Synthesis of 2,3-dihydro-1,4-dithiinyl nucleosides via Pummerer-type glycosidation

Article abstract of DOI:10.1016/j.tetlet.2010.09.060

A straightforward procedure for the preparation of nucleoside analogue 1 and its regioisomer 2 containing a dihydro-1,4-dithiin as sugar moiety has been accomplished in four steps by our readily available heterocyclic system 5. Nucleobase insertion was ca

Full text of DOI:10.1016/j.tetlet.2010.09.060

Tetrahedron Letters 51 (2010) 6060–6063
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2,3-dihydro-1,4-dithiinyl nucleosides via Pummerer-type
glycosidation
⇑
Concetta Paolella, Daniele D’Alonzo, Annalisa Guaragna , Flavio Cermola, Giovanni Palumbo
Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, via Cinthia, 4 I-80126 Napoli, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward procedure for the preparation of nucleoside analogue 1 and its regioisomer 2 contain-
ing a dihydro-1,4-dithiin as sugar moiety has been accomplished in four steps by our readily available
heterocyclic system 5. Nucleobase insertion was carried out by direct addition of N4-acetylcytosine to
sulfoxide derivatives via Pummerer-type glycosidation reaction.
Received 7 August 2010
Revised 10 September 2010
Accepted 15 September 2010
Available online 19 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Heterocyclic nucleosides
Dithiins
Nucleoside analogues
Pummerer-type glycosidation
1. Introduction
of our investigations regarding the development of novel de novo
synthetic methodologies for the preparation of natural and
The structural requirements of antiviral and antitumour nucleo-
sides to be recognized by cellular/viral enzymes rely on three key
elements: (a) the hydroxymethyl group, necessary for nucleoside
phosphorylation, (b) the heterocyclic base moiety, involved in
the main recognition processes through specific hydrogen bonds,
and (c) the sugar moiety, which can be considered as a spacer to
connect the hydroxymethyl group and the nucleobase in the cor-
rect orientation. A wide number of structural modifications at
the carbohydrate moiety have been devised, with the aim to re-
place the furanose ring with units resembling the conformational
features of natural nucleosides.1 Particularly, replacement of the
sugar skeleton with acyclic moieties, n-membered rings (with
n = 3–7), equipped in some cases with exo- or endo-cyclic double
bonds, has been reported.2 Such systems quite often contain car-
bon, one or more heteroatoms3 in place of/or along with endo-cyc-
lic oxygen, resulting in major functional changes in the nucleoside
subunits. Such a wide structural diversity in nucleoside architec-
tures has led, over the years, to the development and approval of
several molecules on the antiviral market in both racemic and
enantiomerically pure form (Chart 1).4
unnatural compounds by three-carbon homologation of various
O
N
NH
base
HO
N
N
NH2
O
HO
spacer
Acyclovir
[anti-HSV]
O
N
NH2
NH2
N
N
N
N
N
N
N
NH
N
HO
HO
HO
N
NH2
N
HO
HO OH
Neplanocin A
[anti-leukemic]
Synadenol
[anti-HCMV]
Lobucavir
[anti-HIV]
O
N
NH2
N
NH2
F
N
N
In this context, our interest in sulfur-containing nucleosides5
and six-membered nucleoside analogues6 took us to open up a
synthetic study on the preparation of heterocyclic nucleosides 1
and 2, in which the sugar moiety is substituted by a 5,6-dihydro-
1,4-dithiine ring (Fig. 1). Such a system has long been at the centre
NH
NH
N
HO
N
S
O
N
O
HO
2
HO
O
S
F
HO
Cyclohexenyl-G
[anti-HSV]
S-2'F-d4C
[anti-HIV]
Racivir
[anti-HIV]
⇑
Corresponding author. Tel./fax: +39 081 674119.
E-mail address: annalisa.guaragna@unina.it (A. Guaragna).
Chart 1. Sugar-modified nucleoside analogues with antiviral activity.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.060

C. Paolella et al. / Tetrahedron Letters 51 (2010) 6060–6063
6061
Table 1
Sulfoxidation of dithiins 5–7
NH2
N
NH2
N
O
Entry Conditionsa
8/9 Ratio (% yield)
N
S
N
R = H
R = Ac
R = PMB
HO
S
O
S
1
2
3
4
m-CPBA (1.0 equiv), ꢀ20 °C
50:50
(60)
55:45
(78)
60:40
(74)
S
PDC (1.0 equiv), ꢀ20 °C
NDb
65:35
(82)
65:35
(80)
85:15
HO
1
2
(84)
c
PDC (1.0 equiv), rt
NDb
—
(41)
Figure 1. Dithiine nucleoside analogues 1 and 2.
50:50
(87)
60:40
(90)
65:35
(85)
L
-DET/tBuOOH/Ti(O-iPr)4,
(2:1.2:1.0 equiv), ꢀ20 °C
-DET/tBuOOH/Ti(O-iPr)4,
(2:1.2:1.0 equiv), ꢀ20 °C
electrophiles.7 Differently from its common employ as elongating
system,7,8 herein we report the use of dithiinyl moiety as sugar
scaffold in place of the furan ring of natural nucleosides to produce
novel analogues endowed with potential antiviral activity.
5
50:50
(89)
57:43
(91)
68:32
(86)
D
a
CH2Cl2 used as solvent in all reactions.
b
ND: not determined (concurrent oxidation of primary hydroxyl group
occurred).
c
Further S-4 oxidation led to formation of a sulfone as the only product of the
2. Results and discussion
reaction.
In spite of the unusual shape of the dithiine skeleton, we eval-
uated its capacity to work as a good spacer to place the nucleobase
and the hydroxymethyl group in the appropriate orientation and
distance for recognition by viral/cellular enzymes. With this aim,
some preliminary Hyperchem calculations9 were carried out, over-
lapping the structures of nucleosides 1 and 2 with those of natural
nucleosides, as well as of other potent antiviral agents. The 1,4-
dithiinyl system demonstrated to possess fairly good structural
features, showing the best superimposition of both the hydroxy-
methyl group and the nucleobase when cytosine analogue (S)-2
was overlapped with the potent antiretroviral agent lamivudine
(3TC, 3) frozen in its bioactive N conformation10 (Fig. 2).
its preparation as well as that of its regioisomer 1 (Fig. 1). More-
over, given the relaxed enantioselectivity displayed by some key
enzymes involved in the activation of deoxycytidine analogues,11
a comparable activity of both enantiomers should be expected. In
this letter, the synthesis of target compounds 1 and 2 as R/S mix-
ture has been performed, as the antiviral evaluation of the racemic
nucleosides would give results regarding both enantiomers in one
procedure.
Synthesis of dithiinyl nucleosides 1 and 2 was envisioned to be
carried out through a Pummerer-type glycosylation reaction on
sulfoxides 8 and 9, in turn obtained from our bis-thioenolether 5
(Scheme 1). As already documented,7 preparation of the 5,6-dihy-
dro-1,4-dithiine ring was easily carried out in four steps from
methyl pyruvate 4 (Scheme 1).
Such studies prompted us to evaluate the biological properties
of such nucleoside and to develop an expeditious procedure for
NH2
NH2
The synthesis began with the protection of free alcohol 5 (Ac2O,
pyridine) and subsequent thioether oxidation of the acetate 6 with
m-CPBA in CH2Cl2 to give a 55:45 mixture of two regioisomers 8b
and 9b in 78% yield.
N
S
N
O
N
S
N
O
O
OH
Sulfoxidation reaction was also attempted using dithiin 5 and
its derivative 7 in presence of various oxidizing agents.12,13 As
shown in Table 1, the use of m-CPBA gave similar results on all sub-
strates, affording the two regioisomeric sulfoxides 8a and 9a in
approximatively 1:1 mixture (R = H) with a slight prevalence for
8 over 9 when R = Ac or PMB. The preference for the oxidation at
S-4 of the dithiine ring was observed in most cases; only the use
of a bulkier oxidizing agent, such as pyridinium dichromate
(PDC), in the oxidation of dithiin 7 led to a greater excess of regio-
isomer 8c (entry 2). Even the use of Kagan–Modena sulfoxidation
S
OH
3
Lamivudine
[anti-HIV and
anti-HBV]
2
( )-
S
Figure 2. Superimposed structures of analogue (S)-2 and lamivudine (3).
S4
O
conditions14
(L-DET or D-DET/tBuOOH/Ti(O-iPr)4) did not affect
1
S
Ref. 7
3
H3C
2
OCH3
the reaction outcome (entries 4 and 5). Sulfoxidation reaction
seemed to be essentially driven by steric hindrance reasons at
RO
5 R = H
6 R = Ac
O
4
allylic position, even though an additional electronic contribute
Ac2O/Py
98%
PMBCl, NaH,
0 ºC to rt
96%
16
was found.15 Indeed, energy calculation (B3LYP/6-31G ) per-
*
7
R = PMB
formed on 6 and 7 provided consistent explanation for the greater
oxidability of S-4 compared to S-1. For both 6 and 7, the HOMO
molecular orbital is more localized on S-4 rather than on S-1 and
coefficient value difference is grater in 7 (Table 2).
As sulfoxides 8 and 9 were obtained, preparation of target
nucleoside analogues was carried out by a Pummerer-type glycos-
idation reaction. First attempts carried out on sulfoxide 8c, under
the same conditions previously reported5 with N4-acetylcytosine,
TMSOTf and TEA in CH2Cl2, led as the only product of the reaction
MCPBA,
CH2Cl2
5 6 7
and
see Table 1
from
,
,
0 ºC
60-78%
O
S
S
S
S
O
RO
RO
9
8
to the unexpected
a,b-unsaturated aldehyde 10. This is probably
the result of an intramolecular oxido-reduction process and, as de-
picted in Scheme 2, it can be conjectured to occur after PMB pro-
tecting group removal, sulfoxide trimethylsilylation, thionum ion
a) R = H, b) R = Ac, c) R = PMB
Scheme 1. Synthesis of sulfoxides 8–9.

6062
C. Paolella et al. / Tetrahedron Letters 51 (2010) 6060–6063
Table 2
Homo coefficients in 6 and 7
Deprotection under common Zemplèn conditions (MeONa/
MeOH) afforded the final target compound 118 in 98% yield. Anal-
ogously, the same reactions, carried out starting from sulfoxide 9b,
led to the desired nucleoside analogue 218 in 71% overall yield
(Scheme 4).
Atom
Dithiin 6
Dithiin 7
S-1
S-4
0.36824
0.44799
0.28018
0.40612
3. Conclusions
O
S
S
TMSOTf, TEA,
N4-AcCy
In summary, a straightforward procedure for the preparation of
dithiinyl nucleoside 1 and 2 has been accomplished in four steps by
ourreadilyavailableheterocyclic system5. Regioselectivityofsulfox-
idation reaction of bis-thioenolethers 6–7 was rationalized on the ba-
sis of both steric and electronic effects. Nucleobase insertion was
carried out by direct addition of N4-acetylcytosine to sulfoxide 8b–
9b via Pummerer-type glycosidation reaction. Evaluation of racemic
1 and 2 as potential antiviral agents is currently in progress and will
be reported elsewhere. In case, further development of asymmetric
Pummerer rearrangements19 and/or enantiomeric resolution of our
mixtures by chiral HPLC will be considered to provide enantiopure
(S)- and (R)-1 as well as their regioisomers (S)- and (R)-2.
S
S
CH2Cl2,
0 ºC to rt
10
O
PMBO
8c
S
O
S
S
S
O
H
H
H+
HO
OTMS
S
S
H
S
S
Acknowledgements
HO
HO
1H and 13C NMR spectra were performed at the ‘Centro Interdi-
partimentale di Metodologie Chimico-Fisiche’ (CIMCF), Università
di Napoli Federico II.
Scheme 2.
a
,b-Unsaturated aldehyde formation.
TMS
NAc
Supplementary data
NHAc
N
TMSOTf,
TEA,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.060.
N
O
N
CH2Cl2
,
S
N
OTMS
0 ºC to rt
S
S
8b
References and notes
S
78%
TMSO
AcO
1. (a) Herdewijn, P. Modified Nucleosides: In Biochemistry Biotechnology and
Medicine; Wiley-VCH GmbH: Weinheim, 2008; (b) Gumina, G.; Choi, Y.; Chu,
C. K. In Antiviral Nucleosides: Chiral Synthesis and Chemotherapy; Chu, C. H. Ed.;
Elsevier B.V., 2003, Chap 1, pp. 1–76.
AcO
11
MeONa
MeOH
98%
2. Ichikawa, E.; Kato, K. Curr. Med. Chem. 2001, 8, 385–423.
1
3. (a) Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chem. Rev. 2010, 110, 3337–
3370; (b) Merino, P. Curr. Med. Chem. 2006, 13, 539–545; (c) Mansour, T. S.;
Storer, R. Curr. Pharm. Design 1997, 3, 227–264.
Scheme 3. Dihydrodithiinyl nucleoside 1 via Pummerer-type glycosidation of 8b.
4. (a) Cihlar, T.; Ray, A. S. Antiviral Res. 2010, 85, 39–58; (b) De Clercq, E. Future
Med. Chem. 2010, 2, 1049–1053; (c) Flexner, C. Nat. Rev. Drug Disc. 2007, 6, 959–
966; (d) De Clercq, E. Nat. Rev. Drug Disc. 2002, 1, 13–25.
5. (a) Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. Eur. J. Org. Chem. 2003,
346–350; (b) Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. Eur. J. Org.
Chem. 1999, 1455–1458.
6. a D’Alonzo, D.; Guaragna, A.; Van Aerschot, A.; Herdewijn, P.; Palumbo, G. J. Org.
Chem. 2010, 75, 6402–6410; (b) D’Alonzo, D.; Van Aerschot, A.; Guaragna, A.;
Palumbo, G.; Schepers, G.; Capone, S.; Rozenski, J.; Herdewijn, P. Chem. Eur. J.
2009, 15, 10121–10131; (c) D’Alonzo, D.; Guaragna, A.; Van Aerschot, A.;
Herdewijn, P.; Palumbo, G. Tetrahedron Lett. 2008, 49, 6068–6070.
7. Guaragna, A.; Pedatella, S.; Palumbo, G. In e-Encyclopedia of Reagents for Organic
Synthesis (e-EROS); Paquette, L. A., Ed.; John Wiley & Sons: New York, US, 2008.
8. Guaragna, A.; D’Alonzo, D.; Paolella, C.; Napolitano, C.; Palumbo, G. J. Org. Chem.
2010, 75, 3558–3568.
9. The models were generated by energy minimization with the amber force field
of the structures using the HYPERCHEM 8.0 software package (Hypercube Inc.).
10. (a) Huang, H.; Chopra, R.; Verdine, G. L.; Harrison, S. C. Science 1998, 282, 1669–
1675; (b) Marquez, V. E.; Ben-Kasus, T.; Barchi, J. J., Jr.; Green, K. M.; Nicklaus,
M. C.; Agbaria, R. J. Am. Chem. Soc. 2004, 126, 543–549.
formation by TEA-mediated elimination and concurred oxidation
of free hydroxyl group, to give aldehyde 10.
On the other hand, as depicted in Scheme 3, under the same
conditions the use of the more stable acetylated sulfoxide 8b al-
lowed to obtain the desired dihydrodithiine nucleoside derivative
1117 as a racemic mixture and in good yield (78%). Similarly to
what observed in Scheme 2, the reaction proceeds through thio-
num ion intermediate mediated by TMSOTf and TEA and subse-
quent attack of silylated nucleobase on thionum ion.
Replacement of CH2Cl2 with CH3CN led to the final product with
approximately the same yield, but prolonged reaction times were
required.
AcHN
11. Eriksson, S.; Munch-Petersen, B.; Johansson, K.; Eklund, H. Cell. Mol. Life Sci.
2002, 59, 1327–1346.
12. All substrates did not exhibit any reactivity when in situ generated TFDO
[methyl(trifluoromethyl)dioxirane] was used.
13. For a thioether oxidation of 5,6-dihydro-1,4-dithiins by photooxygenation, see:
Cermola, F.; Guaragna, A.; Iesce, M. R.; Palumbo, G.; Purcaro, R.; Rubino, M.;
Tuzi, A. J. Org. Chem. 2007, 72, 10075–10080.
TMSOTf, TEA,
N 4-AcCy
N
N
S
CH2Cl2
,
0 ºC
9b
O
S
75%
AcO
´
´
14. Wojaczynska, E.; Wojaczynski, J. Chem. Rev. 2010, 110, 4303–4356.
15. full electronic contribution has been observed when the sulfoxidation
reaction was performed on methyl ester derivative 13, in which the electron
withdrawing group at C-2 position made S-4 atom weak nucleophile.
A
12
2
MeONa
MeOH
95%
a
However 13 could not be used for providing nucleoside 2, owing to fair
instability of sulfoxide 14 to subsequent reaction conditions.
Scheme 4. Dihydrodithiinyl nucleoside 2 via Pummerer-type glycosidation of 9b.

C. Paolella et al. / Tetrahedron Letters 51 (2010) 6060–6063
6063
45.65, H, 4.44, N, 12.26, S, 18.84. Under the same conditions, starting from 9b
compound 12 was obtained (75% yield). {6-[40-(Methylcarboxamido)-2-oxo-
1,2-dihydro-1-pyrimidinyl]-5,6-dihydro-1,4-dithiin-2-yl}methyl acetate (12)
1H NMR (400 MHz, CDCl3): d 2.13 (s, 3H, OCOCH3), 2.25 (s, 3H, NHCOCH3),
3.26 (dd, 1H, J = 2.0, 13.9 Hz, 1H, CHaS), 3.35 (dd, 1H, J = 4.6, 13.9 Hz, 1H, CHbS),
4.70 (d, J = 12.7 Hz, 1H, CHaO), 4.73 (d, J = 12.7 Hz, 1H, CHaO), 6.45 (s, 1H, HC@),
6.48 (dd, J = 2.0, 4.6 Hz, 1H, CHS), 7.47 (d, J = 7.5 Hz, 1H, H-5), 7.80 (d, J = 7.5 Hz,
1H, H-6), 8.35 (s, 1H, NH). 13CNMR (50 MHz, CDCl3): ppm 20.8 (CH3CO), 24.9
(CH3CO), 28.8 (CH2S), 53.8 (CHS), 67.2 (CH2O), 96.4 (C-5), 116.0 (HC@), 123.1
(C@CH2), 147.2 (C-6), 154.8 (C@O), 162.7 (C@N), 170.6 (C@O). Signal
assignments have been unambiguously determined on the basis of 2D
experiments. Anal. calcd for C13H15N3O4S2: C, 45.73, H, 4.43, N, 12.31, S,
18.78. Found: C, 45.80, H, 4.44, N, 12.28, S, 18.70.
S
S
m-CPBA
CH2Cl2
,
0 ºC
S
S
O
86%
O
O
OCH3
OCH3
13
14
16. Theoretical calculations were performed by SPARTAN 08 Quantum mechanics
program.
18. Data for (R/S) 4-amino-1-[5-(hydroxymethyl)-2,3-dihydro-1,4-dithiin-2-yl]-1,2-
dihydro-2-pyrimidinone (1): 1H NMR (200 MHz, CD3OD): d 3.18–3.25 (m, 2H,
CH2S), 4.12 (dd, J = 0.9, 13.0 Hz, 1H, CHaOH), 4.21 (dd, J = 0.9, 13.1 Hz, 1H,
CHbOH), 5.87 (d, J = 7.6 Hz, 1H, H-6), 6.34 (dd, J = 2.8, 3.8 Hz, 1H, CHS), 6.39 (d,
J = 0.9 Hz, 1H, HC@), 7.66 (d, J = 7.6 Hz, 1H, H-5). 13CNMR (50 MHz, CD3OD):
ppm 30.6 (CH2S), 55.2 (CHS), 67.2 (CH2O), 95.5 (C-5), 113.1 (HC@), 130.6
(C@CH2), 145.2 (C-6), 157.8 (C@O), 167.8 (C@N). Anal. calcd for C9H11N3O2S2:
C, 42.01, H, 4.31, N, 16.33, S, 24.92. Found: C, 41.94, H, 4.30, N, 16.28, S, 25.00.
Data for (R/S) 4-amino-1-[6-(hydroxymethyl)-2,3-dihydro-1,4-dithiin-2-yl]-1,2-
dihydro-2-pyrimidinone (2): 1H NMR (200 MHz, CD3OD): d 3.15-3.34 (m, 2H,
CH2S), 4.05 (d, J = 13.1 Hz, 1H, CHaOH), .4.07 (d, J = 13.1 Hz, 1H, CHbOH), 5.84
(d, J = 7.6 Hz, 1H, H-6), 6.25 (dd, J = 2.5, 4.8 Hz, 1H, CHS), 6.46 (d, J = 0.9 Hz, 1H,
HC@), 7.63 (d, J = 7.6 Hz, 1H, H-5). 13CNMR (75 MHz, CD3OD): ppm 31.8 (CH2S),
54.0 (CHS), 67.2 (CH2O), 95.3 (C-5), 112.0 (HC@), 130.5 (C@CH2), 145.4 (C-6),
157.6 (C@O), 167.4 (C@N). Signal assignments have been unambiguously
determined on the basis of 2D experiments. Anal. calcd for C9H11N3O2S2: C,
42.01, H, 4.31, N, 16.33, S, 24.92. Found: C, 41.90, H, 4.32, N, 16.37, S, 24.99.
19. Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter, D. J. Angew. Chem., Int. Ed.
2010, 49, 5832–5844.
17. Pummerer-type glycosidation reaction. Typical procedure: To a suspension of N4-
acetylcytosine (0.30 g, 2.0 mmol) in CH2Cl2 (10 mL) TEA (0.8 mL, 6.1 mmol)
and TMSOTf (1.1 mL, 6.1 mmol) were added at 0 °C and under N2 atmosphere.
The mixture was left at room temperature for 30 min, after this time the
mixture was cooled at 0 °C and a solution of sulfoxide 8b (0.28 g, 1.36 mmol)
was added dropwise. The reaction was warmed at room temperature for 2 h,
then saturated aq NaHCO3 was added until neutrality. The mixture was
extracted with EtOAc and washed with water; the organic layers were dried
(Na2SO4) and evaporated under reduced pressure to give a crude product
whose chromatography afforded the pure {5-[40-(methylcarboxamido)-2-oxo-
1,2-dihydro-1-pyrimidinyl]-5,6-dihydro-1,4-dithiin-2-yl}methyl acetate (11)
(78% yield). 1H NMR (500 MHz, CDCl3): d 2.11 (s, 3H, OCOCH3), 2.24 (s, 3H,
NHCOCH3), 3.26 (dd, J = 2.3, 14.6 Hz, 1H, CHaS), 3.40 (dd, J = 4.4, 14.6 Hz, 1H,
CHbS), 4.61 (d, J = 12.7 Hz, 1H, CHaO), 4.65 (d, J = 12.7 Hz, 1H, CHbO), 6.40 (dd,
J = 2.3, 4.4 Hz, 1H, CHS), 6.47 (s, 1H, HC@), 7.44 (d, J = 7.3 Hz, 1H, H-5), 7.84 (d,
J = 7.3 Hz, 1H, H-6), 8.42 (s, 1H, NH). 13CNMR (50 MHz, CDCl3): ppm 20.7
(CH3CO), 24.9 (CH3CO), 30.6 (CH2S), 53.0 (CHS), 67.4 (CH2O), 96.2 (C-5), 114.1
(HC@), 124.3 (C@CH2), 147.4 (C-6), 155.1 (C@O), 162.5 (C@N), 170.5 (C@O).
Anal. calcd for C13H15N3O4S2: C, 45.73, H, 4.43, N, 12.31, S, 18.78. Found: C,