Probing the reactivity of nebularine N1-oxide. A novel approach to C-6 C-substituted purine nucleosides

Article abstract of DOI:10.1016/j.tet.2011.06.080

A novel approach to the synthesis of purine nucleoside analogues, featuring the reaction of the C6-N1-O^- aldonitrone moiety of 9-ribosyl-purine (nebularine) N1-oxide with some representative dipolarophiles, as well as Grignard reagents, is repo

Full text of DOI:10.1016/j.tet.2011.06.080

Tetrahedron 67 (2011) 6138e6144
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Tetrahedron
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Probing the reactivity of nebularine N1-oxide. A novel approach to
C-6 C-substituted purine nucleosides
,
c
,
a
a
Stefano D’Errico a, Vincenzo Piccialli b, Giorgia Oliviero a , Nicola Borbone , Jussara Amato ,
*
,
c
Valentina D’Atri a, Gennaro Piccialli a
a
ꢀ
Dipartimento di Chimica delle Sostanze Naturali, Universita degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy
Dipartimento di Chimica Organica e Biochimica, Universita degli Studi di Napoli Federico II, Via Cynthia 4, 80126 Napoli, Italy
Facolta di Scienze Biotecnologiche, Universita degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy
b
c
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
A novel approach to the synthesis of purine nucleoside analogues, featuring the reaction of the C6eN1eOꢀ
aldonitrone moiety of 9-ribosyl-purine (nebularine) N1-oxide with some representative dipolarophiles, as
well as Grignard reagents, is reported. Addition of Grignard reagents to the electrophilic C-6 carbon of the
substrate allows a facile access to C-6 C-substituted purine nucleosides without using metal catalysts. 1,3-
Dipolar cycloaddition processes lead to novel nucleoside analogues via opening, degradation or ring-
enlargement of the pyrimidine ring of the base system of the first-formed isoxazoline or isoxazolidine
cycloadduct.
Article history:
Received 9 May 2011
Received in revised form 10 June 2011
Accepted 24 June 2011
Available online 30 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
development of new methods for the introduction of C-sub-
stituents at C-6.
In the last decades many research groups have focused their
attention to the preparation of new modified nucleosides and nu-
cleotides with the aim of expanding the pool of molecules with
potential antineoplastic, antihypertensive and antiviral activities.1
In this context, efforts have been directed to the synthesis of
sugar2 and/or base3-modified nucleosides. A large number of
nucleobase analogues exist and several nucleoside analogues have
been employed against cancer and viral diseases. In addition, base-
modified nucleosides often show fluorescent properties,4 and can
be used as fluorescent probes for the analysis of DNA and RNA
structures as well as for analysing the interaction of DNA and RNA
with binding proteins. Purine bases and nucleosides bearing a C- or
N-substituent at C-6 represent an important class of compounds
possessing a broad spectrum of biological effects including cyto-
static, antiviral, antibacterial as well as receptoremodulation ac-
tivity.5 The reactivity imparted to purines and related nucleosides
by halogenation at C-6 has opened the way to the construction of
new libraries of C-6 modified nucleosides generally through direct
aromatic nucleophilic substitution (SNAr),6 or metal-mediated
cross-coupling processes3a,7 (Fig. 1). The most reliable methods to
access C-6 C-substituted nucleosides use metal or organometal-
mediated reactions.3a However, there is still a great need for the
PREVIOUS APPROACHES
OUR APPROACH
1,3-Dipolar
cycloaddition
Metal-mediated
cross-coupling
Grignard
reagents
X
N
SNAr
O
N
N
6
1
6
N
N
N
N
N
O
O
HO
RO
HO
R
RO
OR
R=H, deoxyribose
R=OH, ribose
X=Cl, Br, I
1a R=H (Nebularine N-1 oxide)
1b R=Ac
1c R=TBDMS
Fig. 1. Approaches to C-6 functionalization of purine nucleosides.
Nitrones are precious substrates used in organic synthesis for
the assembly of structurally complex nitrogen-containing com-
pounds. Their most well-studied reactions are the 1,3-dipolar cy-
cloadditions (1,3-DC) and the nucleophilic addition of
organometallic reagents.8 We reasoned that 9-ribosyl-purine
(nebularine) N1-oxide (1a, Fig. 1), embodying a potentially reactive
C6eN1eOꢀ nitrone moiety, could allow the C-6 functionalization of
the purine base. To probe this concept the reactivity of sugar-
protected 1b and 1c (Fig. 1) towards some representative
* Corresponding author. Tel.: þ39 081678540; fax: þ39 081678552; e-mail ad-
dress: golivier@unina.it (G. Oliviero).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.080

S. D’Errico et al. / Tetrahedron 67 (2011) 6138e6144
6139
dipolarophiles as well as Grignard reagents, respectively, was ex-
plored. The results obtained are described in the present paper.
isoxazoline or isoxazolidine adduct did not survive. Therefore, the
nucleoside products obtained from such processes are all derived
from the cleavage of the N1eO bond in the cycloadduct followed in
some cases by further evolution of the first-formed C-6 substituted
purine system. In particular, reaction of 1b with an equimolar
amount of dimethyl acetylenedicarboxylate in THF gave the two
unusual nucleoside analogues 2 (25%) and 4 (40%) (Table 1, entry 1)
2. Results and discussion
20,30,50-Tri-O-acetyl-nebularine N1-oxide (1b, Fig. 1) was used as
starting material for 1,3-DC processes whereas 20,30,50-tri-O-(tert-
butyldimethylsilyl)-nebularine N1-oxide (1c, Fig. 1) was employed
to test the addition of Grignard reagents. Compounds 1b and 1c
were synthesised from 20,30,50-tri-O-acetyl-nebularine and 20,30,50-
tri-O-(tert-butyldimethylsilyl)-nebularine, respectively,9 by re-
action of nebularine with catalytic amounts of methyltrioxo-
rhenium (MeReO3) in the presence of H2O2, as described in the
literature for the preparation of the corresponding purine N1-
oxide.10 Though the cycloaddition of aromatic N-oxides of various
heterocyclic systems has extensively been investigated,11 to our
knowledge no report exists in the literature on the reactivity of N-
oxides of purine nucleosides in cycloaddition reactions.
possessing modified heterocyclic base systems. Compound
2
proved unstable as such giving a mixture of partially deacetylated
products on standing. However, its fully deacetylated derivative 3,
obtained by treatment of 2 with NH4OH (concd) in MeOH, was
a stable product, which was used for NMR characterisation. Com-
pound 4 contains the 5:7-fused imidazo[4,5-d][1,3]diazepine ring
system. The 1H NMR spectrum of 4 recorded in CD3OD showed it to
be a mixture of two tautomers in a 7:3 ratio. 2D-NMR studies car-
ried out in this solvent gave no conclusive evidences on the
structure of 4 that was eventually solved by performing NMR
analyses in DMSO-d6 where the major tautomer 4 was present in
88% amount. Few examples of nucleoside analogues based on this
base framework (ring-expanded nucleosides, RENs) exist all dis-
playing significant biological activities.13 The interest towards this
type of substances is keen and the facile access to this framework is
particularly appealing. In particular, compound 4 is the first ex-
ample of a C-7 analogue of coformycin,13c (Fig. 2) a highly potent
inhibitor of adenosine deaminase (ADA), an enzyme playing a key
role in purine metabolism.14
Reaction of compound 1b with some representative dipolar-
ophiles was carried out as shown in Table 1 and Scheme 1, to give
the novel nucleoside analogues 2 and 4e7, the structure of which
was determined by high-field 2D-NMR analyses. As expected,12 in
all the analysed cases, we observed that the first-formed
Table 1
Reaction of 1b with dipolarophiles
Entry
Dipolarophile
Conditions
(solvent)
Products
(yield %)
1
Dimethyl
rt, 2 h (THF)
2 (25%),
4 (40%)
NR
5 (45%),
6 (30%)
NR
acetylenedicarboxylate
3-Phenyl-2-propynenitrile
3-Phenyl-2-propynenitrile
OH
2
3
rt, 16 h (THF)
Reflux, 4 h (dioxane)
HN
N
4
5
6
7
N-Methylmaleimide
N-Methylmaleimide
Diphenylacetylene
rt, 5 h or reflux,
overnight (THF)
Reflux, 5 h,
(dioxane/toluene, 1:1)
Reflux, overnight
(THF or dioxane)
Reflux, overnight
(toluene)
N
N
O
7 (60%)
NR
HO
HO
OH
Coformycin
Dimethyl maleate or
dimethyl fumarate
NR
NR: no reaction.
Fig. 2. Structure of coformycin.
CO2Me
N
MeO2C
N
iv
N
6
7
N
+
N
MeO
iii
N
H2N
2
N
R1
R(OAc)3
R1=R(OAc)3
4
-O
3 R1=R(OH)3
N+
Ph
N
N
CN
O
N
Ph
N
HO
v
i, ii
O
N
N
N
Nebularine
N
AcO
6
6
+
N
N
N
AcO
OAc
R(OAc)3
R(OAc)3
1b
5
6
Me
N
O
O
R=Ribose
vi
HO
N
N
HN 6
N
R(OAc)3
Mixture of C-6
7
diastereomers
Scheme 1. Reaction of 1b with dipolarophiles: i. Ac2O/pyridine;9 ii. MeReO3eH2O2 (30% aq), MeOH, rt, overnight (80% over two steps); iii. NH4OH (concd)eMeOH, rt, 30 min; iv.
Dimethyl acetylenedicarboxylate, THF, rt, 2 h; v. 3-phenyl-2-propynenitrile, dioxane, reflux, 4 h; vi. N-methylmaleimide, dioxane/toluene (1:1), reflux, 5 h.

6140
S. D’Errico et al. / Tetrahedron 67 (2011) 6138e6144
A tentative explanation for the formation of 2 and 4 is depicted
Non-symmetric 3-phenyl-2-propynenitrile failed to react with
1b at room temperature in THF (Table 1, entry 2) but gave a mixture
of C-6 substituted nucleosides 5 (45%) and 6 (30%) when the pro-
cess was conducted in dioxane at reflux (entry 3). Compound 5 is
likely derived from the opening of isoxazoline ring in one of the two
expected diastereomeric adducts 13 (Scheme 3) induced by loss of
the C6-H proton and aromatization of the heterocyclic system. On
the other hand, it seems hazardous trying to hypothesize a mech-
anistic route to C-6 benzoylated 6. However, it can be envisaged
that the oxidative cleavage of the double bond in the other adduct
(13, X¼Ph, Y¼CN), with loss of a two-carbon fragment and aro-
matization, should occur to generate 6. As far as we know, the direct
introduction of acyl substituents at C-6 of the purine nucleoside
system has never been reported before, and this type of substances
is still rather rare.
in Scheme 2. Generation of their base system calls for the extrusion
of a two-carbon fragment from the initially-formed isoxazoline
adduct 8. In particular, formation of 2 can be explained via iso-
xazoline opening with concomitant base aromatization, to give the
C-6 substituted species 9 (route a) followed by loss of a COeCO2Me
fragment with formation of a two-carbon chain at C-6 (10).12
Evolution of 9 towards the conjugated species 10 via attack of
a nucleophile at the ketone carbonyl seems logical and would well
explain formation of the exocyclic double bond in 10. Trans-
formation of dimethyl a-ketosuccinates, such as 9 into methyl ac-
etates by loss of this structural fragment has previously been
reported.15 The electron-withdrawing effect of the exocyclic un-
saturated ester moiety in the latter may then be responsible for the
opening of the pyrimidine ring through attack of MeOH at C-2,
possibly in the work-up and/or purification step, to eventually give
2. This type of reactivity at C-2 in 10 is strongly reminiscent of that
exhibited by the N1-2,4-dinitrophenyl-inosine derivatives, pre-
viously studied in our group, leading to formation of AICAR de-
Oxidative
cleavage
to give 6
rivatives.16 The imidazo 4-substituted framework of
unprecedented.
2 is
X=CN, Y=Ph
Y
X
5
N1-O cleavage
CN
Ph
H
and aromatization
O
N
N
6
N
1b
+
1
X=Ph, Y=CN
N
6
R(OAc)3
13
Scheme 3. A mechanistic hypothesis for the formation of 5 and 6.
Early attempts to induce reaction of 1b with N-methyl-
maleimide in THF, both at room temperature and at reflux (Table 1,
entry 4), were unsuccessful. However, when the process was car-
ried out in dioxane/toluene (1:1) at reflux (entry 5) the C-6 de-
rivative 7 was obtained in a 60% yield as a 1:1 mixture of
diastereomers, once again through isoxazoline opening and oxi-
dation at the maleimide portion. The ratio of isomers in the ini-
tially-formed mixture varied with HPLC purification (silica column)
and/or on standing up to ca. 1:2, likely as a consequence of the
acidity of the C-6 proton next to the maleimide moiety. NMR data
could not provide unambiguous evidence on which is the major
diastereomer. Considering that the maleimide portion in 7 is sus-
ceptible to further synthetic modifications,18 access to C-6 mal-
eimido-derivatives, such as 7 opens the way to the preparation of
more complex and functionalised C-6 nucleoside derivatives.
Maleimido- or N-methylmaleimido-containing substances, both of
natural and non-natural origin, usually display significant bi-
ological properties. For example, showdomycin19 is a potent nu-
cleoside antibiotic isolated from Streptomyces showdoensis, while
bisindolylmaleimides are known to be potent protein kinase C
(PKC) inhibitors.20
Scheme 2. A mechanistic hypothesis for the formation of 2 and 4.
Finally, diphenylacetylene failed to react with 1b also on pro-
longed reflux both in THF and dioxane (Table 1, entry 6). Similar
results were obtained with dimethyl maleate and dimethyl fuma-
rate on reflux in toluene, also using excess reagents (Table 1, entry
7). The above results showed that nebularine oxide derivative 1b
displays the characteristic reactivity of nitrones towards electron-
poor dienophiles.
To further test the nitrone reactivity showed by 1a, we next
investigated the reaction of sugar-silylated 1c with some repre-
sentative Grignard reagents. It is known that nitrones smoothly
undergo nucleophilic addition of organometallic reagents. Indeed,
treatment of 1c with a 2-fold excess of a Grignard reagent afforded
the C-6 C-substituted N1-hydroxy adducts 14 as single products
(Table 2 and Scheme 4). These substances slowly decomposed on
standing, partly giving dehydration to C-6 substituted nebularine
derivatives 15e18. This process was pushed towards the latter
As for compound 4, Stauss et al.17 reported formation of 2-
methyl-4-phenyl-5H-benzo[d][1,3]diazepin-5-carboxylic acid es-
ters as by-products of the reaction of 2-methyl-4-phenyl-quina-
zoline 3-oxide with dimethyl and diethyl acetylenedicarboxylates
and a plausible mechanistic hypothesis was given for the reaction
path leading to the benzodiazepine system. In particular, formation
of a cyclopropane-containing intermediate was postulated to be
responsible for the pyrimidine ring enlargement. In a similar way, it
is conceivable that the seven-membered ring in 4 can originate
from the electrocyclic opening of an aziridine-containing in-
termediate (11, Scheme 2), in turn formed by the fragmentation/
rearrangement of the initial adduct 8 (route b). The ring-enlarged
compound 12 would once again undergo elimination of the
a-
ketoester side-chain possibly via nucleophilic attack at the ketone
carbonyl during work-up.

S. D’Errico et al. / Tetrahedron 67 (2011) 6138e6144
6141
substances in nearly quantitative yields, by treatment of the crude
C6-adducts with Ac2O in pyridine (6:4) at 50 ꢁC. Formation of
15e18 indicated, as reported in the literature,21 the more electro-
philic nature of the C-6 atom of the nucleobase when compared to
the C-2 atom. The structure of the obtained compounds was
ascertained by high-field 2D NMR and comparison with literature
data (see Experimental section).
NMR spectra were performed on a Varian Mercury Plus 400 MHz
and Varian Unity Inova 700 MHz in CDCl3, CD3OD or DMSO-d6
solvents. Chemical shifts are reported in parts per million (d) rela-
tive to the residual solvent signals: CHCl3 7.27, CD2HOD 3.31,
CD2HSOCD3 2.49 for 1H NMR; CDCl3 77.0, CD2HOD 49.0,
CD2HSOCD3 39.5 for 13C NMR. 1H NMR chemical shifts were
assigned by 2D-NMR experiments. The abbreviations s, br s, d, dd
and m stand for singlet, broad singlet, doublet, doublet of doublets
and multiplet, respectively. HPLC analyses and purifications were
carried out on a Jasco UP-2075 Plus pump equipped with a Jasco
UV-2075 Plus UV detector using a 4.60ꢂ150 mm LUNA (Phenom-
Table 2
Reaction of 1c with Grignard reagents
Entry
Grignard reagent (equiv)
Conditions
(solvent)
Products (yield%,
over two steps)
enex) silica column (particle size 5 mm) eluted with a linear gra-
dient of AcOEt in hexane (from 50 to 100% in 30 min, flow
1.0 mL minꢀ1, system A; from 80 to 100% in 30 min, flow
1.0 mL minꢀ1, system B; from 50 to 100% in 60 min, flow
1.0 mL minꢀ1, system C) or using a 4.8ꢂ150 mm C-18 reverse-phase
1
2
3
4
Methylmagnesium bromide (2)
Vinylmagnesium bromide (2)
Phenylmagnesium bromide (2)
Propinylmagnesium bromide (2)
rt, 2 h (THF)
rt, 2 h (THF)
rt, 2 h (THF)
rt, 2 h (THF)
15 (82%)
16 (71%)
17 (82%)
18 (80%)
column (particle size 5
mm) eluted with a linear gradient of MeOH
-O
N
HO
R'
N
R'
N
6
N
N
N
N
N
N
R'MgBr, THF
(2 equiv.), 2h, r.t.
Ac2O-pyridine
(6:4), 1h, 50°C
N
O
N
N
O
O
RO
RO
RO
RO
OR
RO
OR
RO
OR
15 R'= Me
14 Mixture of C-6
1c R=TBDMS
16 R'= CH=CH2
17 R'= Ph
diastereomers
18 R'= C CMe
Scheme 4. Reaction of 1c with representative Grignard reagents.
Overall, reaction of 1c with Grignard reagents is of general ap-
plicability, working well with various types of substituents on the
organometallic partner, leading to compounds 15e18 in good yields
comparable22 to, or better7,23 than, those reported in the literature.
It is worth noting that our process allows the direct introduction of
a C-substituent on C-6 without using a metal catalyst. Based on
both the facile reaction and purification procedures it is conceivable
that the process can be easily performed on gram scale opening the
way to obtain large amounts of C-6 C-substituted nucleosides
without employing different reaction conditions.
in H2O (from 0 to 100% in 60 min, flow 1.0 mL minꢀ1, system D). UV
spectra were recorded on a Jasco V-530 UV spectrophotometer.
High Resolution MS spectra were recorded on a Bruker APEX II FT-
ICR mass spectrometer using electrospray ionization (ESI) tech-
nique in positive mode. IR spectra were recorded on a Jasco FT-
IRFTIR 430 spectrophotometer. Optical rotations were determined
on a Jasco polarimeter using a 1 dm cell at 20 ꢁC; concentrations are
in g/100 mL. Column chromatography was performed on silica gel
(Merck, Kieselgel 60, 0.063e0.200 mm). Analytical TLC analyses
were performed using F254 silica gel plates (0.2 mm, Merck). TLC
spots were detected under UV light (254 nm).
3. Conclusions
4.2. Synthesis of 20,30,50-tri-O-acetyl-nebularine N1-oxide (1b)
In conclusion, an unprecedented approach to the C-6 C-func-
tionalization of the purine nucleoside base system has been ex-
plored. In some cases, 1,3-DC reactions led to unexpected,
structurally intriguing, products through new reaction pathways.
Studies are in progress to investigate the scope of the described
processes as well as to further explore the synthetic potential of
nebularine N1-oxide. Since purine nucleosides, such as 14, em-
bodying the 6,9-dihydro-1H-purin-1-ol moiety are unprecedented,
future efforts will also focus on using these addition products to
prepare nucleoside analogues possessing novel modifications on
the base system. We believe that the developed procedures may
have future synthetic applications.
Nebularine was acetylated overnight with Ac2Oepyridine under
standard conditions to give essentially pure triacetate. A mixture of
MeReO3 (5 mg, 0.02 mmol) and 30% aqueous H2O2 (0.4 mL,
4.0 mmol) in methanol (6 mL) was stirred at room temperature for
10 min. Then crude 20,30,50-tri-O-acetyl-nebularine (378 mg,
1.0 mmol) in methanol (4 mL) was added dropwise while stirring.
Stirring was continued at room temperature overnight. Then the
solvent was removed under reduced pressure and the crude was
purified on a silica gel column eluted with increasing amounts of
MeOH in CHCl3 (from 0 to 10%) to afford pure 20,30,50-tri-O-acetyl-
nebularine N1-oxide 1b (315 mg, 80% over two steps).
Compound 1b: white foam; ½a D20
ꢃ
ꢀ16.1 (c 0.13, CH3OH), 1H NMR
4. Experimental section
4.1. General methods
(400 MHz, CD3OD) dH 9.16 (d, J¼1.8 Hz, 1H), 9.04 (d, J¼1.8 Hz, 1H),
8.76 (s, 1H), 6.34 (d, J¼5.0 Hz,1H), 6.03e5.98 (m, 1H), 5.69e5.65 (m,
1H), 4.52e4.48 (m, 1H), 4.44 (dd, J¼12.2, 3.5 Hz, 1H), 4.39 (dd,
J¼12.2, 4.9 Hz, 1H), 2.14 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H); 13C NMR
(100 MHz, CD3OD) dC 172.1, 171.3, 171.1, 150.5, 146.4, 145.3, 139.3,
135.5, 88.5, 81.7, 74.2, 71.7, 64.0, 20.6, 20.4, 20.2; m/z (HRESIMS)
All reagents were obtained from commercial sources (Sigmae
Aldrich) and were used without further purification. 1H and 13C

6142
S. D’Errico et al. / Tetrahedron 67 (2011) 6138e6144
395.1212 ([MþH]þ, C16H19N4O8, requires 395.1203); IR (neat) nmax
1748, 1495, 1424, 1369, 1229 cmꢀ1; UV (MeOH) lmax 242, shoulder
267 nm.
Compound 6: oil; ½a D20
ꢃ
ꢀ6.33 (c 0.6, CH3OH), 1H NMR (400 MHz,
CD3OD) dH 9.10 (s, 1H, H-2), 8.71 (s, 1H, H-8), 8.00e7.95 (m, 2H, Ph
ortho-H), 7.73e7.67 (m, 1H, Ph para-H), 7.57e7.51 (m, 2H, Ph meta-
0
0
0
0
H), 6.41 (d, J1 ,2 ¼5.0 Hz, 1H, H-1 ), 6.16e6.12 (m, 1H, H-2 ),
5.78e5.75 (m, 1H, H-30), 4.53e4.39 (complex signal, 3H, H-40 and
Ha,b-50), 2.16 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.06 (s, 3H, CH3); 13C
NMR (100 MHz, CD3OD) dC 192.8, 172.3, 171.4, 171.1, 154.7, 154.0,
152.9, 148.3, 136.6, 135.6, 133.4, 131.8, 129.6, 88.8, 81.8, 74.5, 71.9,
64.1, 20.9, 20.5, 20.4; IR (neat) nmax 1747, 1674, 1582, 1226 cmꢀ1; m/z
(HRESIMS) 483.1522 ([MþH]þ, C23H23N4O8, requires 483.1516); UV
(MeOH) lmax 265 nm.
4.3. Reaction of 1b with dimethyl acetylenedicarboxylate.
Synthesis of 2e4
A solution of 1b (50 mg, 0.13 mmol) and dimethyl acetylene-
dicarboxylate (18 mg, 0.13 mmol) in dry THF (2.5 mL) was stirred at
room temperature. After 2 h the process was complete (TLC mon-
itoring, AcOEt/MeOH, 95:5) and the solvent was evaporated under
reduced pressure. The crude was purified on a silica gel column
eluted with increasing amounts of MeOH in AcOEt (from 0 to 20%)
affording two main products: compound 2 (16 mg, 25%) and 4
(23 mg, 40%). The purity of 4 was checked by HPLC analysis (System
A, tR¼30.0 min see General methods). Compound 2 (10 mg,
0.021 mmol) was treated with a concentrated aqueous solution of
NH4OH (0.5 mL) in MeOH (0.5 mL) for 30 min at room temperature.
The solvent was removed in vacuo and the crude was desalified by
RP-HPLC (System D, tR¼18.8 min, see General methods) to give pure
3 (7.4 mg, 99%).
4.5. Reaction of 1b with N-methylmaleimide. Synthesis of 7
A solution of 1b (5 mg, 0.013 mmol) and N-methylmaleimide
(14 mg, 0.13 mmol), in dioxane/toluene (1:1, v/v, 2.5 mL) was
refluxed. After 5 h the process was complete (TLC monitoring,
AcOEt/MeOH, 95:5) and the solvent was removed under reduced
pressure. The crude was purified by HPLC (System B, tR¼16.0 min,
see General methods) affording 7 (4.0 mg, 60%) as an inseparable
mixture of diastereomers.
Compound 7: oil; 1H NMR (400 MHz, CD3OD) dH (mixture of di-
astereomers) 8.95 (s, 0.3H), 8.64 (s, 0.3H), 8.23 (s, 0.7H), 8.09 (s, 0.7H),
6.36 (d, J¼4.5 Hz, 0.3H), 6.19 (d, J¼5.1 Hz, 0.7H), 6.15e6.11 (m, 1H,
0.3H), 5.98e5.92(m, 0.7H), 5.80e5.73 (m, 0.3H), 5.69e5.62(m, 0.7H),
5.29 (s, 0.7H), 5.16 (d, J¼2.7 Hz, 0.3H), 4.51e4.32 (complex signal, 3H),
3.06 (s, 0.9H), 3.01 (s, 2.1H), 2.14 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.07 (s,
3H, CH3); 13C NMR (100 MHz, CD3OD) dC 177.4, 172.2, 171.3, 171.2,
153.7, 147.0, 146.2, 145.0, 141.4, 123.9, 89.0, 88.4, 88.2, 81.7, 74.6, 74.2,
73.9, 71.8, 69.1, 64.1, 25.4, 24.1, 20.7, 20.4, 20.3; IR (neat) nmax 3335,
Compound 3: white foam; ½a D20
ꢃ
ꢀ15.6 (c 0.50, CH3OH), 1H NMR
(400 MHz, CD3OD) dH 7.89 (s, 1H, H-2), 7.87 (s, 1H, HC]N), 7.71 (s,
0
0
0
0
1H, HC]C), 5.82 (d, J1 ,2 ¼4.8 Hz, 1H, H-1 ), 4.44e4.41 (m, 1H, H-2 ),
4.27e4.24 (m, 1H, H-30), 4.02e3.99 (m, 1H, H-40), 3.87 (s, 3H,
0
0
0
0
0
CH3OC]N), 3.82 (dd, J5 a,5 b¼12.1, J5 a,4 ¼3.2 Hz, 1H, Ha-5 ), 3.72 (dd,
J5 b,5 a¼12.2, J5 b,4 ¼3.8 Hz, 1H, Hb-5 ), 3.63 (s, 3H, CH3OC]O); 13C
NMR (100 MHz, CD3OD) dC 171.4, 158.9, 150.4, 134.7, 133.1, 118.9,
92.7, 89.3, 85.7, 76.0, 71.2, 62.3, 53.9, 51.2; m/z (HRESIMS) 357.1421
([MþH]þ, C14H21N4O7, requires 357.1410); IR (neat) nmax 3330, 1634,
1575 cmꢀ1; UV (MeOH) lmax 271 nm.
0
0
0
0
0
1740, 1699, 1584 cmꢀ1
C21H24N5O10, requires 506.1523); UV (MeOH) lmax 267, 346 nm.
;
m/z (HRESIMS) 506.1531 ([MþH]þ,
Compound 4: oil; 1H NMR (700 MHz, DMSO-d6) dH (major
tautomer) 8.90 (s, 1H, H-5), 8.77 (s, 1H, H-2), 6.34 (d, J¼5.3 Hz, 1H,
H-10), 6.10e6.07 (m, 1H, H-20), 5.68e5.63 (m, 1H, H-30), 4.42e4.39
4.6. Preparation of 20,30,50-tri-O-(tert-butyldimethylsilyl)-
nebularine N1-oxide
(complex signal, 2H, H-40 and Ha-50), 4.25 (dd, J5 b,5 a¼12.9,
0
0
0
0
0
J5 b,4 ¼6.0 Hz,1H, Hb-5 ), 4.20 and 4.19 (br s,1H each, Ha,b-8), 3.63 (s,
20,30,50-Tri-O-(tert-butyldimethylsilyl)-nebularine was prepared
as described.9b A mixture of MeReO3 (5 mg, 0.02 mmol) and 30%
aqueous H2O2 (0.4 mL, 4.0 mmol) in methanol (6 mL) was stirred at
room temperature for 10 min. Then 20,30,50-tri-O-(tert-butyldime-
thylsilyl)-nebularine9b (595 mg, 1.0 mmol) in methanol (6 mL) was
dropwise added while stirring. The stirring was continued at room
temperature overnight. Then the solvent was removed under re-
duced pressure and the crude was purified on a silica gel column
eluted with increasing amounts of AcOEt in hexane (up to 20%) to
afford pure 20,30,50-tri-O-(tert-butyldimethylsilyl)-nebularine N1-
oxide 1c (513 mg, 84% yield).
3H, OCH3), 2.12 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1.99 (s, 3H, CH3). 13
C
NMR (175 MHz, CD3OD) dC 169.9, 169.4, 169.2 (two carbons), 154.5,
151.9, 150.3, 145.4, 132.9, 85.9, 79.5, 71.8, 69.9, 62.6, 51.9, 38.0, 20.4,
20.3, 20.1; IR (neat) nmax 1746, 1598, 1223 cmꢀ1; m/z (HRESIMS)
451.1451 ([MþH]þ, C19H23N4O9, requires 451.1465); UV (MeOH)
lmax 263 nm.
4.4. Reaction of 1b with 3-phenyl-2-propynenitrile. Synthesis
of 5 and 6
A
solution of 1b (50 mg, 0.13 mmol) and 3-phenyl-2-
Compound 1c: white solid, mp 126e127 ꢁC; ½a D20
ꢀ16.1 (c 0.80,
ꢃ
propynenitrile (14 mg, 0.16 mmol), in dioxane (2.5 mL) was
refluxed for 4 h (TLC monitoring, AcOEt/hexane, 8:2) and then the
solvent was evaporated under reduced pressure. The crude was
purified on a silica gel column eluted with increasing amounts of
AcOEt in hexane (from 50 to 100%) to give 5 (30 mg, 45%) and 6
(19 mg, 30%), the purity of which was checked by HPLC analysis
(System C, 5 tR¼22.3 min; 6 tR¼18.2 min, see General methods).
CHCl3), 1H NMR (400 MHz, CD3OD) dH 9.16 (br s, 1H), 9.02 (br s, 1H),
8.88 (s, 1H), 6.12 (d, J¼4.7 Hz, 1H), 4.91e4.87 (m, 1H), 4.75e4.70 (m,
1H), 4.44e4.40 (m, 1H), 4.06 (dd, J¼11.5, 4.1 Hz, 1H), 3.86 (dd,
J¼11.5, 2.4 Hz, 1H), 0.95 (br s, 18H), 0.82 (s, 9H), 0.15 (br s, 9H), 0.13
(s, 3H), 0.03 (s, 3H), ꢀ0.18 (s, 3H); 13C NMR (100 MHz, CD3OD) dC
150.0, 146.4, 145.6, 139.2, 135.2, 90.1, 87.0, 77.2, 72.9, 63.4, 26.5, 26.4,
26.2, 19.3, 18.9, 18.7, ꢀ4.0, ꢀ4.3, ꢀ4.7, ꢀ5.1, ꢀ5.3; m/z (HRESIMS)
633.3312 ([MþH]þ, C28H54N4NaO5Si3, requires 633.3300); IR (neat)
nmax 2930, 2858, 1255, 1139, 837, 778 cmꢀ1; UV (CHCl3) lmax 280,
253 nm.
Compound 5: white solid mp 116e117 ꢁC; ½a D20
ꢀ50.6 (c 0.11,
ꢃ
CH3OH), 1H NMR (400 MHz, CD3OD) dH 8.62 (s, 1H, H-2), 8.46 (s, 1H,
H-8), 7.83e7.78 (m, 2H, Ph ortho-H), 7.54e7.50 (m, 1H, Ph para-H),
0
0
0
7.49e7.44 (m, 2H, Ph meta-H), 6.33 (d, J1 ,2 ¼5.0 Hz, 1H, H-1 ),
6.00e5.96 (m, 1H, H-20), 5.69e5.66 (m, 1H, H-30), 4.52e4.36
(complex signal, 3H, H-40 and Ha,b-50), 2.14 (s, 3H, CH3), 2.08 (s, 3H,
CH3), 2.07 (s, 3H, CH3); 13C NMR (175 MHz, CD3OD) dC 194.7, 172.2,
171.4, 171.2, 152.2, 149.1, 145.3, 143.5, 140.7, 132.3, 129.0, 125.1, 121.7,
88.4, 81.8, 74.6, 71.8, 64.1, 20.6, 20.5, 20.3; IR (neat) nmax 2205, 1742,
1616, 1239 cmꢀ1; m/z (HRESIMS) 522.1620 ([MþH]þ, C25H24N5O8,
requires 522.1625); UV (MeOH) lmax 364 nm.
4.7. General procedure for reaction of 1c with Grignard
reagents. Synthesis of 15e18
In a flamed round-bottomed flask charged with dry nitrogen, 1c
(50 mg, 0.082 mmol), dissolved in dry THF (0.5 mL), was added via
cannula. To the flask the Grignard reagent (2 equiv) in THF was
slowly added and the mixture was stirred for 2 h (TLC monitoring:

S. D’Errico et al. / Tetrahedron 67 (2011) 6138e6144
6143
hexane/AcOEt, 4:6) at room temperature. The reaction was
quenched by addition of a 1 M solution of NH4Cl (1 mL), diluted
with AcOEt (10 mL) and extracted with brine (1 mL). The organic
layer was separated, dried (Na2SO4), filtered and concentrated
under rotary evaporation. The crude was dissolved in a mixture of
Ac2Oepyridine (6:4, 0.5 mL) and the solution was kept at 50 ꢁC for
1 h. The crude was evaporated in vacuo and purified over a silica gel
column eluted with increasing amounts of EtOAc in hexane (up to
20%). The fractions containing the product were collected and
evaporated to afford pure 15e18.
Originali) for financial support. The authors are thankful to Dr. Luisa
Cuorvo for technical assistance.
References and notes
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2001, 8, 385.
4.7.1. 20,30,50-Tri-O-(tert-butyldimethylsilyl)-6-methyl nebularine 15.
Compound 15: white solid (41 mg, 82% yield), ½a D20
ꢀ36.8 (c 0.50,
ꢃ
CH3OH), mp 74e76 ꢁC; 1H NMR (400 MHz, CDCl3) dH 8.83 (s, 1H, H-
2), 8.38 (s, 1H, H-8), 6.11 (d, J¼5.2 Hz,1H, H-10), 4.72e4.66 (m, 1H, H-
20), 4.34e4.32 (m,1H, H-30), 4.17e4.12 (m,1H, H-40), 4.02 (dd, J¼11.4,
0
0
3.9 Hz, 1H, H-5a ), 3.79 (dd, J¼11.4, 2.5 Hz, 1H, H-5b ), 2.87 (s, 3H,
CH3), 0.99 (s, 9H, C(CH3)3), 0.94 (s, 9H, C(CH3)3), 0.78 (s, 9H, C(CH3)3),
0.15 (s, 3H, CH3), 0.14 (s, 3H, CH3), 0.11 (br s, 6H, 2ꢂ CH3), 0.05 (s, 3H,
CH3), ꢀ0.28 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) dC 159.2, 152.2,
150.4, 142.7, 133.5, 88.2, 85.6, 75.8, 72.0, 62.5, 19.5, 18.5, 18.1, 17.8,
ꢀ4.4, ꢀ4.6, ꢀ4.7, ꢀ5.1, ꢀ5.4; m/z (HRESIMS) 609.3679 ([MþH]þ,
C29H57N4O4Si3, requires 609.3688); IR (neat) nmax 2955, 2930, 2859,
1599, 1256, 837, 777 cmꢀ1; UV (CHCl3) lmax 260 nm.
3. (a) Hocek, M. Eur. J. Org. Chem. 2003, 245; (b) Bork, J. T.; Lee, J. W.; Chang, Y. T.
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Czech. Chem. Commun. 2006, 71, 788; (e) Nagy, A.; Kotschy, A. Tetrahedron Lett.
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4.7.2. 20,30,50-Tri-O-(tert-butyldimethylsilyl)-6-vinyl nebularine 16.
Compound 16: colourless oil22 (37 mg, 71% yield); ½a 2D0
ꢀ44.6 (c
ꢃ
0.51, CH3OH), 1H NMR and 13C NMR data are in agreement with
reported data;22 m/z (HRESIMS) 621.3681 ([MþH]þ, C30H57N4O4Si3,
requires 621.3688); IR (neat) nmax 2931, 2859, 1583, 1256, 837,
778 cmꢀ1; UV (CHCl3) lmax 285 nm.
ꢁ
6. (a) Veliz, E. A.; Beal, P. A. J. Org. Chem. 2001, 66, 8592; (b) Fleysher, M. H.; Bloch,
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Messere, A.; Montesarchio, D.; Piccialli, G.; Santacroce, C.; Varra, M. J. Chem. Soc.,
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istry; Padwa, A., Ed.; John: New York, NY, 1984; (b) Confalone, P. N.; Huie, E. M.
Org. React.1988, 36,1; (c) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates
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Lombardo, M.; Trombini, C. Synthesis 2000, 759; (l) Merino, P. In Science of Syn-
thesis; Padwa, A., Ed.; Thieme: Stuttgart, Germany, 2004; Vol. 27; (m) Merino, P.;
Franco, S.; Merchan, F. L.; Tejero, T. Synlett 2000, 442; (n) Lombardo, M.; Trombini,
C. Curr. Org. Chem. 2002, 6, 695.
4.7.3. 20,30,50-Tri-O-(tert-butyldimethylsilyl)-6-phenyl nebularine 17.
Compound 17: colourless oil (45 mg, 82% yield); ½a D20
ꢀ96.4 (c 0.11,
ꢃ
CH3OH) 1H NMR (400 MHz, CDCl3) dH 9.01 (s, 1H, H-2), 8.82e8.75
(m, 2H, HPh), 8.46 (s, 1H, H-8), 7.61e7.49 (m, 3H, HPh), 6.18 (d,
J¼5.4 Hz,1H, H-10), 4.78e4.72 (m,1H, H-20), 4.38e4.32 (m,1H, H-30),
0
4.19e4.14 (m, 1H, H-40), 4.05 (dd, J¼11.3, 4.1 Hz, 1H, H-5a ), 3.82 (dd,
0
J¼11.3, 2.8 Hz, 1H, H-5b ), 0.97 (s, 9H, C(CH3)3), 0.96 (s, 9H, C(CH3)3),
0.79 (s, 9H, C(CH3)3), 0.16 (s, 3H, CH3), 0.15 (s, 3H, CH3), 0.13 (br s, 6H,
2ꢂ CH3), 0.03 (s, 3H, CH3), ꢀ0.25 (s, 3H, CH3); 13C NMR (100 MHz,
CDCl3) dC 154.9, 152.3, 143.3, 135.7, 131.6, 130.9, 129.8, 128.6, 88.2,
85.7, 75.7, 72.1, 62.6, 26.1, 25.8, 25.6, 18.5, 18.1, 17.8, ꢀ4.4, ꢀ4.6, ꢀ4.7,
ꢀ5.0, ꢀ5.3, ꢀ5.4; m/z (HRESIMS) 693.3649 ([MþNa]þ,
C34H58N4NaO4Si3, requires 693.3664); IR (neat) nmax 2954, 2930,
2858, 1579, 1567, 1256, 836, 777 cmꢀ1; UV (CHCl3) lmax 291 nm.
9. (a) Nair, V.; Richardson, S. G. J. Org. Chem. 1980, 45, 3969; (b) Kati, W. M.;
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4.7.4. 20,30,50-Tri-O-(tert-butyldimethylsilyl)-6-propynyl nebularine
18. Compound 18: colourless oil (41 mg, 80% yield); ½a D20
ꢀ61.3 (c
ꢃ
0.12, CH3OH) 1H NMR (700 MHz, CDCl3) dH 8.88 (s, 1H, H-2), 8.46 (s,
1H, H-8), 6.12 (d, J¼5.2 Hz, 1H, H-10), 4.66e4.62 (m, 1H, H-20),
4.31e4.28 (m, 1H, H-30), 4.16e4.13 (m, 1H, H-40), 4.01 (dd, J¼11.4,
12. Freeman, J. P. Chem. Rev. 1983, 63, 241.
0
0
3.9 Hz, 1H, H-5a ), 3.80 (dd, J¼11.4, 2.5 Hz, 1H, H-5b ), 2.25 (s, 3H,
CH3), 0.95 (s, 9H, C(CH3)3), 0.93 (s, 9H, C(CH3)3), 0.77 (s, 9H,
C(CH3)3), 0.15 (s, 3H, CH3), 0.14 (s, 3H, CH3), 0.10 (br s, 6H, 2ꢂ CH3),
0.05 (s, 3H, CH3), ꢀ0.29 (s, 3H, CH3); 13C NMR (175 MHz, CDCl3) dC
152.5, 151.2, 143.9, 142.2, 134.7, 97.1, 88.1, 85.8, 76.0, 75.3, 72.0, 62.5,
26.0, 25.8, 25.6, 18.5, 18.0, 17.8, 5.1, ꢀ4.4, ꢀ4.6, ꢀ4.7, ꢀ5.1, ꢀ5.3; m/z
(HRESIMS) 655.3519 ([MþNa]þ, C31H56N4NaO4Si3, requires
655.3507); IR (neat) nmax 2956, 2859, 2243, 1580, 1259, 837,
776 cmꢀ1; UV (CHCl3) lmax 286 nm.
13. (a) Erion, D. M.; Kasibhatla, S. R.; Bookser, B. V.; van Poelje, P. D.; Reddy, R. M.;
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15. Yamanaka, H.; Nitsuma, S.; Sakamoto, T.; Mizugaki, M. Chem. Pharm. Bull. 1979,
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Acknowledgements
We are grateful to the ‘Polo delle Scienze e delle Tecnologie per
la Vita’ (Progetto F.A.R.O., Finanziamento per l’Avvio di Ricerche
€
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