Protecting groups transfer: Unusual method of removal of tr and TBDMS groups by transetherification

Article abstract of DOI:10.1080/15257770802257846

The triphenylmethyl (Tr) group undergoes a transfer (transetherification or disproportionation) between the molecules of 5'-O-Tr-2'-deoxynucleosides in a process mediated by anhydrous sulfates of Cu+2, Fe+2, or Ni+2 to yield mixtures of 3',5'-bis-O-Tr and 3'-O-Tr products. If phenylmethanol is present in a reaction medium, detritylation results with concomitant formation of phenylmethyl triphenylmethyl ether. The behavior of t-butyldimethylsilyl (TBDMS) group in 5'-O-TBDMS-2'-deoxynucleosides is exactly the same. Such type of transetherifications was not observed before for the O-Tr and O-TBDMS groups. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770802257846

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Protecting Groups Transfer: Unusual
Method of Removal of Tr and Tbdms
Groups by Transetherification
Nadia L. D. Cabral a , Luciano J. Hoeltgebaum Thiessen a & Bogdan
Doboszewski a b
a Department of Pharmacy , UFPE , Recife, Brazil
b Department of Chemistry , UFRPE , Recife, Brazil
Published online: 11 Aug 2008.
To cite this article: Nadia L. D. Cabral , Luciano J. Hoeltgebaum Thiessen & Bogdan Doboszewski
(2008) Protecting Groups Transfer: Unusual Method of Removal of Tr and Tbdms Groups by
Transetherification, Nucleosides, Nucleotides and Nucleic Acids, 27:8, 931-948
To link to this article: http://dx.doi.org/10.1080/15257770802257846
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Nucleosides, Nucleotides and Nucleic Acids, 27:931–948, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802257846
PROTECTING GROUPS TRANSFER: UNUSUAL METHOD
OF REMOVAL OF TR AND TBDMS GROUPS
BY TRANSETHERIFICATION
Nadia L. D. Cabral,1 Luciano J. Hoeltgebaum Thiessen,1 and
Bogdan Doboszewski1,2
1Department of Pharmacy, UFPE, Recife, Brazil
2Department of Chemistry, UFRPE, Recife, Brazil
2
CuSO4
(FeSO4 or NiSO4)
B
B
B
RO
HO
+
RO
O
O
O
xylenes, bp
RO
HO
RO
B
B
HO
RO
O
CuSO4
O
+ PhCH2OR
+ PhCH2OH
xylenes, bp
AcO
R: -Tr; -TBDMS
AcO
The triphenylmethyl (Tr) group undergoes a transfer (transetherification or disproportionation)
between the molecules of 5ꢁ-O-Tr-2ꢁ-deoxynucleosides in a process mediated by anhydrous sulfates of
Cu+2, Fe+2, or Ni+2 to yield mixtures of 3ꢁ,5ꢁ-bis-O-Tr and 3ꢁ-O-Tr products. If phenylmethanol is
present in a reaction medium, detritylation results with concomitant formation of phenylmethyl
triphenylmethyl ether. The behavior of t-butyldimethylsilyl (TBDMS) group in 5ꢁ-O-TBDMS-2ꢁ-
deoxynucleosides is exactly the same. Such type of transetherifications was not observed before for
the O-Tr and O-TBDMS groups.
Keywords
t-Butyldimethylsilyl; deoxynucleoside; deprotection; intermolecular;
transetherification; triphenylmethyl
INTRODUCTION
The triphenylmethyl (Ph3C-, Tr-) group is frequently used to protect
primary hydroxyl function due to a strong preference of the tritylating
Received 11 May 2006; accepted 27 March 2008.
Scientific initiation scholarships for NLDC and LJHT founded by the Brazilian National Research
Council (CNPq) are appreciated.
Address correspondence to Bogdan Doboszewski, Department of Chemistry, UFRPE, 52171-900,
Recife, PE, Brazil. E-mail: bdoboszewski@yahoo.com.br
931

932
N. L. D. Cabral et al.
agents toward the less hindered positions.[1–5] Detritylation is routinely
performed in acidic or reductive medium.[1–5] A recent review summarizes
different de-O-tritylation procedures up to the year 2005[6] and is amended
by seven newest methods: HClO4/silica,[7] CBr4/MeOH/UV,[8,9] SbCl3,[10]
Nafion-H,[11] HCO2H-diethyl ether (formolysis),[12] VO(OTf)2,[13] and
silica sulfuric acid.[14]
The t-butyldimethylsilyl (TBDMS) group also gained popularity to
protect primary –OH functions.[1–5] Desilylation mediated by fluoride
ions coming from tetraalkylammonium fluorides is a routine, even
though the ammonium salts can co-migrate with the deprotected
product during a chromatography to make purifications difficult.
Many alternative deprotection methods are known.[1–5] Selective
deprotections of bis-silylated compounds have been reviewed.[15] The
following methods of removal of O-TBDMS group have been published
since the year 2000: SbCl3,[16] 1-chloroethyl chloroformate/MeOH,[17]
CH3COCH2P+(Ph)3Br−,[18]
H2-Pd/C,[19–22]
BiO(ClO4),[23]
I2/
microwave,[24] Nafion-H/NaI,[25] KOH/EtOH,[26] ZrCl4,[27] CsCO3,[28]
1,1,3ꢁ,3ꢁ-tetramethylguanidine,[29]
ZrCl4/Ac2O,[30]
AcCl/MeOH,[31]
NaIO4,[32] ZnBr2,[33] Et3N+→ O−,[34] Ce(OTf)4,[35] CeCl3/ CH3CN/
NaI,[36] anh.
KF/33% HBr/AcOH,[37] Br2/MeOH,[38] BiCl3/NaI,[39] KF/Al2O3,[40]
− [41]
Bu4N+
Br3
,
BCl3,[42]
InCl3,[43]
P(i-PrNCH2CH2)3N,[44]
CCl4/MeOH/ultrasounds,[45] Ce(NH4)2(NO3)6/SiO2,[46] HCO2H-diethyl
ether (formolysis),[12] TiCl4 complex by EtOAc or CH3NO2,[47] (CH3)3
SiCl-KF.2H2O,[48] polyvinylpolypyrrolidone-Br2,[49] and VO(OTf)2.[13]
An interesting method of detritylation in a neutral and nonreducing
medium in 6-O-Tr-glucopyranosides was described by Randazzo and col-
leagues, and involves a treatment of the substrates with anhydrous sulfates of
bivalent cations like Co+2, Cu+2, Fe+2, Ni+2 or Zn+2 in benzene or toluene
at reflux.[50] This process was rationalized in terms of the interaction of the
metal cations with the oxygen atom of the –O-Tr moiety, which weakens the
–O–Tr bond and facilitates formation and departure of the trityl cation.
Unexpected results obtained during application of this procedure to the
5ꢁ-O-trityl-2ꢁ-deoxynucleosides and further to the 5ꢁ-O-t-butyldimethylsilyl-2-
deoxynucleosides are the objectives of this communication.
RESULTS AND DISCUSSION
5ꢁ-Protected derivatives 1–4 are frequently used as starting materials.
Since the publication of Randazzo et al.[50] deals with the triphenylmethy-
lated compounds, we started the experiments with 5-O-Tr-thymidine 1[51]
and 5-O-Tr-2-deoxyuridine 2.[52] Treatment of either 1 or 2 with anhydrous
CuSO4 in refluxing toluene or xylenes furnished (in the order of decreasing

Protecting Groups Transfer
933
SCHEME 1 Behaviour of 5ꢁ -O-Tr substrates during CuSO4 (FeSO4, NiSO4) treatment.
mobility on TLC) 3ꢁ,5ꢁ-bis-O-Tr derivatives 5[53]/6, 3ꢁ-O-Tr derivatives 7[54]/8
and small quantities of thymine 9/uracil 10 and deprotected nucleosides
11/12 (Scheme 1).
Unreacted compounds 1/2 which are slightly more polar than their 3ꢁ-
O- regioisomeric counterparts 7/8 could be recovered. The position of the
–O-Tr group in 7/8 is evident from the shape of the signal belonging to
the exchangeable proton 5ꢁ-OH, which is a triplet (J = 7.4HZ in both 7/8;
DMSO-d6) due to the presence of two vicinal hydrogen atoms. Formation of
the unexpected compounds 5/6 and 7/8 can be rationalized in terms of a
capture of the electrophilic triphenylmethyl cation present in 31 (see below)
by the –OH group of another molecule. In this way 1/2 are converted to
5/6 liberating 11/12 with two –OH groups, which can react with Ph3C+
to regenerate 1/2 or to furnish 3ꢁ-O -protected products 7/8. Likewise 5/6
can lose a trityl group to form 1/2 or 7/8. The sulfates of Fe+2 and Ni+2
gave similar results, however CuSO4 furnished the cleanest reactions and
was used in the following work.
In order to suppress the unwanted intermolecular transfer (transetheri-
fication, disproportionation) of the triphenylmethyl group and to promote
deprotections, we added PhCH2OH as a nucleophile to trap the triph-
enylmethyl cation (Scheme 2). Treatment of the bis-protected compounds
5/6 with CuSO4 and PhCH2OH in boiling xylenes furnished (in the order

934
N. L. D. Cabral et al.
SCHEME 2 Behaviour of 5ꢁ -O-Tr substrates during CuSO4-PhCH2OH treatment.
of increasing polarity on TLC): a small amount of triphenylmethane 13,
phenylmethyl triphenylmethyl ether 1455, traces of free bases T/U 9/10 and
deprotected nucleosides 11/12 isolated in ca. 50% yield. These medium
yields are probably a consequence of adsorption of 11/12 on CuSO4. As
expected, triphenylmethyl cation was indeed captured by PhCH2OH to
form ether 14. A mechanism of formation of triphenylmethane 13 will be
discussed later. The same process was applied to 1/2 and furnished 11/12 in
similar yields. 3ꢁ-O-Acetyl-5ꢁ-O-triphenylmethyl derivatives 15[51]/16[52] gave
17[51]/18[52] in ca. 75% yield under the same conditions. The procedure
failed however for the 3ꢁ-deoxy-5ꢁ-O-triphenylmethylthymidine 19 (see be-
low). This may suggest that a 3ꢁ-oxygenated functionality should be present
in a molecule of a substrate to chelate a Cu+2 cation.

Protecting Groups Transfer
935
SCHEME 3 Behaviour of 5ꢁ -O-TBDMS substrates during CuSO4 treatment.
t-Butyldimethylsilyl group, which is another commonly used protection
behaved in the same way: either an intermolecular transfer (transether-
ification, disproportionation; Scheme 3) or a deprotection (Scheme 4)
took place as a function of the conditions applied. t-Butyldimethylsilyl
phenylmethyl ether 24 could be isolated if PhCH2OH was used. As in the
case of 19, 5ꢁ-O-t-butyldimethylsilyl-2ꢁ,3ꢁ-dideoxyuridine 27 did not react
under these conditions.
Both 19 and 27 were prepared using a slightly modified protocol
of Barton[56,57] as shown in the Scheme 5. Methyl iodide routinely
used to obtain the intermediate xanthates is known to methylate the
nucleobases.[58,59] This unwanted side reaction was completely suppressed
by using propyl bromide to capture the intermediate anions 28. The
xanthates 29/30 were then treated with tri-n-butyltin hydride and α,αꢁ-
azo-bis-isobutyronitrile to give the deoxygenated products 19/27. The
compound 19 was previously obtained via a deoxygenation of its 3ꢁ-O-
phenoxythiocarbonyl predecessor.[60]
The processes shown in the Schemes 1 through 4 can be rationalized
as follows. Chelation of the metal cation by the 3ꢁ and 5ꢁ oxygen function-
alities furnished the intermediates 31 in their northern conformation. The
inertness of the 3ꢁ-deoxygenated compounds 19 and 27 strongly indicates a
critical role of the 3ꢁoxygen atom and also seems to exclude an alternative
mode of chelation via the 5ꢁ-O and the endocyclic oxygen atom. The latter
possibility was claimed to take place by Matteucci and Caruthers during their
work on ZnBr2 removal of dimethoxytritylated 2ꢁ-deoxynycleosides.[61] If R
= -Tr this chelation evidently weakened the 5ꢁO – Tr bond as suggested
in the literature 50 and permitted a departure of the triphenylmethyl
cation which attacked any nearby nucleophilic site (either an –OH group
of another molecule of a nucleoside or a molecule of PhCH2OH). It is
also known that a Ph3C+ moiety is a selective oxidant of secondary alcohols
(in a form of their triphenylmethyl, t-butyl or trimethylsilyl ethers) via a
hydride abstraction.[62,63] This property can be used to explain formation
of triphenylmethane 13 and free nucleobases 9/10 (Scheme 6). Thus, ab-
straction of a hydrogen anion from the position 3ꢁ furnished 13 and a cation
32, which underwent a fragmentation to yield the ketonucleosides 33, and

936
N. L. D. Cabral et al.
SCHEME 4 Behaviour of 5ꢁ -O-TBDMS substrates during CuSO4-PhCH2OH treatment.
SCHEME 5 3ꢁ Deoxygenation of 1/4 using a Barton-type procedure.

Protecting Groups Transfer
937
SCHEME 6 Possible mechanism of formation of Ph3CH and thymine/uracil.
regenerated Ph3C+. The ketonucleosides 33 are known to be unstable[64–66]
and suffer a fragmentation to release the nucleobases and furan 34.[64] An
independent source of triphenylmethane 13 could be a chain reaction[67]
which involved Ph3C+ and alkyl triphenyl ethers, particularly 14, as shown in
the Scheme 6. Since the behavior of t-butyldimethylsilyl nucleoside deriva-
tives used in this work is the same as their triphenylmethyl counterparts,
one can surmise that cationic t-butyldimethylsilyl species were transiently
formed during the reactions described above. One needs to point out
that the inertness of the 5ꢁ-O-TBDMS-2ꢁ,3ꢁ-dideoxyuridine 27 toward Cu+2
cation demonstrates some limitations of the desilylation procedure devised
by Dalla Cort (Lewis acid, e.g., Cu+2, CH3CN, rt).[68]
One has to distinguish the intermolecular transfers of a TBDMS group
presented here from its intramolecular migration,[69,70] which can be a
nuisance during a work related to nucleosides and carbohydrates. Also, an
example of a triphenylmethyl ether isomerization similar to this presented
here, but promoted by protic acid was noticed during a total synthesis of
a racemic fungal secondary metabolite brefeldin A.[71] Finally, chelation of

938
N. L. D. Cabral et al.
two hydroxyl groups by Cu+2 suggested in this work as a necessary event,
is known to take place in a basic medium in carbohydrates and permits to
achieve some selective alkylations.[70]
In summary, a new method of removal of both O-Tr and O-TBDMS
groups in 2ꢁ-deoxynucleosides under neutral and nonreducing conditions
was devised. Practical significance of some of the deprotections using
CuSO4/PhCH2OH presented here (e.g., 1–6, 20, 21) doesn’t seem to be
broad due to medium yields (∼50%) probably resulting from irreversible
adsorption on CuSO4, however a rare process of transetherification was
clearly demonstrated. Deprotections of the 3ꢁ-O-acetylated substrates 15,16,
25 and 26 proceeded in higher yields (69–74%) which were not optimized
and there is a scope for improvements. Application of this procedure to
2ꢁ-deoxypurine nucleosides and to carbohydrates will be published in due
course.
EXPERIMENTAL
General Methods
Column chromatography was performed on a silica gel G 70–230 mesh,
and TLC chromatography on aluminum plates precoated with silica gel
60 F254, both from Merck (Darmstadt, Germany). 10% H2SO4 in MeOH
was used to char the TLC chromatograms. “Xylenes” refers to a mixture of
isomers. This solvent was dried by azeotropic distillation. CuSO4 was dried
at ca. 130◦ during 4 hours. The NMR spectra were recorded on a Varian
200MHz or 300MHz instruments in DMSO-d6 solutions unless otherwise
stated. Exact mass measurements of samples judged to be at least 95% pure
by 1H NMR were performed on a Jeol SX 102A spectrometer using an FAB
mode in NaOAc-thioglycerol matrices or using a CI mode and CH4 as a
reagent gas.
3ꢁ,5ꢁ-Bis-O-triphenylmethylthymidine 5
and 3ꢁ-O-triphenylmethylthymidine 7
A mixture of 5ꢁ-O-triphenylmethylthymidine 151 (1.30 g, 2.7 mmol) in
xylenes (30 ml) and CuSO4 (2.5 g, 15.7 mmol), was stirred at reflux during
4 hours with exclusion of moisture (argon blanket or a CaCl2 guard tube).
To get a sample for TLC examination, few drops of the reaction slurry were
evaporated in a conical flask in a stream of air, and the same volume of
MeOH was added to solubilize the organic products. TLC of this solution
showed the presence of 5, 7, unreacted substrate 1, thymine 9 and thymidine
11 in this order of decreasing mobility. In CHCl3- MeOH 10:0.4 the Rfs are
as follow: 5, 0.81; 7, 0.47; 1, 0.28; in CHCl3-MeOH 10:1 9, 0.30 and 11, 013.
Silica gel was added to a reaction mixture and the solvent was evaporated.
The residue was applied on a top of a chromatography column prepared

Protecting Groups Transfer
939
in CHCl3. Gradient elution using 0 →15% MeOH in CHCl3 gave 5 (0.68 g,
35%), 7 (0.078 g, 6%) and 11(0.052 g, 8%).
5: foam; lit.[53] m.p.122–124◦; 1H (200 MHz): 11.33(s,1H, exchangeable,
NH); 7.37–7.00 (16H, aromatic, 6); 6.21(dd, J = 5.9Hz, 8.5Hz, 1H, 1);
4.22(bs, 1H, 3ꢁ); 3.88(bs, 1H, 4ꢁ); 3.05(d, J = 9.1Hz, 1H, 5ꢁ); 2.89(dd, J =
3.6Hz, 9.2Hz, 5ꢁꢁ); 1.91–1.61(unresolved, 2H, 2ꢁ,2ꢁꢁ); 1.42(s, 3H, 5Me).
13C (50MHz): 163.69; 150.50; 144.03; 143.48; 135.39; 128.52; 128.24;
127.48; 127.34; 109.83; 87.38; 86.75; 84.33; 75.03; 63.99; 11.87.
HRMS (FAB): calc. for (C48H42N2O5+ Na): 749.2991; found: 749.2985.
1
7: foam; lit.[54] m.p.125–130◦ (benzene-petroleum); H (200 MHz):
11.24(s, 1H, exchangeable, NH); 7.59–7.21(16H, aromatic, 6); 6.19(dd, J =
5.3HZ, 8.6HZ, 1H, 1ꢁ); 4.92(t, J = 4.7Hz, exchangeable, 1H, 5ꢁOH); 4.27(d,
J = 5.5Hz, 1H, 3ꢁ); 3.76(broad s, 1H, 4ꢁ); 3.41–3.23(superimposed on the
signal of residual H2O, 5ꢁ); 3.19–3.06(m, 1H, 5ꢁꢁ); 1.70(s superimposed on
the unresolved signal, 3H, 2, 5Me); 1.52(dd, J = 5.8HZ, 13.1Hz, 1H, 2ꢁꢁ).
13C (50 MHz): 163.72; 150.58; 144.25; 135.86; 128.61; 128.22; 127.71;
127.44; 109.71; 87.38; 86.30; 83.99; 75.26; 61.50; 12.35.
HRMS (FAB): calc. for (C29H28N2O5 + Na): 507.1896; found: 507.1880.
2ꢁ-Deoxy- 3ꢁ,5ꢁ-bis-O-triphenylmethyluridine 6
and 2ꢁ-deoxy-3ꢁ-O-triphenylmethyluridine 8
Using the same procedure and the chromatography conditions as
described above, 2ꢁ-deoxy-5ꢁ-O-triphenylmenthyluridine 2[52] (1.27 g, 2.7
mmol) and CuSO4 (1.3 g, 8.1 mmol) in xylenes (15 ml) furnished 6 (0.71,
37%), 8 (0.076 g, 6%) and 12(0.062 g, 10%).
6: foam; 1H (200 MHz): 11.39(s, exchangeable, 1H, NH); 7.48(d,
J = 8.3HZ, 1H, 6); 7.44–7.00(15H, aromatic); 6.16(t, J = 6.7HZ, 1H,
1ꢁ); 5.42(d, J = 8.1HZ, 1H, 5); 4.17(bs, 1H, 3ꢁ(4ꢁ)); 3.93(bs, 1H, 4ꢁ(3ꢁ);
3.17–2.92(unresolved, 2H, 5ꢁ,5ꢁꢁ); 1.78–1.62(unresolved, 2H, 2ꢁ,2ꢁꢁ).
HRMS (FAB): calc. for (C47H40N2O5+Na): 735.2835; found: 735.2841.
8: foam; 1H (200 MHz): 11.29(s, 1H, exchangeable, NH); 7.75(d, 1H, J
= 8.2HZ, 6); 7.44–7.23(15H, aromatic); 6.19(t, 1H, J = 7.1HZ, 1); 5.57(d, J
= 8.2HZ, 1H, 5); 4.92(t, J = 4.7HZ, 1H, exchangeable, 5ꢁOH); 4.27(bs, 1H,
3ꢁ); 3.67(s, 1H, 4ꢁ); 3.26(d, J = 11.8HZ, 1H, 5ꢁ); 3.07(d, J = 11.8HZ, 1H, 5ꢁꢁ).
HRMS (FAB): calc. for (C28H26N2O5 +Na): 493.1739; found: 493.1743.
3ꢁ,5ꢁ-Bis-O-t-butyldimethylsilylthymidine 20
and 3ꢁ-O-t-butyldimethylsilylthymidine 22
Using the same procedure as described above 5ꢁ-O-t-
butyldimethysilylthymidine 3[71] (1.6 g, 4.5 mmol) and CuSO4 (1.7 g, 10.6
mmol) in xylenes (15 ml) furnished 20[71] (0.70 g, 33%), 22[71] (0.072 g,

940
N. L. D. Cabral et al.
4.5%) and 11(0.109 g, 10%) after chromatography using a gradient
(0→15%) of MeOH in CH2Cl2.
20: m.p. 140–142◦ (CH2Cl2); lit.[71] m.p. 144–145◦ (hexane); 1H
(200MHz): 11.28(s, 1H, exchangeable, NH); 7.36(d, J = 1.4HZ, 1H,
6ꢁ); 6.09(t, J = 7.1HZ, 1H, 1ꢁ); 4.29(quintette, J = 2.5HZ, 1H, 3ꢁ);
3.72–3.64(unresolved, 3H, 4,5ꢁ,5ꢁꢁ); 2.13(ddd, J = 6.3HZ, 7.8HZ, 13.5HZ,
1H, 2ꢁ); 1.99(ddd, J = 3.0HZ, 5.4HZ, 13.0HZ, 1H, 2ꢁꢁ); 1.71(s, 3H, 5Me);
0.81(s, 18H, 2xtBu); 0.06(s, 12H, 4xMe).
22: m.p. 80–83◦ (CH2Cl2-MeOH); lit.[71] 83–84◦ (EtOH-H2O); 1H
(200MHz): 11.23(s, 1H, exchangeable, NH); 7.58(d, J = 1.0HZ, 1H, 6ꢁ);
6.07(dd, J = 6.0HZ, 7.8Hz, 1H, 1ꢁ); 5.01(t, J = 5.2HZ, 1H, exchangeable,
5ꢁOH); 4.33(quintette, J = 2.8HZ, 1H, 3ꢁ); 3.67(apparent q, J = 3HZ, 1H,
4ꢁ); 3.51–3.44(unresolved, 2H, 5ꢁ,5ꢁꢁ); 2.10(ddd, J = 6.3HZ, 7.7HZ, 14.0HZ,
1H, 2ꢁ); 1.94(ddd, J = 3.2HZ, 6.2HZ, 13.0HZ, 1H, 2ꢁꢁ); 1.69(s, 3H, 5Me);
0.85(s, 9H, -tBu); 0.06(s, 6H, 2xMe).
2ꢁ-Deoxy-3ꢁ,5ꢁ-bis-O-t-butyldimethylsilyluridine 21
and 2ꢁ-deoxy-3ꢁ-O-t-butyldimethylsilyluridine 23
Using the same procedure and the chromatography conditions as
described above, 2ꢁ-deoxy-5ꢁ-O-t-butyldimethylsilyluridine 2[72,73] (1.19g,
3.5mmol) and CuSO4 (1.4 g, 8.7 mmol) in xylenes (12 ml) furnished 21
(0.57 g, 36%), 23 (0.071 g, 6%) and 12(0.08 g, 10%).
1
21: foam; H (200MHz): 11.28(s,1H, exchangeable, NH); 7.64(d, J =
8.2HZ, 1H, 6ꢁ); 6.06(t, J = 6.4HZ, 1H, 1ꢁ); 5.52(d, J = 8.0HZ, 1H, 5ꢁ); 4.30(q,
J = 4HZ, 1H, 4ꢁ); 3.76–3.57(m, 3H, 4ꢁ,5ꢁ,5ꢁꢁ); 2.16(dd, J = 6.1HZ, 12.8HZ,
1H, 2ꢁ); 2.02(dd, J = 5.7HZ, 12.8HZ, 1H, 2ꢁꢁ); 0.90(s, 18H, 2xtBu); ca 0(s,
6H, 2xMe).
HRMS (FAB): calc. for (C21H40N2O5Si2 + Na): 479.2373; found:
479.2372.
23: foam; 1H (200MHz): 11.33(bs, 1H, exchangeable, NH); 7.81(d, J =
8.1Hz, 1H, 6ꢁ); 6.13(t, J = 6.7Hz, 1H, 1ꢁ); 5.63(dd, J = 2.0Hz, 8.1Hz, 1H,
5ꢁ); 5.08(t, J = 5.2Hz, 1H, exchangeable, 5OH); 4.39(quintette, J = 2.8Hz,
2.9Hz, 5.4Hz, 1H, 3ꢁ); 3.75(q, J = 3.3Hz, 1H, 4ꢁ); 3.59–3.47(m, 2H, 5ꢁ,5ꢁꢁ);
2.26–2.00(m, 2H, 2ꢁ,2ꢁꢁ); 0.86(s, 9H, -tBu); 0.07(s, 6H, 2xMe).
13C (50MHz): 163.67; 150.78; 140.98; 102.27; 87.84; 84.44; 72.46; 61.16;
26.07; 18.09; −4.44; −4.51. The signal of the C2ꢁ is hidden under the signal
of the solvent.
HRMS (FAB): calc. for (C15H26N2O5Si + Na): 365.1509; found:
365.1516.
Triphenylmethane 13, Phenylmethyl Triphenylmethyl Ether 14
and Thymidine 11
3ꢁ,5ꢁ-Bis-O-triphenylmethylthymidine 5[53] (0.98 g, 1.35 mmol), CuSO4,
(1.8 g, 11.3 mmol), and PhCH2OH (1.5 ml, 14.5 mmol) in xylenes

Protecting Groups Transfer
941
(15 ml) were stirred at reflux during 5 hours under exclusion of moisture.
TLC (hexane) showed a presence of triphenylmethane 13 (Rf 0.36) and
phenylmethyl triphenylmetyl ether 14 (Rf 0.15). TLC run twice in CH2Cl2-
MeOH 10:1 showed a small amount of thymine 9 (Rf 0.37) and the
main product thymidine 11 (Rf 0.18). No traces of 2-deoxyribose were
noticed. The reaction mixture was filtered through a sintered glass and
the solids were washed with MeOH. Silica gel was added to the filtrate
and the solvents were evaporated. The residue was applied on a top of a
chromatography column prepared in hexane. Elution with hexane gave
13 (0.011 g, 3%). Elution with hexane-EtOAc 99:1 gave 14 (0.74 g, 78%).
Elution with a gradient of MeOH in CH2Cl2 (0→20%) furnished 11 (0.17 g,
51%).
Under the same conditions 5ꢁ-O-triphenylmethylthymidine 1[51] (1.0 g,
2.1 mmol), CuSO4, (1.8g, 11.3 mmol) and PhCH2OH (1.3ml, 12.6 mmol)
in xylenes (15ml) furnished 11 (0.24g, 49%).
13: 1H (200MHz, CDCl3): 7.35–7.03(15H, aromatic); 5.55(s, 1H, −CH).
13C (50MHz, CDCl3): 143.84; 129.41; 128.25; 126.24; 56.78.
14: m.p. 102–104◦ (hexane); lit.[55] m.p. 95◦ (EtOH); 1H (200MHz,
CDCl3): 7.55–7.21(15H, aromatic); 4.18(s, 2H, -CH2Ph).
13C (50MHz, CDCl3): 144.40; 139.39; 128.98; 128.51; 128.11; 127.33;
127.27; 127.18; 87.17; 65.88.
11: 11.28(s, exchangeable, 1H, NH); 7.69(s, 1H, 6ꢁ); 6.16(t, 1H, J
= 6.6Hz and 7.0Hz, 1H, 1ꢁ); 5.23(d, J = 4.0Hz, exchangeable, 1H,
3OH); 5.05(t, J = 4.8Hz, exchangeable, 1H, 5ꢁOH); 4.28–4.18 and
3.80–3.70(both unresolved, 1H each, 3ꢁ,4ꢁ); 3.68–3.46(apparent AB, 2H,
5ꢁ,5ꢁꢁ); 2.18–1.96(unresolved, 2H, 2ꢁ,2ꢁꢁ); 1.76(s, 3H, Me).
Deprotections of 2ꢁ-Deoxy-3ꢁ,5ꢁ-bis-O-triphenylmethyluridine 6
and 2ꢁ-Deoxy-5ꢁ-O-triphenylmethyluridine 2 Using
CuSO4/PhCH2OH
The same procedure as applied above, but using 2ꢁ-deoxy-3ꢁ,5ꢁ-bis-O-
triphenylmethyluridine 6 (1.11 g, 1.5 mmol), CuSO4 (1.5 g, 9.4 mmol),
and PhCH2OH (1.5 ml, 14.5 mmol) in xylenes (15 ml) furnished 2ꢁ-
deoxyuridine 12 (0.16 g, 46%). 2ꢁ-Deoxy-5ꢁ-O-triphenylmethyluridine 2
(0.49 g, 1.0 mmol), CuSO4, (0.58 g, 3.6 mmol), and PhCH2OH (0.5 ml,
4.8 mmol) in xylenes (15 ml) furnished 12 (0.12 g, 49%). 12: 11.29(bs,
exchangeable, 1H, NH); 7.85(d, J = 8.2Hz, 1H, 6); 6.15(t, J = 6.8Hz, 6.6Hz,
1H, 1ꢁ); 5.63(d, J = 8.0Hz, 1H, 5ꢁ); 5.25(d, exchangeable, J = 2.6Hz, 1H,
3ꢁOH); 5.02(bs, exchangeable, half-width = 10.3Hz, 1H, 5ꢁOH); 4.29–4.16
and 3.84–3.72 (both unresolved, 1H each, 3ꢁ,4ꢁ); 3.65–3.44(unresolved, 2H,
5ꢁ,5ꢁꢁ); 2.18–1.96(unresolved, 2H, 2ꢁ,2ꢁꢁ).

942
N. L. D. Cabral et al.
t-Butyldimethylsilyl phenylmethyl ether 24 and thymidine 11
3ꢁ,5ꢁ-O-t-butyldimethylsilylthymidine 20[72] (1.32g, 2.81 mmol) was
stirred with CuSO4 (1.51 g, 9.50 mmol) and PhCH2OH (1.8 ml, 17.4 mmol)
in xylenes (15 ml) at reflux. TLC (a sample was prepared in the same way
as described before for detritylation of 5, 6, 1, and 2) showed a spot of t-
butyldimethylsilyl phenylmethyl ether 24 (Rf 0.29 in hexane-EtOAc 20:0.1);
thymine 9 and thymidine 11 were visible after running a plate in CH2Cl2-
MeOH 10:1; Rfs were 0.29 and 0.12, respectively. Workup as for detritylation
of 5,6,1 and 2, and chromatography (the column was prepared in hexane)
furnished 24 (0.76g, 61%, elution with hexane-EtOAc 20–0.1). Subsequent
elution with a gradient of MeOH in CH2Cl2 (0→20%) furnished thymidine
11 (0.37 g, 55%).
24: oil; 1H (200MHz): 7.30(5H, aromatic); 4.70(s, 2H, -CH2Ph); 0.90(s,
9H, -tBu); 0.06(s, 6H, 2xMe).
13C: 141.20; 128.16; 126.88; 125.97; 64.24; 25.73; 17.92; −5.43.
HRMS: molecular ion was not visible in a CI mode.
Under the same conditions 5ꢁ-O-t-butyldimethylsilylthymidine 3[72] (0.6
3 g, 1.70 mmol), CuSO4 (0.9 g, 5.6 mmol), and PhCH2OH (0.8 ml, 7.7
mmol) in xylenes (15 ml) furnished thymidine 11 (0.21 g, 48%). The ether
24 was not isolated.
Likewise 3ꢁ,5ꢁ-O-bis-t-butyldimethylsilyl-2ꢁ-deoxyuridine 21 (1.46 g, 3.2
mmol), CuSO4 (1.7 g, 10.6 mmol), and PhCH2OH (1.8 ml, 17.4 mmol)
in xylenes (15 ml) furnished 24 (0.92 g, 65%) and 2ꢁ-deoxyuridine 12 (0.39
g, 53%) after chromatography in the same system as above. Under the same
conditions 4[73,74](0.54g, 1.7 mmol) was deprotected using CuSO4 (0.8 g,
5.0 mmol) and PhCH2OH (0.7 ml, 6.7 mmol) in xylenes (15 ml) to yield 12
(0.18 g, 49%).
3ꢁ-O-Acetylthymidine 17
A. 3ꢁ-O-Acetyl-5ꢁ-O-triphenylmethylthymidine[51[15 (0.69 g, 1.3 mmol),
CuSO4 (1.1 g, 6.9 mmol), and PhCH2OH (1.0 ml, 9.6 mmol) in xylenes
(15 ml) were stirred at reflux during 2 hours. TLC showed that a new more
polar compound was formed. The reaction mixture was filtered through a
sintered glass and the solids were washed with MeOH. Silica gel was added
and xylenes and methanol were evaporated. The residue was applied on
a top of a chromatography column prepared in CH2Cl2. Elution using a
0→10% gradient of MeOH in CH2Cl2 furnished 17 (0.28 g, 74%). The ether
14 was not isolated.
B. 3ꢁ-O-Acetyl-5ꢁ-O-t-butyldimethylsilylthymidine 25[75] (1.2 g, 3.3
mmol), CuSO4 (2.1 g, 13.2 mmol), and PhCH2OH (1.8 ml, 17.4 mmol)
in xylenes (15 ml) furnished 17 (0.59 g, 69%) using the same procedure as
described above.

Protecting Groups Transfer
943
17: m.p. 175–177◦ (CH2Cl2-MeOH); lit.[51] 176◦ (acetone); 1H
(300MHz): 11.37(s, 1H, exchangeable, NH); 7.75(d, J = 1.2Hz, 1H,
6ꢁ); 6.19(t, J = 7.4Hz, 1H, 1ꢁ); 5.37(t, J = 5.3Hz, 1H, exchange-
able, 5ꢁOH); 5.24–5.21(unresolved, 1H, 3ꢁ); 4.03–3.98(unresolved, 1H,
4ꢁ); 3.80–3.62(partially superimposed on the residual H2O signal, 5ꢁ,5ꢁꢁ);
2.35–2.21(unresolved, 2H, 2ꢁ,2ꢁꢁ); 2.08(s, 3H, OAc); 1.80(s, 3H, 5Me).
3ꢁ-O-Acetyl-2ꢁ-deoxyuridine 18
A. 3ꢁ-O-Acetyl-2ꢁ-deoxy-5ꢁ-O-triphenylmethyluridine 16[52] (0.71 g, 1.39
mmol), CuSO4 (0.9 g, 5.6 mmol), and PhCH2OH (1.0 ml, 9.6 mmol)
in xylenes (15 ml) were stirred at reflux during 2 hours. TLC showed
that a substrate was no longer present. Workup as described for 17 and
chromatography in the same system furnished 18[52] (0.27 g, 73%). The
ether 14 was not isolated.
B.3ꢁ-O-Acetyl-5ꢁ-O-t-butyldimethylsilyl-2ꢁ-deoxyuridine 26 (1.4 g, 3.6
mmol), CuSO4 (2.2 g, 13.8 mmol), and PhCH2OH (1.8 ml, 17.4 mmol)
in xylenes (15 ml) furnished 18 (0.71 g, 72%) using the same procedure as
described above. The ether 24 was not isolated.
18: m.p. 173–174◦ (CH2Cl2-MeOH); lit.[52] m.p. 188◦ (EtOH-
1
acetone-cyclohexane); H (300MHz): 11.40(bs, 1H, exchangeable), NH);
7.90(d,1H, J = 8.1Hz, 6); 6.17(t, 1H, J = 7.2Hz, 1ꢁ); 5.70(d, 1H, J = 8.1Hz,
5); 5.34(t, J = 4.6Hz, 1H, exchangeable, 5ꢁOH); 5.25–5.19(m, 1H, 3ꢁ);
4.02(apparent q, J = 2.7Hz, 1H, 4ꢁ); 3.63(apparent t, J = 3.8Hz, 2H, 5ꢁ,5ꢁꢁ);
2.32–2.22(m, 2H, 2ꢁ,2ꢁꢁ); 2.07(s, 3H, -OAc).
3ꢁ-O-Acetyl-5ꢁ-O-t-butyldimethylsilyl-2ꢁ-deoxyuridine 26
Conventional acetylation of 4 in a mixture of Ac2O-Py 2:1 followed by
extraction (CH2Cl2 /H2O) furnished 26 (69%) after crystallization from
EtOAc-hexane. M.p. 144–145◦. 1H (300MHz): 11.44(bs, 1H, exchangeable,
NH); 7.77(d, J = 8.4Hz, 1H, 5ꢁ); 6.15(dd, J = 6.0Hz, 8.1Hz, 1H, 1ꢁ); 5.65(d, J
= 8.1Hz, 1H, 5ꢁ); 5.21–5.15(m, 1H, 3ꢁ); 4.09(apparent q, J = 2.5Hz, 1H, 4ꢁ);
2.38(ddd, J = 1.8Hz, 6.0Hz, 14.0Hz, 1H, 2ꢁ); 2.23(ddd, J = 6.3Hz, 8.0Hz,
14.1Hz, 1H, 2ꢁꢁ); 2.07(s, 3H, -OAc); 0.88(s, 9H, -tBu); 0.08(s, 6H, 2xMe).
The signals of the H5ꢁ,5ꢁꢁ protons were superimposed on the residual H2O
signal at 3.95–3.80 ppm.
HRMS (FAB): calc. for (C17H28N2O6Si + Na): 407.1614; found:
407.1611.
3ꢁ-O-[(Propylthio)thiocarbonyl]-5ꢁ-O-triphenylmethylthymidine 29
To
a
cold (ice bath) and stirred solution of 5ꢁ-O-
triphenylmethylthymidine 1 (0.9 g, 1.8 mmol) in DMSO (5 ml) under

944
N. L. D. Cabral et al.
a blanket of argon was added CS2 (2 ml) and 5N NaOH (1 ml). The
mixture turned red. After 0.5 hours propyl bromide (2.8 ml, 32 mmol) was
added via a syringe. The solution turned yellow. The ice bath was removed
and stirring was continued for 1 hour. The reaction mixture was partitioned
between CH2Cl2 and H2O. The organic layer was evaporated and the yellow
residue was applied on a top of a chromatography column prepared in
CH2Cl2. Elution using a gradient of MeOH in CH2Cl2 (0→5%) furnished
1
a yellowish syrup of 29 (0.80 g, 72%). H (200MHz, MeOH-d4): 7.59(d,
J = 1Hz, 1H, 6ꢁ); 7.37–7.12(15H, aromatic); 6.27(t, J = 7.2Hz, 1H, 1ꢁ);
6.20–6.12(unresolved, 1H, 3ꢁ); 4.28–4.08(unresolved, 1H, 4ꢁ); 3.51(dd, J
= 2.8Hz, 10.6Hz, 1H, 5ꢁ); 3.30(dd, J = 2.4Hz, 10.2Hz, 1H, 5ꢁꢁ); 3.03(t, J =
7.2Hz, 2H, -SCH2-); 2.53(dd, J = 7.0Hz, 7.4Hz, 2H, 2ꢁ,2ꢁꢁ); 1.61(hextette, J
= 7.2Hz, 2H,-CH2CH3); 1.32(d, J = 1Hz, 3H, 5Me); 0.91(t, J = 7.4Hz, 3H,
-CH2CH3).
13C (50MHz): 215.93; 166.13; 152.20; 144.73; 137.09; 129.87; 129.10;
128.59; 112.09; 88.99; 86.04; 85.21; 84.76; 65.11; 38.98; 38.66; 22.95; 13.71;
12.13.
HRMS: molecular ion was invisible in a CI mode.
5ꢁ-O-t-butyldimethylsilyl-2ꢁ-deoxy-3ꢁ-O-
[(propylthio)thiocarbonyl]uridine 30
Compound 4 (0.51 g, 1.5 mmol) was converted to a its propyl xanthate
using DMSO (5 ml), CS2 (1.6 ml), 5N NaOH (0.8 ml), and propyl bromide
(2.3 ml, 25 mmol) as described for 29. Workup and chromatography
(0→5% gradient of MeOH in CH2Cl2) furnished 30 (0.47 g, 69%) as a
yellow syrup. 1H (200MHz, MeOH-d4): 7.96(d, J = 8.0Hz, 1H, 6ꢁ); 6.35(dd,
J = 5.6Hz, 8.4Hz, 1H, 1ꢁ); 6.03(d, J = 5.6Hz, 1H, 3ꢁ); 5.71(d, J = 8.0Hz, 1H,
5ꢁ); 4.35(bs, 1H, 4ꢁ); 4.06(dd, J = 2.2Hz, 11.6Hz, 1H, 5ꢁ); 3.96(dd, J = 2.2Hz,
11.4Hz, 1H, 5ꢁꢁ); 3.16(t, J = 7.2Hz, 2H, -SCH2-); 2.67(dd, J = 5.6Hz, 14.0Hz,
1H, 2ꢁ); 2.34(ddd, J = 6.2Hz, 8.4Hz, 14.4Hz, 1H, 2ꢁꢁ); 1.75(hextette, J =
7.3Hz, 2H, -CH2CH3); 1.05(t, J = 7.2Hz, 3H, -CH2CH3); 0.96(s, 9H, tBu);
0.17(s, 6H, 2xMe). HRMS: molecular ion was invisible in a CI mode.
3ꢁ-Deoxy-5ꢁ-O-triphenylmethylthymidine 19
To a boiling solution of 29 (0.58 g, 1 mmol) in toluene (15 ml) was
added dropwise a solution of Bu3SnH (97%, 0.53 ml, 1.9 mmol) and AIBN
(0.03 g, 0.19 mmol) in toluene (10 ml) during 15 minutes. under a blanket
of argon. Reflux was maintained for 1 hour. Evaporation of the solvent gave
an oil that was applied on a top of a chromatography column prepared in
CH2Cl2. Elution using a gradient of MeOH in CH2Cl2 (0→5%) furnished
1
19 (0.31 g, 68%) as a foam; lit.;[60] foam; H (300MHz): 11.33(s, 1H,
exchangeable, NH); 7.48(s, 1H, 6ꢁ); 7.38–7.21(15H, aromatic); 5.98(dd,

Protecting Groups Transfer
945
J = 3.0Hz, 6.3Hz, 1H, 1ꢁ); 4.18–4.06(unresolved, 2H, 4ꢁ,5ꢁ); 2.36–2.18 and
2.08–1.88(two groups of unresolved signals, 4H, 2ꢁ,2ꢁꢁ,3ꢁ,3ꢁꢁ); 1.46(s, 3H,
5Me). The signal of the proton 5ꢁꢁ was hidden under the signal of the
residual H2O at 3.90- 3.50 ppm.
13C (75MHz): 164.38; 150.80; 143.86; 136.22; 128.56; 128.33; 127.55;
109.51; 86.54; 85.34; 79.62; 65.21; 31.47; 25.86; 12.25.
5ꢁ-O-t-Butyldimethylsilyl-2ꢁ,3ꢁ-dideoxyuridine 27
Compound 30 (0.42 g, 0.91 mmol) in toluene (15 ml) was deoxygenated
and purified as described for 29, using Bu3SnH (97%, 0.55 ml, 2 mmol) and
AIBN (0.03 g, 0.19 mmol) in toluene (15 ml) to furnish 27 (0.29 g, 61%). 1H
(200MHz, CDCl3): 9.09(bs, 1H, exchangeable, NH); 8.08(d, J = 8.0Hz, 1H,
6ꢁ); 6.04(dd, J = 2.8Hz, 6.4Hz, 1H, 1ꢁ); 5.62(d, J = 8.2Hz, 1H, 5ꢁ); 4.20–3.93
and 3.74–3.60(two groups of unresolved signals, 3H, 4,5,5ꢁꢁ); 2.48–1.80(two
groups of unresolved signals, 4H, 2ꢁ,2ꢁꢁ,3ꢁ,3ꢁꢁ); 0.89(s, 9H, -tBu); 0.07(s, 6H,
2xMe).
HRMS (FAB): calc. for (C15H26N2O4Si + Na): 349.1554; found:
349.1548.
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