Nucleotides part LXXIX1: New building blocks for photolithographic syntheses of oligoribonucleotides

Article abstract of DOI:10.1002/hlca.201000403

Two series of new ribonucleoside 3′-phosphoramidites (see 36-42) carrying the photolabile [2-(2-nitrophenyl)propoxy]carbonyl group at the 5′-O-position were synthesized and characterized as monomeric building blocks for photolithographic syntheses of RNA

Full text of DOI:10.1002/hlca.201000403

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Nucleotides
Part LXXIX1)
New Building Blocks for Photolithographic Syntheses of Oligoribonucleotides
by Christoph Hermann, Evgeny Kvassiouk, and Wolfgang Pfleiderer*
Fachbereich Chemie, Universitꢀt Konstanz, Postfach 5560, D-78457 Konstanz
(phone: þ 49-7531-882279; fax: þ 49-7531-883138; e-mail: Wolfgang.Pfleiderer@uni-konstanz.de)
Two series of new ribonucleoside 3’-phosphoramidites (see 36 – 42) carrying the photolabile [2-(2-
nitrophenyl)propoxy]carbonyl group at the 5’-O-position were synthesized and characterized as
monomeric building blocks for photolithographic syntheses of RNA chips. Base protection was achieved
in the well-known manner by the 2-(4-nitrophenyl)ethyl (npe) and the [2-(4-nitrophenyl)ethoxy]car-
bonyl (npeoc) group. The carbohydrate moiety carried in addition the 2’-O-(tetrahydro-4-methoxy-2H-
pyran-4-yl) group for blocking the 2’-OH function.
1. Introduction. – Based upon the photolability of the 2-nitrobenzyl group [2] and its
derivatives, their use in nucleic acid [3 – 10], carbohydrate [11], and peptide [12 – 14]
chemistry is common practise. More recently, photolabile 5’-protection of 2’-
deoxyribonucleoside 3’-phosphoramidites have also successfully been employed in
the solid-phase synthesis of DNA probe arrays [15 – 18]. There are numerous
publications describing the photolabile protection of OH, COOH, NH2, SH, and
C¼O functions [19]. Since the quantum yield of photodeprotection is highly influenced
by substitutions at the benzene ring or the CH2 C-atom [20] of the 2-nitrobenzyl group,
a large variety of structural modifications is known.
The reported photochemical reactions of the o-NO2 groups with C(b) atoms
[21][22] suggested that the homologous 2-(2-nitrophenyl)ethyl group [23] might also
be useful as a photocleavable protecting function. We developed new types of very
efficient photolabile protecting groups based upon the [2-(2-nitrophenyl)propoxy]car-
bonyl [nppoc] moiety [24], determined the mechanism of cleavage [25], and could
improve the cleavage rate by intramolecular sensitization [26 – 28]. Caged nucleosides
[29] have also been applied, and the use of new building blocks for photolithographic
oligonucleotide array formation was very successful [29][30].
2. Syntheses. – Two new types of building blocks for photolithographic oligor-
ibonucleotide synthesis were obtained based on two series of nucleobase-protected
starting materials carrying either the phenoxyacetyl (pac) (see 2 – 4 [30][31]) or the [2-
(4-nitrophenyl)ethoxy]carbonyl (npeoc) group (see 5 – 7 [32]) at the amino functions
1
)
Part LXXVIII: [1].
ꢁ 2011 Verlag Helvetica Chimica Acta AG, Zꢂrich

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of the ribonucleosides. Guanosine was further protected at the O6-position by the 2-(4-
nitrophenyl)ethyl group (see 7) for solubility reasons (Scheme).
Scheme
The next steps included the 3’,5’-protection by Markiewiczꢃs 1,1,3,3-tetraisopropyl-
disiloxane-1,3-diyl group (see 8 – 14 [33 – 36]) and was followed by the introduction of
the tetrahydro-4-methoxy-2H-pyran-4-yl residue at the 2’-OH position leading to 15 –
21. Deprotection of the silyl group by fluoride ion proceeded well and led to the
modified ribonucleosides 22 – 28. Several compounds of these two series have been
described before [32][33][36], and the new types have been prepared by similar
procedures.
The interconversion of compounds 22 –28 into the 5’-O-{[2-(2-nitrophenyl)propoxy]-
carbonyl} (¼ 5’-[2-(2-nitrophenyl)propyl carbonate]) derivatives 29 – 35 proceeded
well on acylation with [2-(2-nitrophenyl)propoxy]carbonyl chloride (¼2-(2-nitrophe-
nyl)propyl carbonochloridate) in pyridine. The final phosphitylation to 36 – 42 was

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achieved by 2-cyanoethyl N,N,N’,N’-tetraisopropylphosphorodiamidite in good to
excellent yields. The newly synthesized compounds were characterized by UV and 1H-
and 31P-NMR spectra as well as elemental analyses.
Experimental Part
General. Products were dried under high vacuum. All solvents used were of anh. grade. TLC:
precoated silica gel (SiO2) thin-layer sheets 60 F254 from Merck. Flash Chromatography (FC): SiO2 (30 –
60 mm, Baker); 0.2 – 0.3 bar. M.p.: Bꢀchi melting-point apparatus B-545; uncorrected. UV/VIS: Perkin-
Elmer Lambda 5; lmax (log e) in nm. 1H-NMR: Bruker AC 250; d in ppm rel. to Me4Si or CDCl3
((D6)DMSO) as internal standard, J in Hz. 31P-NMR: Jeol JMN-GX400.
N4-(Phenoxyacetyl)cytidine (2) [31]. A mixture of cytidine (30.0 g, 0.12 mol) and hexamethyldisi-
lazane (300 ml) was refluxed for 4 h and then evaporated, and the residue was dissolved in pyridine
(200 ml). A suspension of 3-methyl-1-(phenoxyacetyl)-1H-imidazol-3-ium chloride (MPIC), prepared
from phenoxyacetyl chloride (pac-Cl; 30.7 g, 0.18 mol) and 1-methyl-1H-imidazole (MeIm; 16.4 g,
0.2 mol), in CH2Cl2 (400 ml) was added at 48 by portions within 30 min. The mixture was stirred at r.t. for
20 h, the CH2Cl2 distilled off, and ice (15 g) added. The soln. was cooled with ice, then conc. NH3 · H2O
(15 ml) was added dropwise, and after stirring for 4 h at r.t., the precipitate was washed with pyridine
(2 ꢀ 100 ml) and CH2Cl2 (2 ꢀ 100 ml). The combined filtrates were concentrated and then treated with
CH2Cl2 (200 ml) in a ultrasonic bath for 5 min. The precipitate was collected by suction and washed with
CH2Cl2, and the solid treated with H2O (200 ml) in an ultrasonic bath again. The precipitate was filtered
off, washed with H2O (3 ꢀ 100 ml), and dried (P4O10) in a vacuum desiccator: 28.3 g (61%) of 2.
Colorless solid. M.p. 180 – 1828. 1H-NMR ((D6)DMSO): 10.99 (s, NH); 8.45 (d, HꢁC(6)); 7.28 (d, 2 arom.
H); 7.10 (d, HꢁC(5)); 6.92 (m, 3 arom. H); 5.77 (d, HꢁC(1’)); 5.49 (d, HOꢁC(2’)); 5.16 (t, HOꢁC(5’));
5.05 (d, HOꢁC(3’)); 4.81 (s, CH2O); 3.95 (m, HꢁC(2’,3’,4’)); 3.71 (m, 1 HꢁC(5’)); 3.60 (m, 1 HꢁC(5’)).
N6-(Phenoxyacetyl)adenosine (3) [31]. As described for 2, with adenosine (32.0 g, 0.12 mol) in
pyridine (200 ml) and chlorotrimethylsilane (Me3Si-Cl) (98.0 g, 0.9 mol) and stirring at r.t. for 2 h. After
cooling to 48, a suspension of MPIC (from pac-Cl (30.7 g, 0.18 mol) and MeIm (16.4 g, 0.2 mol)) in
CH2Cl2 (400 ml) was added within 30 min. After stirring for 18 h at r.t., analog workup gave 39.0 g (81%)
of 3. Colorless solid. M.p. 110 – 1128 (from EtOH/H2O 1:1). 1H-NMR ((D6)DMSO): 10.96 (s, NH); 8.73
(s, HꢁC(2)); 8.68 (s, HꢁC(8)); 7.37 – 6.90 (m, 5 arom. H); 6.01 (d, HꢁC(1’)); 5.55 (d, HOꢁC(2’)); 5.25 (d,
HOꢁC(3’)); 5.13 (t, HOꢁC(5’)); 5.03 (s, CH2O); 4.61 (m, HꢁC(2’)); 4.17 (m, HꢁC(3’)); 3.97 (m,
HꢁC(4’)); 3.66 (m, 1 HꢁC(5’)); 3.58 (m, 1 HꢁC(5’)).
N2-(Phenoxyacetyl)guanosine (4) [31]. As described for 3, with guanosine (28.3 g, 0.1 mol) and
Me3Si-Cl (81.6 g, 95 ml, 0.74 mol) in pyridine (300 ml), MPIC (from pac-Cl (25.6 g, 0.15 mol) and MeIm
(13.9 g, 0.17 mol)) in CH2Cl2 (400 ml): 35.0 g (84%) of 4. Colorless solid. M.p. 128 – 1338 (dec.).
1H-NMR ((D6)DMSO): 11.85, 11.78 (2s, 2 NH); 7.33 – 6.92 (m, 5 arom. H); 5.81 (d, HꢁC(1’)); 5.49 (d,
HOꢁC(2’)); 5.18 (d, HOꢁC(3’)); 5.03 (t, HOꢁC(5’)); 4.86 (s, CH2O); 4.44 (m, HꢁC(2’)); 4.12 (m,
HꢁC(3’)); 3.90 (m, HꢁC(4’)); 3.59 (m, 2 HꢁC(5’)).
N4-{[2-(4-Nitrophenyl)ethoxy]carbonyl}cytidine (5) [32].
N6-{[2-(4-Nitrophenyl)ethoxy]carbonyl}adenosine (6) [32].
N2-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-O6-[2-(4-nitrophenyl)ethyl]guanosine (7) [32].
3’,5’-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)uridine (8) [33]. A soln. of uridine (9.8 g, 40 mmol)
in pyridine (100 ml) was treated with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (tipdsCl2) (14.0 g,
44 mmol) for 18 h at r.t. Then, MeOH (2 ml) was added with stirring, and after 10 min, the soln. diluted
with CHCl3 (200 ml) and washed with NaHCO3 soln. (2 ꢀ 150 ml). The org. layer was dried (Na2SO4) and
concentrated and the residue co-concentrated with toluene (2 ꢀ 100 ml) and CHCl3 (2 ꢀ 150 ml): 19.0 g
(97%) of 8. Amorphous solid foam which was used for the next step to 15 without further purification.
1H-NMR ((D6)DMSO): 11.36 (s, NH); 7.68 (d, HꢁC(6)); 5.59 (d, HOꢁC(2’)); 5.52 (d, HꢁC(1’)); 5.50 (d,
HꢁC(5)); 4.20 – 3.85 (m, HꢁC(2’,3’,4’), CH2(5’)); 1.03 – 0.95 (m, 4 i-Pr).
N4-(Phenoxyacetyl)-3’,5’-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)cytidine (9). As described for 8,
with 2 (20.0 g, 53 mmol) and tipdsCl2 (18.3 g, 58 mmol) in pyridine (150 ml): 32.1 g (97%) of 9.

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Amorphous foam, pure enouph for the next step. 1H-NMR ((D6)DMSO): 11.01 (s, NH); 8.14 (d,
HꢁC(6)); 7.28 – 6.92 (m, 5 arom. H); 7.13 (d, HꢁC(5)); 5.79 (d, HOꢁC(2’)); 5.60 (d, HꢁC(1’)); 4.81 (s,
CH2O); 4.40 (s, HꢁC(3’); 4.06 (m, HꢁC(2’,4’), CH2(5’)); 1.04 – 0.94 (m, 4 i-Pr).
N6-(Phenoxyacetyl)-3’,5’-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)adenosine (10) [34]. As de-
scribed for 9, with 3 (20.0 g, 50 mmol) and tipdsCl2 (17.3 g, 55 mmol) in pyridine (150 ml): 30.9 g
(98%) of 10. Amorphous solid. 1H-NMR ((D6)DMSO): 10.98 (s, NH); 8.59 (s, HꢁC(2)); 8.54 (s,
HꢁC(8)); 7.32 – 6.93 (m, 5 arom. H); 5.98 (d, HꢁC(1’)); 5.71 (d, HOꢁC(2’)); 5.02 (s, CH2O); 4.77 (s,
HꢁC(3’); 4.59 (m, HꢁC(2’)); 4.04 (m, HꢁC(4’), CH2(5’)); 1.03 – 0.94 (m, 4 i-Pr).
N2-(Phenoxyacetyl)-3’,5’-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)guanosine (11) [35]. As de-
scribed for 9, with 4 (20.8 g, 50 mmol) and tipdsCl2 (17.3 g, 55 mmol) in pyridine (150 ml): crude 11
which was purified by CC (SiO2 (8 ꢀ 15 cm), hexane/AcOEt 4 :1 and hexane/AcOEt/acetone 4 :1:1):
27.6 g (84%) of 11. Amorphous foam. 1H-NMR ((D6)DMSO): 11.90, 11.80 (2s, 2 NH); 8.06 (s, HꢁC(8));
7.35 – 6.90 (m, 5 arom. H); 5.79 (d, HꢁC(1’)); 5.73 (d, HOꢁC(2’)); 4.86 (s, CH2O); 4.33 (m, HꢁC(2’,3’));
4.00 (m, HꢁC(4’), CH2(5’)); 1.04 – 0.94 (m, 4 i-Pr).
N4-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-3’,5’-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)cytidine
(12) [36].
N6-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-3’,5’-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)adenosine
(13) [36].
N2-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-O6-[2-(4-nitrophenyl)ethyl]-3’,5’-O-(1,1,3,3-tetraisopropyl-
disiloxane-1,3-diyl)guanosine (14) [36].
2’-O-(Tetrahydro-4-methoxy-2H-pyran-4-yl)-3’,5’-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)uri-
dine ( ¼ 1-{Tetrahydro-2,2,4,4-tetraisopropyl-9-[(tetrahydro-4-methoxy-2H-pyran-4-yl)oxy]-6H-furo[3,2-
f][1,3,5,2,4]trioxadisilocin-8-yl}uracil; 15) [36].
N4-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)-3’,5’-O-(1,1,3,3-tetraisopropyldisi-
loxane-1,3-diyl)cytidine (16). A mixture of 9 (16.6 g, 26.8 mmol), (ꢁ)-camphor-10-sulfonic acid (CSA;
2.0 g, 8.9 mmol), molecular sieves (MS; 4.5 g), and 3,6-dihydro-4-methoxy-2H-pyran (5.0 g, 43.8 mmol)
in CH2Cl2 (100 ml) was stirred at r.t. for 18 h and then neutralized by pyridine (2 ml). The molecular
sieves were filtered off and washed with CHCl3 (200 ml). The combined filtrate was washed with
NaHCO3 soln., the org. phase dried (Na2SO4), concentrated and co-concentrated with toluene (100 ml),
and the residue purified by CC (SiO2 (5 ꢀ 15 cm), hexane/acetone 9 :1 and 6 :1): 2.3 g of 9 and 10.7 g
(60%) of 16. Amorphous foam. 1H-NMR ((D6)DMSO): 11.05 (s, NH); 8.24 (d, HꢁC(6)); 7.28 – 6.92 (m, 5
arom. H); 7.13 (d, HꢁC(5)); 5.94 (d, HꢁC(1’)); 4.81 (s, CH2O); 4.44 (d, HꢁC(2’)); 4.16 (m, HꢁC(3,ꢃ4’),
1 HꢁC(5’)); 3.95 (dd, 1 HꢁC(5’)); 3.65, 3.50 (2m, CH2OCH2); 3.23 (s, MeO); 1.98, 1.78 (2m, CH2CCH2);
1.04 – 0.95 (m, 4 i-Pr).
N6-(Phenoxyacetyl)-2’-O-(4-tetrahydro-4-methoxy-2H-pyran-4-yl)-3’,5’-O-(1,1,3,3-tetraisopropyldisil-
oxane-1,3-diyl)adenosine (17). As described for 16, with 10 (10.0 g, 15.5 mmol), CSA (1.0 g, 4.3 mmol),
MS (3.5 g), and 3,6-dihydro-4-methoxy-2H-pyran (5.0 g, 43.8 mmol) in CH2Cl2 (70 ml). Neutralization
by pyridine (1 ml), workup and CC gave 2.3 g of 10 and 6.5 g (76%) of 17. Amorphous foam. 1H-NMR
((D6)DMSO): 10.97 (s, NH); 8.58 (s, HꢁC(2.8)); 7.32 – 6.93 (m, 5 arom. H); 6.11 (d, HꢁC(1’)); 5.02 (s,
CH2O); 4.98 (d, HꢁC(2’); 4.90 (m, HꢁC(3’)); 4.15 – 3.90 (m, HꢁC(4’), 1 HꢁC(5’)); 3.95 (dd, 1 HꢁC(5’));
3.70, 3.42 (2m, CH2OCH2); 3.17 (s, MeO); 1.77 (m, CH2CCH2); 1.03 – 0.99 (m, 4 i-Pr).
N2-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)-3’,5’-O-(1,1,3,3-tetraisopropyldisi-
loxane-1,3-diyl)guanosine (18). As described for 16, with 11 (6.0 g, 0.9 mmol), CSA (0.2 g, 0.9 mmol),
MS (2.0 g), and 3,6-dihydro-4-methoxy-2H-pyran (8.3 g, 72.7 mmol) in CH2Cl2 (30 ml) for 8 h.
Neutralization by pyridine (1 ml), workup, and CC gave 5.5 g (78%) of 18. Colorless solid. M.p. 173 –
1
1748 (from EtOH). H-NMR ((D6)DMSO): 11.84, 11.50 (2s, 2 NH); 8.18 (s, HꢁC(8)); 7.33 – 6.95 (m, 5
arom. H); 5.88 (d, HꢁC(1’)); 4.85 (s, CH2O); 4.71 (d, HꢁC(2’)); 4.47 (m, HꢁC(3’)); 4.05 (m, HꢁC(4’),
1 HꢁC(5’)); 3.95 (m, 1 HꢁC(5’)); 3.69, 3.40 (2m, CH2OCH2); 3.04 (s, MeO); 1.78 (m, CH2CCH2); 1.01 –
1.01 (m, 4 i-Pr).
N4-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)-3’,5’-O-(1,1,3,
3-tetraisopropyldisiloxane-1,3-diyl)cytidine (19) [36].
N6-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)-3’,5’-O-(1,1,3,
3-tetraisopropyldisiloxane-1,3-diyl)adenosine (20) [36].

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N2-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-O6-[2-(4-nitrophenyl)ethyl]-2’-O-(tetrahydro-4-methoxy-
2H-pyran-4-yl)-3’,5’-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)guanosine (21) [36].
2’-O-(Tetrahydro-4-methoxy-2H-pyran-4-yl)uridine (22) [36].
N4-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)cytidine (23). To a soln. of 16
(10.5 g, 14.3 mmol) in THF (80 ml) was added Bu4NF · 3 H2O (12.2 g, 38.6 mmol) in THF (50 ml) with
stirring. After 10 min, the mixture was neutralized by AcOH (9.2 ml, 154.4 mmol) in THF (30 ml) and
concentrated. The residue was dissolved in CHCl3 (500 ml), the soln. washed with NaHCO3 soln.
(200 ml) and H2O (100 ml), dried (Na2SO4), and concentrated, and the residue crystallized from EtOH:
1
6.2 g (88%) of 23. Colorless crystals. M.p. 150 – 1528. H-NMR ((D6)DMSO): 11.02 (s, NH); 8.40 (d,
HꢁC(6)); 7.32 – 6.90 (m, 5 arom. H); 7.16 (d, HꢁC(5)); 6.09 (d, HꢁC(1’)); 5.17 (m, HOꢁC(3’),
HOꢁC(5’)); 4.81 (s, CH2O); 4.34 (d, HꢁC(2’)); 3.96 (m, HꢁC(3’,4’)); 3.95 (dd, 1 HꢁC(5’)); 3.70 – 3.30 (m,
1 HꢁC(5’), CH2OCH2); 2.90 (s, MeO); 1.67 (m, CH2CCH2).
N6-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)adenosine (24). As described for 23,
with 17 (8.0 g, 10.5 mmol) in THF (70 ml) and Bu4NF (8.0 g, 25.4 mmol) in THF (80 ml) and stirring at
r.t. for 10 min. Neutralization with AcOH (5.7 ml) in THF (10 ml), evaporation, and purification of the
residue by CC (SiO2 (5 ꢀ 25 cm), CHCl3 and CHCl3/MeOH 20 :1) gave 4.7 g (87%) of 24. Amorphous
foam. 1H-NMR ((D6)DMSO): 10.97 (s, NH); 8.79 (s, HꢁC(2)); 8.70 (s, HꢁC(8)); 7.32 – 6.94 (m, 5 arom.
H); 6.16 (d, HꢁC(1’)); 5.32 (d, HOꢁC(3’)); 5.26 (t, HOꢁC(5’)); 5.03 (s, CH2O); 4.96 (d, HꢁC(2’)); 4.16
(m, HꢁC(3’)); 4.03 (m, HꢁC(4’)); 3.68 – 3.19 (m, CH2(5’), CH2OCH2); 2.57 (s, MeO); 1.72, 1.51 (2m,
CH2CCH2).
N2-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)guanosine (25). As described for 24,
with 18 (7.9 g, 9.4 mmol), THF (50 ml), and Bu4NF (8.3 g, 26 mmol) in THF (35 ml): 4.4 g (87%) of 25.
1
Amorphous foam. H-NMR ((D6)DMSO): 11.84, 11.79 (2s, 2 NH); 8.32 (s, HꢁC(8)); 7.34 – 6.95 (m, 5
arom. H); 5.79 (d, HꢁC(1’)); 5.21 (d, HOꢁC(3’)); 5.15 (t, HOꢁC(5’)); 4.85 (s, CH2O); 4.72 (dd, HꢁC(2’));
4.10 (m, HꢁC(3’)); 3.97 (m, HꢁC(4’)); 3.95 (m, 1 HꢁC(5’)); 3.70 – 3.40 (m, 1 HꢁC(5’), CH2OCH2); 2.60
(s, MeO); 1.70, 1.52 (2m, CH2CCH2).
N4-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)cytidine (26)
[36].
N6-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)adenosine (27)
[36].
N2-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-O6-[2-(4-nitrophenyl)ethyl]-2’-O-(tetrahydro-4-methoxy-
2H-pyran-4-yl)guanosine (28) [36].
2’-O-(Tetrahydro-4-methoxy-2H-pyran-4-yl)uridine 5’-[2-(2-Nitrophenyl)propyl Carbonate] (29). To
a soln. of 22 (4.9 g, 13.7 mmol) in abs. pyridine (60 ml) was added slowly, at ꢁ 308 under Ar and stirring,
2-(2-nitrophenyl)propyl carbonochloridate [24] (nppoc-Cl; 5.0 g, 20.5 mmol) in CH2Cl2 (20 ml). After
5 h, the temp. was raised to ꢁ 108, then MeOH (1 ml) added, and the mixture stirred at r.t. for 1 h. The
mixture was diluted with CHCl3 (20 ml), the soln. washed with NaHCO3 soln. (100 ml), dried (Na2SO4),
concentrated and co-concentrated with toluene (2 ꢀ 50 ml), and the residue purified by CC (SiO2 (6.5 ꢀ
10 cm), CHCl3 and CHCl3/MeOH 50 :1): first 3.96 g (37%) of the 3’,5’-di-O-acylated derivative and then
4.1 g (53%) of 29. Amorphous foam. UV (MeOH): 206 (4.29), 257 (4.08). 1H-NMR ((D6)DMSO): 11.41
(s, NH); 7.81 – 7.44 (m, HꢁC(6), 4 arom. H); 5.93 (d, HꢁC(1’)); 5.62 (d, HꢁC(5)); 5.34 (d, HOꢁC(3’));
4.28 (m, HꢁC(4’), CH2(5’), CH2O); 3.99 (d, HꢁC(2’)); 3.91 (m, HꢁC(3’)); 3.47 (m, MeCHCH2O,
CH2OCH2); 2.96 (s, MeO); 1.66 (m, CH2CCH2); 1.27 (d, MeCHCH2O). Anal. calc. for C25H31N3O12
(565.5): C 53.09, H 5.52, N 7.43; found: C 52.80, H 5.53, N 7.27.
N4-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)cytidine 5’-[2-(2-Nitrophenyl)propyl
Carbonate] (30). As described for 29, with 23 (6.9 g, 14 mmol), pyridine (100 ml), and nppoc-Cl (4.14 g,
17 mmol) in CH2Cl2 (40 ml). Purification by CC (SiO2 (6.5 ꢀ 12 cm), CHCl3, CHCl3/MeOH 50 :1) gave
5.3 g (60%) of 30. Amorphous foam and 2.0 g (18%) of the di-O-acylated derivative. UV (MeOH): 208
(4.56), 248 (4.30), 300 (3.91). 1H-NMR ((D6)DMSO): 11.06 (s, NH); 8.09 – 6.90 (m, HꢁC(6), HꢁC(5), 9
arom. H); 6.02 (d, HꢁC(1’)); 5.37 (d, HOꢁC(3’)); 4.83 (s, CH2OCO); 4.38 (d, HꢁC(2’)); 4.27 (m, CH2(5’),
CH2O); 4.05 (m, HꢁC(3’)); 3.96 (m, HꢁC(4’)); 3.46 (m, MeCHCH2O, CH2OCH2); 2.91 (s, MeO); 1.65
(m, CH2CCH2); 1.26 (d, MeCHCH2O). Anal. calc. for C33H38N4O13 · H2O (716.7): C 55.30, H 5.62, N 7.81;
found: C 55.33, H 5.41, N 7.56.

Helvetica Chimica Acta – Vol. 94 (2011)
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N6-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)adenosine 5’-[2-(2-Nitrophenyl)-
propyl Carbonate] (31). As described for 29, with 24 (4.9 g, 9.5 mmol), pyridine (50 ml), and nppoc-
Cl (3.4 g, 14 mmol) in CH2Cl2 (20 ml). Purification by CC (SiO2 (5 ꢀ 15 cm), CHCl3, CHCl3/MeOH
50 :1) gave 4.3 g (61%) of 31. Amorphous foam. UV (MeOH): 206 (4.57), 269 (4.40). 1H-NMR
((D6)DMSO): 10.96 (s, NH); 8.70, 8.66 (2s, HꢁC(2), HꢁC(8)); 7.84 – 6.92 (m, 9 arom. H); 6.16 (d,
HꢁC(1’)); 5.52 (d, HOꢁC(3’)); 5.03 (m, HꢁC(2’), CH2OCO); 4.29 (m, HꢁC(3’,4’), CH2(5’), CH2O);
3.60 – 3.20 (m, MeCHCH2O, CH2OCH2); 2.57 (s, MeO); 1.72, 1.52 (2m, CH2CCH2); 1.25 (d,
MeCHCH2O). Anal. calc. for C34H38N6O12 · H2O (740.7): C 55.13, H 5.44, N 11.34; found: C 55.33, H
5.38, N 11.21.
N2-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)guanosine 5’-[2-(2-Nitrophenyl)-
propyl Carbonate] (32). As described for 29, with 25 (4.6 g, 8.65 mmol) in pyridine (50 ml) and
nppoc-Cl (2.95 g, 14 mmol) in CH2Cl2 (20 ml). Purification by CC (SiO2 (6.5 ꢀ 10 cm), CHCl3, CHCl3/
MeOH 50 :1) gave 4.85 g (76%) of 32. Amorphous foam. UV (MeOH): 204 (4.61), 254 (4.26), 275 (sh,
4.14). 1H-NMR ((D6)DMSO): 11.79, 11.72 (2s, 2 NH); 8.22 (s, HꢁC(8)); 7.68 – 6.94 (m, 9 arom. H); 5.97
(d, HꢁC(1’)); 5.41 (d, HOꢁC(3’)); 4.85 (s, CH2OCO); 4.79 (m, HꢁC(2’)); 4.31 (m, HꢁC(3’,4’), CH2O);
4.12 (m, CH2(5’)); 3.60 (m, MeCHCH2O); 3.40 (m, CH2OCH2); 2.68 (s, MeO); 1.72, 1.52 (2m,
CH2CCH2); 1.27 (d, MeCHCH2O). Anal. calc. for C34H38N6O13 · H2O (756.7): C 55.96, H 5.32, N 11.10;
found: C 56.26, H 5.30, N 10.99.
N4-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)cytidine 5’-[2-
(2-Nitrophenyl)propyl Carbonate] (33). As described for 29, with 26 (6.0 g, 10.6 mmol), pyridine
(60 ml), and nppoc-Cl (3.08 g, 12.6 mmol) in CH2Cl2 (20 ml). Isolation and purification by FC (SiO2
(6.5 ꢀ 12 cm), CH2Cl2 (200 ml), CH2Cl2/MeOH 100 :1 ! 100 :3) gave 4.21 g (53%) of 33. Colorless
foam. UV (MeOH): 205 (4.57), 246 (4.34), 281 (sh, 4.19). 1H-NMR ((D6)DMSO): 10.86 (s, NH); 8.16 (d,
2 H o to NO2); 8.00 (m, 1 H o to NO2 (nppoc)); 7.81 (d, HꢁC(6)); 7.68 (m, 2 arom H (nppoc)); 7.60 (d, 2 H
m to NO2); 7.48 (m, 1 arom.H (nppoc)); 7.00 (m, HꢁC(5)); 6.00 (d, HꢁC(1’)); 5.35 (d, HOꢁC(3’)); 4.39 –
4.26 (m, 7 H, CH2OCO (npeoc), CH2OCO (nppoc), HꢁC(2’), CH2(5’)); 4.03 (m, HꢁC(3’)); 3.95 (m,
HꢁC(4’)); 3.67 – 3.41 (m, MeCHCH2O, CH2OCH2); 3.08 (t, ArCH2); 2.89 (s, MeO); 1.70 (m, CH2CCH2);
1.27 (d, MeCHCH2O). Anal. calc. for C34H39N5O15 (757.7): C 53.90, H 5.19, N 9.24; found: C 54.08, H 5.27,
N 9.09.
N6-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)adenosine 5’-[2-
(2-Nitrophenyl)propyl Carbonate] (34). As described for 29, with 27 (6.0 g, 10.13 mmol), pyridine
(60 ml), and nppoc-Cl (2.94 g, 12.15 mmol) in CH2Cl2 (30 ml), all at ꢁ 308. Isolation by FC (SiO2 (6.5 ꢀ
12 cm), CH2Cl2 (300 ml), CH2Cl2/MeOH 100 :1 ! 100 :3) gave 5.0 g (63%) of 34. Colorless foam. UV
(MeOH): 206 (4.64), 266 (4.48). 1H-NMR (CDCl3): 8.73 (s, HꢁC(2)); 8.34 (br. s, NH); 8.17 (m, HꢁC(8),
2 H o to NO2); 8.00 (m, 1 H o to NO2 (nppoc)); 7.61 – 7.34 (m, 3 arom. H of nppoc, 2 H m to NO2); 6.18 (d,
HꢁC(1’)); 5.06 (m, HꢁC(2’)); 4.54 (t, CH2OCO (npeoc)); 4.49 – 4.23 (m, HꢁC(3’,4’), CH2(5’), CH2OCO
(nppoc)); 3.85 – 3.36 (m, MeCHCH2O, CH2OCH2); 3.16 (t, ArCH2); 2.95 (s, HOꢁC(3’)); 2.81 (s, MeO);
1.80 (m, CH2CCH2); 1.38 (d, MeCHCH2O). Anal. calc. for C35H39N7O14 · 0.5 H2O (790.7): C 53.16, H 4.97,
N 12.40; found: C 53.08, H 5.02, N 12.09.
N2-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-O6-[2-(4-nitrophenyl)ethyl]-2’-O-(tetrahydro-4-methoxy-
2H-pyran-4-yl)guanosine 5’-[2-(2-Nitrophenyl)propyl Carbonate] (35). As described for 29, with 28
(6.0 g, 8.1 mmol), pyridine (60 ml), and nppoc-Cl (2.57 g, 10.56 mmol) in CH2Cl2 (60 ml). Isolation by
FC (SiO2 (6.5 ꢀ 12 cm), CH2Cl2 (300 ml), CH2Cl2/MeOH 100 :1 ! 100 :3) gave 6.3 g (82%) of 35.
Colorless foam. UV (MeOH): 204 (sh, 4.66), 214 (4.68), 268 (4.57). 1H-NMR (CDCl3): 8.16 (m, 4 H o to
NO2); 7.92 (d, HꢁC(8)); 7.75 (d, 1 H o to NO2 (nppoc)); 7.60 – 7.32 (m, 3 arom. H of nppoc, 4 H m to NO2,
NH); 6.00 (d, HꢁC(1’)); 5.20 (m, HꢁC(2’)); 4.80 (t, CH2OCO (npe)); 4.47 – 4.20 (m, HꢁC(3’,4’), CH2(5’),
CH2OCO (nppoc), CH2O); 3.77 – 3.37 (m, MeCHCH2O, CH2OCH2); 3.31 (t, ArCH2 (npe)); 3.12 (t,
ArCH2 (npeoc)); 2.87 (s, MeO); 2.79 (s, OHꢁC(3’)); 1.80 (m, CH2CCH2); 1.36 (d, MeCHCH2O). Anal.
calc. for C43H46N8O17 (946.9): C 54.54, H 4.90, N 11.83; found: C 54.45, H 4.95, N 11.43.
2’-O-Tetrahydro-4-methoxy-2H-pyran-4-yl)uridine 3’-(2-Cyanoethyl N,N-Diisopropylphosphorami-
dite) 5’-[2-(2-Nitrophenyl)propyl Carbonate] (36). A mixture of 29 (6.1 g, 10.8 mmol), 2-cyanoethyl
N,N,N’,N’-tetraisopropylphosphorodiamidite (ceOP(NiPr2)2) (4.87 g, 16.18 mmol), and 1H-tetrazole
(0.38 g, 5.4 mmol) in CH2Cl2 (50 ml) was stirred at r.t. for 20 h. After dilution with CHCl3 (200 ml), the

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mixture was washed with NaHCO3 soln. (2 ꢀ 100 ml), the org. layer dried (Na2SO4) and concentrated,
the residue dissolved in CH2Cl2 (20 ml), and then the soln. dropwise added into hexane (800 ml). The
precipitate was filtered off and dissolved again in CH2Cl2 (100 ml), and the soln. concentrated: 8.2 g
(99%) of 36. Colorless foam. UV (MeOH): 204 (4.42), 258 (4.09). 31P-NMR (CHCl3): 152.2401;
152.1958; 150.0892; 150.0302. Anal. calc. for C34H48N5O13P (765.7): C 53.33, H 6.32, N 9.14; found:
C53.61, H 6.74, N 9.21.
N4-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)cytidine 3’-(2-Cyanoethyl N,N-Di-
isopropylphosphoramidite) 5’-[2-(2-Nitrophenyl)propyl Carbonate] (37). As described for 36, with 30
(5.08 g, 7.27 mmol), ceOP(NiPr2)2 (3.06 g, 10.17 mmol), and 1H-tetrazole (0.24 g, 3.4 mmol): 6.4 g (98%)
of 37. Colorless foam. UV (MeOH): 217 (4.32), 249 (4.28), 300 (3.90). 31P-NMR (CHCl3): 152.0044,
151.9308, 150.2807, 150.1923. Anal. calc. for C42H55N6O16P (898.9): C 56.12, H 6.17, N 9.35; found: C55.91,
H 6.36, N 9.21.
N6-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)adenosine 3’-(2-Cyanoethyl N,N-
Diisopropylphosphoramidite) 5’-[2-(2-Nitrophenyl)propyl Carbonate] (38). As described for 36, with
31 (6.0 g, 8.3 mmol), ceOP(NiPr2)2 (3.25 g, 10.8 mmol), and 1H-tetrazole (0.25 g, 3.6 mmol): 7.4 g (96%)
of 38. Colorless foam. UV (MeOH): 215 (4.44), 258 (sh, 4.24), 270 (4.33). 31P-NMR (CHCl3): 152.4466,
150.2218, 150.1628. Anal. calc. for C43H55N8O13P (922.9): C 55.96, H 6.00, N 12.14; found: C 56.10, H 6.24,
N 12.15.
N2-(Phenoxyacetyl)-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)guanosine 3’-(2-Cyanoethyl N,N-
Diisopropylphosphoramidite) 5’-[2-(2-Nitrophenyl)propyl Carbonate] (39). As described for 36, with
32 (4.57 g, 6.18 mmol), ceOP(NiPr2)2 (2.8 g, 9.2 mmol), and 1H-tetrazole (0.22 g, 3.1 mmol): 5.68 g
(98%) of 39. Colorless foam. UV (MeOH): 207 (4.54), 254 (4.25), 275 (sh, 4.12). 31P-NMR (CHCl3):
152.4317; 152.3875; 150.2954; 150.2660. Anal. calc. for C43H55N8O14P (930.9): C 55.00, H 5.90, N 11.93;
found: C 54.56, H 6.36, N 11.82.
N4-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)cytidine 3’-(2-
Cyanoethyl N,N-Diisopropylphosphoramidite) 5’-[2-(2-Nitrophenyl)propyl Carbonate] (40). To a
mixture of 33 (5.66 g, 7.47 mmol) and 1H-tetrazole (0.24 g, 3.34 mmol) in CH2Cl2 (60 ml) was dropwise
added ceOP(NiPr2)2 (3.2 g, 10.6 mmol) under N2 and then stirred at r.t. for 22 h. The mixture was diluted
with CH2Cl2 (100 ml) and washed with NaHCO3 soln. (2 ꢀ 100 ml), the org. layer dried (Na2SO4) and
concentrated, and the residue purified by FC (SiO2 (5 ꢀ 12 cm), toluene (100 ml), toluene/AcOEt 7:3 !
1:4). The product fractions were concentrated and finally co-concentrated with CH2Cl2: 6.69 g (93%) of
40. Colorless foam. UV (MeOH): 205 (4.69), 246 (4.42), 281 (sh, 4.25). 1H-NMR (CDCl3): 8.18 (d, 2 H o
to NO2); 7.92 – 7.83 (m, NH, 1 H o to NO2(nppoc)); 7.77 (d, HꢁC(6)); 7.59 (m, 1 arom. H); 7.48 (m, 1
arom. H); 7.41 (m, 2 H m to NO2, 1 arom. H); 7.15 (d, HꢁC(5)); 6.25 (m, HꢁC(1’)); 4.50 – 4.20 (m,
CH2O(npeoc), CH2O, HꢁC(2’,3’,4’), CH2(5’)); 4.00 – 3.40 (m, CH2OCH2, MeCHCH2O, CH2OP,
2 Me2CH); 3.12 (t, ArCH2); 3.0 (s, MeO); 2.67 – 2.57 (m, CH2CN); 1.9 – 1.70 (m, CH2CCH2); 1.39 (d,
MeCHCH2O); 1.30 – 1.10 (m, 2 Me2CH). 31P-NMR (CDCl3): 151.89; 151.82; 150.18; 150.12. Anal calc.
for C43H56N7O16P (957.9): C 53.92, H 5.89, N 10.24; found: C 53.68, H 6.16, 10.28.
N6-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-2’-O-(tetrahydro-4-methoxy-2H-pyran-4-yl)adenosine 3’-(2-
Cyanoethyl N,N-Diisopropylphosphoramidite) 5’-[2-(2-Nitrophenyl)propyl Carbonate] (41). As descri-
bed for 40, with 34 (2.13 g, 2.72 mmol), 1H-tetrazole (0.12 g, 1.71 mmol), and ceOP(NiPr2)2 (1.6 g,
5.3 mmol) in CH2Cl2 (30 ml). FC (SiO2, toluene/AcOEt 7:3 ! 4 :3) gave 2.04 g (76%) of 41. Colorless
foam. UV (MeOH): 206 (4.77), 266 (4.55). 1H-NMR (CDCl3): 8.75 (s, HꢁC(2)); 8.30 – 8.16 (m, HꢁC(8),
NH, 2 H o to NO2); 7.78 (m, 1 H o to NO2(nppoc)); 7.58 (m, 1 arom. H); 7.50 – 7.30 (m, 3 arom. H, 2 H m
to NO2); 6.16 (t, HꢁC(1’)); 5.30 – 5.10 (m, HꢁC(2’)); 4.56 – 4.30 (m, CH2O(npeoc), CH2O, HꢁC(3’,4’),
CH2(5’)); 4.00 – 3.29 (m, CH2OCH2, MeCHCH2O, CH2OP, 2 MeCH); 3.16 (t, ArCH2); 2.69 (m,
CH2CN); 2.60 (s, MeO); 1.9 – 1.60 (m, CH2CCH2); 1.35 (d, MeCHCH2O); 1.30 – 1.10 (m, 2 Me2CH). 31P-
NMR (CDCl3): 152.37; 152.34; 150.15; 150.10. Anal calc. for C44H56N9O15P (981.95): C 53.82, H 5.75, N
12.87; found: C 53.64, H 6.20, 12.38.
N2-{[2-(4-Nitrophenyl)ethoxy]carbonyl}-O6-[2-(4-nitrophenyl)ethyl]-2’-O-(tetrahydro-4-methoxy-
2H-pyran-4-yl)guanosine 3’-(2-Cyanoethyl N,N-Diisopropylphosphoramidite) 5’-[2-(2-Nitrophenyl)-
propyl Carbonate] (42). As described for 40, with 35 (2.84 g, 3.0 mmol), 1H-tetrazole (0.12 g,
1.71 mmol), and ceOP(NiPr2)2 (1.8 g, 5.7 mmol) in CH2Cl2 (40 ml). FC (SiO2, toluene (200 ml),

Helvetica Chimica Acta – Vol. 94 (2011)
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toluene/AcOEt 7:3 ! 2 :3) gave 2.53 g (74%) of 42. Colorless foam. UV (MeOH): 204 (4.70), 268
1
(4.53). H-NMR (CDCl3): 8.15 (m, 4 H o to NO2); 7.94 (s, HꢁC(8)); 7.75 (m, 1 H o to NO2(nppoc));
7.60 – 7.40 (m, NH, 4 H m to NO2, 3 arom. H); 6.00 (d, HꢁC(1’)); 5.50 (m, HꢁC(2’)); 4.82 (t,
CH2CH2O(npe)); 4.50 – 4.27 (m, CH2O(npeoc), CH2O, HꢁC(3’,4’), CH2(5’)); 4.10 – 3.29 (m, CH2OCH2,
MeCHCH2O, CH2OP, 2 Me2CH, ArCH2(npe)); 3.13 (t, ArCH2(npeoc)); 2.72 (m, CH2CN); 2.60 (s,
MeO); 1.9 – 1.60 (m, CH2CCH2); 1.35 (d, MeCHCH2O); 1.28 – 1.10 (m, 2 Me2CH). 31P-NMR (CDCl3):
152.56; 152.43; 150.38; 150.16. Anal calc. for C52H63N10O18P (1147.1): C 54.44, H 5.54, N 12.21; found: C
54.72, H 5.74, N 11.87.
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Received October 29, 2010