Probing of PSE acetal protection for nucleoside chemistry

Article abstract of DOI:10.1016/j.tetlet.2007.03.153

The use of phenylsulfonylethylidene (PSE) acetal as a new 3′,5′-bridged protecting group in nucleoside chemistry is reported. The PSE acetal demonstrates to be compatible with Lewis acids used in standard glycosylation reactions. In addition, a selective 2′-O-deacylation from a 3′,5′-O-(phenylsulfonyl)-2′-O-acetyl nucleoside can be achieved, giving access to subsequent chemical modifications in 2′ position. However, the PSE acetal cleavage surprisingly appeared to be purine/pyrimidine base dependent.

Full text of DOI:10.1016/j.tetlet.2007.03.153

Tetrahedron Letters 48 (2007) 3851–3854
Probing of PSE acetal protection for nucleoside chemistry
Jean-Pierre Uttaro,a Lycia Uttaro,a Arnaud Tatibouet,b Patrick Rollin,b
a
a,
*
´
´
Christophe Mathe and Christian Perigaud
aInstitut des Biomole´cules Max Mousseron (IBMM), UMR 5247 CNRS—UM1—UM2, Universite´ Montpellier 2,
Case Courrier 1705, Place E. Bataillon, 34095 Montpellier Cedex 05, France
bInstitut de Chimie Organique et Analytique, UMR 6005, Universite´ d’Orle´ans, B.P. 6759, 45067 Orle´ans, France
Received 9 March 2007; revised 23 March 2007; accepted 27 March 2007
Available online 2 April 2007
Abstract—The use of phenylsulfonylethylidene (PSE) acetal as a new 30,50-bridged protecting group in nucleoside chemistry is
reported. The PSE acetal demonstrates to be compatible with Lewis acids used in standard glycosylation reactions. In addition,
a selective 20-O-deacylation from a 30,50-O-(phenylsulfonyl)-20-O-acetyl nucleoside can be achieved, giving access to subsequent
chemical modifications in 20 position. However, the PSE acetal cleavage surprisingly appeared to be purine/pyrimidine base
dependent.
Ó 2007 Elsevier Ltd. All rights reserved.
Nucleoside analogues are an important class of clinically
useful drugs possessing antiviral1 and anticancer activi-
ties.2 In most cases, the synthesis of such biologically
active compounds involves reaction of persilylated
heterocyclic bases with peracylated sugars in the pres-
ence of a Lewis acid catalyst, such as SnCl4 or TMSOTf,
followed by chemical modifications on the sugar residue.
This synthetic strategy requires multiple steps related to
the selective introduction-cleavage of hydroxyl protect-
ing groups.3 Recently, phenylsulfonylethylidene (PSE)
acetal, was introduced as a new protection for 1,2 and
1,3-diols4 owing to its atypical properties.5 Indeed,
PSE acetals are resistant to acid-catalyzed hydrolysis,
whereas they can be removed under reductive or basic
conditions. In this respect, we have evaluated the
potential of the PSE acetal as a new protective group
in nucleoside chemistry.
O
HO
OH
O
a
b
c
O
1
O
D-xylose
PhSO2H2C
O
O
O
O
2
O
O
O
O
O
O
d
PhSO2H2C
OAc
O
O
OAc
3
4
Scheme 1. Reagents and conditions: (a) Me2CO, H2SO4, CuSO4, rt,
15 h; (b) HCl 0.2%, 6 h, rt, 92% (two steps); (c) NaH, BPSE, Bu4NBr,
THF, rt, 12 h, 88%; (d) (i) 80% AcOH, reflux, 3 h, (ii) Ac2O, DMAP,
C5H5N, 12 h, 87% (2 steps).
The study began with the preparation of 1,2-di-O-acetyl-
into previously described PSE acetal derivatives 3
was performed in 88% yield in accordance with the
literature.4 In a preliminary assay, hydrolytic cleavage
of the isopropylidene group from compound 3 and
acetylation of the hemiacetal intermediate was at-
tempted in one step using H2SO4/AcOH/Ac2O. Unfor-
tunately, the desired product was isolated in poor
yield. However, applying a two-step procedure (80%
AcOH under reflux, then Ac2O/pyridine/DMAP cat.)
provided in good yield compound 4 as an inseparable
mixture of two anomers7 (a/b 1/3, anomeric ratio based
3,5-O-(2-phenylsulfonyl)ethylidene-D-xylofuranose
4
(Scheme 1) as a new osidic condensable precursor.
Compound 4 was synthesized in five steps from
commercially available D-xylose in 70% overall yield.
Briefly, D-xylose was converted into 1,2-O-isopropylid-
ene-D-xylofuranose 2 following a synthetic pathway
previously reported by Gosselin et al.6 Conversion of 2
*
Corresponding author. Tel.: +33 4 67 14 38 55; fax: +33 4 67 04 20
1
29; e-mail: perigaud@univ-montp2.fr
on H NMR spectra).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.153

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J.-P. Uttaro et al. / Tetrahedron Letters 48 (2007) 3851–3854
NH2
HO
O
A
A
OH
O
O
N
O
a
PhSO2H2C
N
O
O
N
OH
OAc
N
a
O
O
O
O
PhSO2H2C
5
9
PhSO2H2C
OAc
OAc
OAc
O
4
5
O
O
U
U
a
O
O
O
O
8
PhSO2H2C
PhSO2H2C
OAc
OH
NH
6
O
O
N
O
Scheme 4. Reagents and conditions: (a) KOH/EtOH 0.6 M, reflux,
8 h, 75% for adenine, 79% for uracil.
b
O
O
O
O
PhSO2H2C
PhSO2H2C
OAc
OAc
OAc
6
4
Scheme 2. Reagents and conditions: (a) adenine, SnCl4, CH3CN, rt,
12 h, 70%; (b) uracil, BSA, CH3CN, reflux, 2 h then compound 4,
TMSOTf, 0 °C to rt, 12 h, then reflux 4 h, 89%.
tively afford xylo-nucleosides 7 (mp 212 °C) and 8 (mp
136 °C). This selective 20-O-deacylation could thus lead
to subsequent chemical modifications on that position.
We then studied the PSE acetal cleavage, which can be
effected under either basic or reductive conditions.4,5
Thus, treatment of 5 with KOH in refluxing methanol
for 8 h gave 9-b-D-xylofuranosyladenine 915 in 75%
yield. Surprisingly however, under the same conditions
compound 6 only afforded the 20-O-deacylated nucleo-
side 8 (79%, Scheme 4).
In order to evaluate the potential interest of the PSE
acetal as protecting group in nucleoside synthesis, two
routine coupling methods (Saneyoshi8 or Vorbruggen9
¨
conditions) were applied starting from compound 4, to
give respectively (owing to 2-O-acyl participation)10
the corresponding protected adenine and uracil b-D-
xylo-nucleoside derivatives 511 and 612 (Scheme 2). The
exclusive presence of the regio-isomers N-9 and N-1
Several other methods were attempted (Cs2CO3/EtOH,
LiNH2/NH3/THF, NaOH/H2O, LDA/THF, LiAlH4/
THF),4 but all of them either led to the 20-O-deacylated
compound 8 or to degradation of the starting material.
The difference observed in the reactivity of nucleoside
analogues 5 and 6 might be explained by the formation
in the uracil series of the N-3-anion, resulting from the
basic conditions required for the PSE cleavage. Thus,
the reaction which occurs between the methylene group
adjacent to the sulfone and bases to achieve PSE acetal
cleavage via a b-elimination, would be prevented by the
negative charge present on the pyrimidine heterocycle.
In order to confirm this hypothesis, a coupling reaction
between compound 4 and N4-benzoyl cytosine, follow-
1
was fully established from their H, 13C NMR and UV
spectra.
In the case of uracil xylo-nucleoside derivative 6, the
yield of the glycosylation step (89%) was improved in
comparison with those usually obtained. For example,
the same reaction conditions applied to 1,2,3,5-tetra-
acetoxy-D-xylofuranose only gave a 70% yield of the
corresponding uracil xylo-nucleoside.13 Further studies
are in progress to rationalize this result, which probably
originates from steric and/or electronic effects attribut-
able to the PSE acetal.
Modification of the sugar moiety of nucleosides may
produce marked changes in the spectrum of their biolog-
ical activity and degree of selective toxicity, as well as in
their chemical and physical properties. In particular,
modification of the 20- and/or 30-positions14 has resulted
in compounds with a broad range of biological activity.
ing Vorbruggen conditions, was performed to produce
¨
compound 10 in 78% yield (Scheme 5). Nevertheless,
as for compound 6, the PSE acetal cleavage remained
unsuccessful. KOH in methanol gave the 20-O-deacy-
lated and 4-N-debenzoylated nucleoside 11 in 76% yield,
whereas LiNH2 in THF/NH3 selectively afforded the 20-
O-deacylated nucleoside 12 in 89% yield.
In order to study the orthogonality of the PSE acetal
with the 20-O-acetyl protection, compounds 5 and 6
have been selectively 20-O-deacylated (K2CO3, MeOH,
room temperature, Scheme 3) in good yield to respec-
These preliminary results seem to indicate that differ-
ences observed for hydrolysis of the PSE acetal in the
purine or pyrimidine nucleoside series is not directly re-
lated to the deprotonation of the aglycon under the used
basic conditions, but seems to be affected by the nature
of the constituting heterocyclic base.
O
O
B
B
O
O
O
O
a
PhSO2H2C
PhSO2H2C
In summary, we have established that the stability of the
PSE acetal is compatible with usual glycosylation condi-
tions. Furthermore, starting from a 30,50-O-(2-phen-
ylsulfonyl)ethylidene-20-O-acetyl nucleoside, an efficient
selective 20-O-deacylation can be achieved, opening ac-
cess to subsequent chemical modifications at the 20 posi-
OAc
OH
7: B = adenine
8: B = uracil
5 or 6
B = uracil or adenine
Scheme 3. Reagents and conditions: (a) K2CO3, MeOH, rt, 5 h, 90%
for adenine and 87% for uracil.

J.-P. Uttaro et al. / Tetrahedron Letters 48 (2007) 3851–3854
3853
NH2
N
O
N
O
O
O
O
O
PhSO2H2C
PhSO2H2C
PhSO2H2C
OH
11
b
NH2
NHBz
N
N
HO
O
N
O
N
a
OH
O
O
O
compound 4
X
OH
OAc
10
c
NHBz
N
O
N
O
O
OH
12
Scheme 5. Reagents and conditions: (a) N4-Bz cytosine, BSA, CH3CN, reflux, 2 h then compound 4, TMSOTf, 0 °C to rt, 12 h, then reflux 4 h, 75%;
(b) KOH, EtOH, reflux, 8 h, 76%; (c) LiNH2, NH3/THF, ꢀ50 °C to rt, 89%.
7. Selected physicochemical data for compound 4. 1H NMR
tion. Nevertheless, the reactivity of the PSE acetal moiety
(300 MHz, CDCl3, 20 °C): d 1.98 (s, CH3a), 2.00 (s,
CH3b), 2.07 (s, CH3b), 3.44 (br d, J = 5.0 Hz, 2H, H-a and
H-b), 3.90 and 4.12 (ABX, J = 13.5, 2.0 Hz, 2H, H-5a),
3.90 and 4.18 (AB, J = 12.8 Hz, 2H, H-5b), 3.97 (br s, 1H,
H3-b), 4.04 (br s, 1H, H-3a), 4.26 (d, 1H, H-4a and H-4b),
4.81 (s, 1H, H-2b), 4.94 (d, 1H, J = 4.5 Hz, H-2a), 5.02 (t,
J = 5.0 Hz, 1H, H-6a and H-6b), 5.97 (s, 1H, H-1b), 6.34
(d, J = 4.5 Hz, 1H, H-1a), 7.51–7.56 (m, 2H), 7.61–7.66
(m, 1H), 7.85–7.88 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3, 20 °C): d 20.3 (CH3a), 20.6 (CH3b), 20.7 (CH3a),
21.0 (CH3b), 60.0 (C-7a), 60.2 (C-7b), 65.8 (C-5a), 66.0
(C-5b), 72.2 (C-3a), 74.4 (C-3b), 75.9 (C-4b), 76.3 (C-2a),
78.4 (C-4a), 80.1 (C-2b), 94.5 (C-6b), 94.8 (C-6a), 95.4 (C-
1a), 99.9 (C-1b), 128.2 (CHarom), 128.9 (CHarom), 133.8
(CHarom), 133.9 (CHarom), 139.8 (Carom), 139.9 (Carom),
169.0 (CO), 169.5 (CO). MS (FAB, GT) 423 (M+Na)+,
341 (MꢀAcOH)+.
appeared unusual; when introduced on a nucleoside skel-
eton, the removal of the protective group under basic
conditions does not follow a general rule, as being suc-
cessful in the case of adenine xylo-nucleoside, but unsuc-
cessful with xylo-nucleoside derivatives of uracil and
cytosine. The nature of the base (purine or pyrimidine)
seems to be at the origin of this different reactivity. In
order to confirm this hypothesis, further investigations
are in progress in our laboratory.
References and notes
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8. Saneyoshi, M.; Satoh, E. Chem. Pharm. Bull. 1979, 27,
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4. Chery, F.; Rollin, P.; De Lucchi, O.; Cossu, S. Synthesis
2001, 286–292.
9. Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
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1981, 114, 1234–1255.
5. (a) Cabianca, E.; Chery, F.; Rollin, P.; Tatiboue¨t, A.; De
Lucchi, O. Tetrahedron Lett. 2002, 43, 585–587; (b)
Chevalier-du Roizel, B.; Cabianca, E.; Tatiboue¨t, A.;
10. Baker, B. R. In The CIBA Foundation Symposium on the
Chemistry and Biology of the Purines; Wolstenholme, G.
E. W., O’Connor, C. M., Eds.; Churchill: London, 1957;
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Rollin, P.; Sinay, P. Tetrahedron 2002, 58, 9579–9583; (c)
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Cabianca, E.; Tatiboue¨t, A.; Rollin, P. Polish J. Chem.
2005, 79, 317–322.
6. Gosselin, G.; Bergogne, M. C.; Imbach, J.-L. In Nucleic
Acid Chemistry, Improved and New Synthetic Procedures,
Methods and Techniques, Part 4; Townsend, L. B., Tipson,
R. S., Eds.; Wiley: New York, 1991; pp 41–45.
11. Selected physicochemical data for compound 5. Mp 123 °C.
1H NMR (300 MHz, CDCl3, 20 °C): d 2.17 (s, 3H, CH3),
3.43 (ddd, J = 14.7, 6.4, 4.2 Hz, 2H, H-70), 4.05 and 4.39
(ABX, J = 13.4, 1.8 Hz, 2H, H-50), 4.15 (br s, 1H, H-30),
4.30 (d, J = 2.2 Hz, 1H, H-40), 4.94 (s, 1H, H-20), 5.10 (dd,
J = 6.3, 4.3 Hz, 1H, H-60), 5.64 (br s, 2H, NH2), 6.16 (s,

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J.-P. Uttaro et al. / Tetrahedron Letters 48 (2007) 3851–3854
1H, H-10), 7.35–7.43 (m, 3H, Harom), 7.76–7.80 (m, 2H,
(75 MHz, CDCl3, 20 °C): d 20.6 (CH3), 59.4 (C-70), 66.0
H
arom), 7.97 (s, 1H, H-2), 8.32 (s, 1H, H-8). 13C NMR
(C-50), 74.8 (C-30), 77.1 (C-40), 79.8 (C-20), 89.7 (C-10),
95.1 (C-60), 101.1 (C-5), 128.2 (CHarom), 129.0 (CHarom),
134.0 (C-6), 139.8 (Carom), 139.9 (CHarom), 149.8 (CO),
163.0 (CO), 168.8 (CO). MS (FAB, GT) 453 (M+H)+, 451
(MꢀH)ꢀ. UV (EtOH 95) kmax = 263 nm (emax = 9200).
(75 MHz, CDCl3, 20 °C): d 20.7 (CH3), 59.5 (C-70), 66.0
(C-50), 74.5 (C-30), 76.8 (C-40), 79.9 (C-20), 88.4 (C-10),
95.0 (C-60), 119.5 (C-5), 128.0 (CHarom), 128.7 (CHarom),
133.5 (CHarom), 138.7 (C-8), 139.6 (Carom), 149.1 (C-4),
153.0 (C-2), 155.3 (C-6), 168.9 (CO). MS (FAB, GT) 476
(M+H)+, 474 (MꢀH)ꢀ. UV (EtOH 95) kmax = 263 nm
20
½aꢁD ꢀ10.0 (c 1.00, CDCl3).
13. Sahabuddin, S.; Ghosh, R.; Achari, B.; Mandal, S. B. Org.
Biomol. Chem. 2006, 4, 551–557.
20
(emax = 16400). ½aꢁD ꢀ46.0 (c 1.00, CDCl3).
12. Selected physicochemical data for compound 6. Mp 153 °C.
1H NMR (300 MHz, CDCl3, 20 °C): d 2.13 (s, 3H, CH3),
3.39 (ddd, J = 14.6, 6.1, 4.5 Hz, 2H, H-70), 4.03 and 4.37
(ABX, J = 13.4, 1.6 Hz, 2H, H-50), 4.08 (br s, 1H, H-30),
4.22 (d, J = 2.0 Hz, 1H, H-40), 4.75 (s, 1H, H-20), 5.08 (dd,
J = 6.1, 4.5 Hz, 1H, H-60), 5.58 (br d, J = 8.2 Hz, 1H, H-
5), 5.80 (s, 1H, H-10), 7.52–7.65 (m, 4H, Harom and H-6),
7.84–7.87 (m, 2H, Harom), 8.97 (br s, 1H, NH). 13C NMR
14. (a) Len, C.; Mackenzie, G. Tetrahedron 2006, 62, 9085–
9107; (b) Pathak, T. Chem. Rev. 2002, 102, 1623–1667; (c)
Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745–
1768.
15. Physicochemical data of compound 9 are in agreement
with those reported in the literature: Gosselin, G.;
Bergogne, M.-C.; Derudder, J.; De Clercq, E.; Imbach,
J.-L. J. Med. Chem. 1986, 29, 203–213.