2. Protection of purine deoxynucleosides with different methoxy derivatives
of a-phenylcinnamic acid.
stirring, DCC (0.005mol) was added, and the reaction mixture was stirred for an
additional 2.5 h. Completion of the reaction was checked by TLC. The precipi-
tated dicyclohexylurea was removed by filtration, and the filtrate was concen-
trated under vacuum to half of its volume and then poured in a 5% sodium
bicarbonate solution and extracted with dichloromethane (4 ꢀ 10mL). The
organic layer was washed with water, dried over Na2SO4, and filtered.
The combined dichloromethane layers were concentrated and the residue
crystallized from diethylether. The product data is summarized in Table 1.
General Method for Preparation of 50-O-Dimethoxytrityl-N-
protected-20-deoxynucleosides
Each N-protected-20-deoxynucleoside (1.0 mmol) was treated with 4,40-
dimethoxytrityl chloride (1.2 mmol) in pyridine (10.0 mL) in the presence of
4-dimethylamino pyridine as catalyst at room temperature (258C) to furnish
its trityl derivative. After completion of the reaction (checked by TLC), the

3074
S. Tripathi, K. Misra, and Y. S. Sanghvi
a
a
a
a
a

New a-Phenyl Cinnamoyl Derivatives
3075
a
a
a
a
a

3076
S. Tripathi, K. Misra, and Y. S. Sanghvi
clear solution was evaporated to a gum under vacuum and worked up by the
procedure reported earlier.[17] Yield, Rf, and lmax of various derivatives is
listed here.
50-O-DMTr-N6-4-Methoxy-a-phenylcinnamoyl-20-O-deoxyadenosine. Yield
85%, Rf 0.76 (dichloromethane:methanol 9.5:0.5 v/v), lmax 272, 286 nm.
50-O-DMTr-N6-a-(4-Methoxyphenyl)cinnamoyl-20-deoxyadenosine. Yield
78%, Rf 0.68 (CH2Cl2:CH3OH 9.5:0.5 v/v), lmax 263, 280 nm.
50-O-DMTr-N6-4,40-bis Methoxy-a-phenylcinnamoyl-20-deoxyadenosine.
Yield 68%, Rf 0.78 (CH2Cl2:CH3OH 9.5:0.5 v/v), lmax 275, 287, 305 nm.
50-O-DMTr-N2-4-Methoxy-a-phenylcinnamoyl-20-deoxyguanosine. Yield
80%, Rf 0.63 (CH2Cl2:CH3OH 9:1 v/v), lmax 267, 285 nm.
50-O-DMTr-N2-a-(4-Methoxyphenyl)-cinnamoyl-20-deoxyguanosine. Yield
72%, Rf 0.69 (CH2Cl2:CH3OH 9:1 v/v), lmax 269, 291 nm.
50-O-DMTr-N2-4,40-bis Methoxy-a-phenylcinnamoyl-20-deoxyguanosine.
Yield 71%, Rf 0.68 (CH2Cl2:CH3OH 9:1 v/v), lmax 257,263, 291 nm.
Study of Deprotection Conditions of N-Protected dA and dG
All the six N-acylated derivatives, three each of dA and dG with substituted
a-phenyl cinnamic acids prepared as described, were taken in small aliquots
and treated with 40% aqueous ammonia solution. All the vials were kept
sealed at 408C for different time intervals. In all sets, the reaction was
quenched by the addition of dilute hydrochloric acid after 0.5, 1.0, 2.0, 3.0,
4.0, 5.0, and 6.0 h. The solvents from the reaction mixture were then evapor-
ated under vacuum and again taken in CH2Cl2. These reaction mixtures were
then subjected to semipreparative TLC (CH2Cl2:CH3OH 9:1; v/v). Two major
bands of relative Rf (0.65 for protected nucleoside and 0.3 for unprotected
nucleoside) were obtained. The two bands were eluted separately in
methanol and their absorbance (OD) was recorded. The percentage of depro-
tection against time was estimated as the OD of the lower band divided by the
total OD of upper and lower band multiplied by 100. Graphs were manually
plotted for time vs. percentage of deprotection for exact comparison
(Figures 1 and 2). The results confirmed that the deprotection was complete
in 4–7 h independent of the protecting group used.
Estimation of Degree of Depurination
The N-protected nucleosides (0.1 mmol) were dissolved in DCM (5 mL) and
the unprotected nucleosides were dissolved in water (5 mL). Each solution
was treated with 80% acetic acid (2 mL) at room temperature. Reaction was
quenched by triethylamine–methanol (4:1 v/v) at varied time intervals. In
the case of dA and its derivatives, the quenching time was 30 min, 1 h, 2 h,

New a-Phenyl Cinnamoyl Derivatives
3077
Figure 1. Deprotection of N6-4-methoxy a-phenylcinnamoyl-dA (B); N6-a-
(4-methoxyphenyl) cinnamoyl-dA (V); N6-4,40-bis methoxy-a-phenylcinnamoyl-dA
(O); N6-benzoyl dA (†), at 408C with 40% ammonia.
4 h, 6 h, 20 h, 30 h, and 60 h, and in the case of dG and its derivatives, the
quenching time was 15 min, 30 min, 1 h, 2 h, 4 h, 10 h, 20 h, and 30 h. After
quenching each fraction was evaporated to dryness and dissolved in
minimum solvent (DCM for N-protected nucleosides and water for unpro-
tected nucleosides). These solutions were run on semipreparative TLC. The
upper band [i.e., depurinated part (free base)] and the lower band (i.e.,
unchanged nucleosides) were scratched and eluted with DCM in the case of
N-protected nucleosides and with water in the case of free nucleosides. UV
absorption was measured at the 288 nm wavelength for N6-4-methoxy-a-
phenylcinnamoyl dA, 290 nm for N6-a-(4-methoxyphenyl)cinnamoyl dA,
285 nm for N6-4,40-bis methoxy-a-phenylcinnamoyl dA, 280 nm for N6-bz-dA,
260 nm for dA, 285 nm for N2-4-methoxy-a-phenylcinnamoyl dG, 290 nm
for N2-a-(4-methoxyphenyl)cinnamoyl dG, 283 nm for N2-4,40-bis methoxy-
a-phenyl cinnamoyl dG, 260 nm for N2-ibu-dG, and 252 nm for dG. Data is
Figure 2. Deprotection of N2-4-methoxy a-phenylcinnamoyl-dG (B); N2-a-
(4-methoxy phenyl) cinnamoyl-dG (V); N2-4,40-bis methoxy-a-phenylcinnamoyl-dG
(O); N2-benzoyl dG (†), at 408C with 40% ammonia.

3078
S. Tripathi, K. Misra, and Y. S. Sanghvi
Figure 3. Depurination of N-protected derivatives of 20-dA; N6-benzoyl-dA (V);
N6-a-phenylcinnamoyl-dA (O); N6-4-methoxy-a-phenylcinnamoyl-dA (B).
shown only for N6-bz-dA and N6-4-methoxy-a-phenylcinnamoyl dA, and a
comparison with previously reported N6-a-phenylcinnamoyl-dA (Figure 3),
and for N2-ibu-dG, N2-4-methoxy-a-phenylcinnamoyl dG, and N2-4-
methoxy-a-phenylcinnamoyl dG (Figure 4).[15]
RESULTS AND DISCUSSION
Using the active ester protocol, all three methoxy derivatives of a-phenyl
cinnamic acid were found to be regioselective for the protection of
Figure 4. Depurination of N-protected derivatives of 20-dG; N2-isobutyryl-dG (B);
N2-a-phenylcinnamoyl-dG (V); N2-4-methoxy- a-phenylcinnamoyl-dG (O).

New a-Phenyl Cinnamoyl Derivatives
3079
exocyclic amino function in purine bases. Most important, acylation of the
sugar hyroxyl group was not observed. This protocol eliminates the two-
step conventional procedure that is commonly employed for the protection
of purine base in nucleosides.
As reported earlier, the a-phenylcinnamoyl group[15] was found to be
better at resisting depurination than benzoyl- and isobutryl-protected dA
and dG, respectively (half life N6-a-phenylcinnamoyl dA is 19.5 h; N6-bz-
dA, 10.5 h; N2-a-phenylcinnamoyl dG, 10.5 h; and N2-ibu-dG, 10 h). The
main reason for the synthesis of these three molecules was to further slow
down the depurination rates and increase the half-life beyond the earlier
report.[15] Gratifyingly, this task was accomplished with 4-methoxy-a-phe-
nylcinnamoyl derivative (a) exhibiting a t1/2 of 30 h for dA (Figure 3) and
a t1/2 of 20 h for dG (Figure 4). To explain the increased half-life of a-phe-
nylcinnamoyl dA, we postulate that the weakly acidic b-hydrogen atom of
the a-phenylcinnamoyl group may form a weak intramolecular hydrogen
bond with the N7 nitogen atom. This interaction may reduce the basicity of
N7 nitrogen atom, making it less prone to attack the proton during
treatment with protonated acid. However, there are two available alternative
p-positions on the two-phenyl rings that may be used for installation of any
electron-donating group, thereby rendering the b-hydrogen more available.
Keeping this rationale in mind, we have introduced two methoxy groups
(c) that may make the b-hydrogen more available for hydrogen bonding with
the N7 of the purine nucleobase. Additionally, introduction of methoxy group
may enhance the solubility of the protected nucleosides in organic solvents,
enabling easy purification of the products. Although derivative c with two
methoxy groups appears to be attractive, lower yield for the protection step
with c was discouraging for scaling purposes and we elected not to pursue
it further. The experimental data (Figures 1 and 2) confirm that the depurina-
tion sensitivity and the efficiency of deprotection were better in cases where
`
the methoxy group was present in the main ring (derivative a) vis-a-vis the
a-phenyl ring (derivative b). This extra stability shown by the derivative a
may be attributed to the introduction of the methoxy group in the p-
position, which enhances the availability of the b-hydrogen atom for
hydrogen bonding. In addition, it is important to note that the bulky nature
of the protecting group may prevent the free rotation of the glycosidic
linkage, strengthening the proposed hydrogen bonding.
The cost of raw materials is of paramount importance in the synthesis of
antisense ODNs. In this regard, we believe that the new active ester protocol
may be more cost efficient than the old protocols. Although use of DCC as a
coupling agent may not be the best choice from an industrial point of view,[18]
we believe that solid-support reagents may provide an alternative.[19] Further-
more, the inherent crystalline nature of these products may assist in circum-
venting the expensive column chromatographic purification step.
In summary, we have developed a novel and one-pot synthetic strategy
for the protection of N-acyl function of purine moiety of deoxyribonucleosides.

3080
S. Tripathi, K. Misra, and Y. S. Sanghvi
The yield was also found to be better in all the cases, a clear-cut advantage over
the existing protocols for synthesizing protected monomers.
It seems that the strategy used in this communication has worked well and
a conclusion may be drawn in favor of using it for further synthesis of ribo
series as well as long oligomers.
ACKNOWLEDGMENT
Thanks are due to Regional Sophisticated Instruments Centre, Central Drug
Research Institute, Lucknow, India, for IR, mass, and NMR spectra. Authors
gratefully acknowledge financial support from ISIS Pharmaceuticals USA.
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