Rearrangement Reactions of 1,N2-Isopropenoguanine Cyclonucleosides

Article abstract of DOI:10.1081/NCN-120027821

Under acid-catalyzed transglycosylation conditions 5′ ,8-cyclo-8-oxo-1,N²-isopropenoguanine nucleosides (1, 10) undergo a ring-opening reaction to 8-oxo-1,N²-isopropenoguanosine derivatives (4, 11) followed by recyclization to fluorescent 5′,3-cyclonucleosides (2, 12).

Full text of DOI:10.1081/NCN-120027821

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Rearrangement Reactions of 1,N 2‐Isopropenoguanine
Cyclonucleosides
Tomasz Zandecki a & Jerzy Boryski a
a Institute of Bioorganic Chemistry , Polish Academy of Sciences , Noskowskiego 12/14,
PL‐61704, Poznan, Poland
Published online: 01 Jun 2007.
To cite this article: Tomasz Zandecki & Jerzy Boryski (2004) Rearrangement Reactions of 1,N 2‐Isopropenoguanine
Cyclonucleosides , Nucleosides, Nucleotides and Nucleic Acids, 23:1-2, 117-126, DOI: 10.1081/NCN-120027821
To link to this article: http://dx.doi.org/10.1081/NCN-120027821
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, Nos. 1 & 2, pp. 117–126, 2004
Rearrangement Reactions of
1,N2-Isopropenoguanine Cyclonucleosidesy
*
Tomasz Zandecki and Jerzy Boryski
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
ABSTRACT
Under acid-catalyzed transglycosylation conditions 5’ ,8-cyclo-8-oxo-1,N2-isoprope-
noguanine nucleosides (1, 10) undergo a ring-opening reaction to 8-oxo-1,N2-
isopropenoguanosine derivatives (4, 11) followed by recyclization to fluorescent 5’ ,3-
cyclonucleosides (2, 12).
Key Words: Cyclonucleosides; Transglycosylation; Wyosine analogs.
INTRODUCTION
Tricyclic analogs of guanosine occur in nature as the so called Y nucleosides,
fluorescent components of the anticodon loop of tRNAPhe from a variety of organisms,
and the simplest representative of their family is wyosine, isolated from Torulopsis
utilis.[1] The Y nucleosides are structurally related to guanosine. A direct modifica-
tion of guanosine in the reaction with bromoacetone leads to 4-desmethylwyosine, i.e.
yIn honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
*
Correspondence: Jerzy Boryski, Institute of Bioorganic Chemistry, Polish Academy of Sciences,
Noskowskiego 12/14, PL-61704, Poznan, Poland; Fax: +4861-852-05-32; E-mail: jboryski@ibch.
poznan.pl.
117
DOI: 10.1081/NCN-120027821
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

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Zandecki and Boryski
1,N2-isopropenoguanosine.[1,2]a Some of its analogs substituted with pseudosugar chains
exhibit potent and selective antiviral activity.[3,4]
Similarly to other fully protected 6-oxopurine nucleosides (e.g. guanosine, inosine),
derivatives of 1,N2-isopropenoguanosine readily undergo a reversible 7>9 transglyco-
sylation in the presence of acidic catalysts.[5] The reaction proceeds via unstable 7,9-
diglycosylpurine intermediates,[6] and only N7 and N9 of the imidazole ring may act as
donors or acceptors of a glycosyl cation.[5–8] Transglycosylation reaction is an in-
termolecular process and therefore, the 6-oxopurine nucleosides may serve as versatile
substrates in the synthesis of new nucleoside analogs by applying the exchange
methods.[5,9–11]
More recently, the possibility of an intramolecular transglycosylation reaction has
been studied in the case of guanine 5’ ,8-cyclo-8-oxo-nucleosides. The cyclonucleosides
of this type, however, do not undergo the anticipated 7>9 isomerization when
subjected to transglycosylation conditions (refluxing in chlorobenzene in the presence
of p-toluenesulfonic acid). Instead of the cleavage of N-glycosylic bond, which would
be required for the isomerization reaction, the 5’ ,8-oxygen bridge is cleaved, and this
results in the formation of 5’ -tosyl-8-oxoguanine derivatives.[12]
In continuation of our study on transglycosylation reactions in the purine cyclo-
nucleoside series, we present in this report the rearrangement reactions of 1,N2-
isopropenoguanosine derivatives, in which the sugar portion and the purine part are
linked together with an additional chemical bond.
RESULTS AND DISCUSSION
The model compound for this study, 8,5’ -Cyclo-8-oxo-2,’ 3’ -O-isopropylidene-
1,N2isopropenoguanosine (1),[13] was prepared from 5’ ,8-cyclo-8-oxo-2’ ,3’ -O-isopropy-
lideneguanosine.[14] The compound was then subjected to the typical conditions for
transglycosylation reaction, i.e. heating in chlorobenzene in the presence of p-
toluenesulfonic acid (0.25 eqs.). The first experiment was performed at a reflux
temperature (132°C). Surprisingly, the reaction resulted in two new fluorescent
products (Scheme 1). The fluorescence and characteristic UV spectrum (maxima at 238
and 306 nm) of the main product might suggest a 3-substitution of the tricyclic
aglycon.[1,2,13] Indeed, the NMR spectra confirmed the structure of 3,5’ -cyclo-8-oxo-
2,’ 3’ -O-isopropylidene-1,N2-isopropenoxoguanosine (2)—an isomer of the substrate 1
(yield 41%). In particular, the signal of C5’ in the 13C NMR spectrum was shifted to
53.94 ppm (73.98 ppm in the spectrum of 1). The second compound, obtained as a
side-product (yield 7.7%), was of a more complicated structure. Two sets of signals in
the proton and carbon NMR, as well as a high molecular weight of MH+ seen in mass
spectrum, showed that the product 3 was a dimer. Its structure was fully elucidated by
using two-dimensional NMR techniques and comparison with spectra of 2: one
fragment of the dimer was identical with the 5’ ,3-cyclonucleoside 2, but substituted at
N7 with a residual portion of an ‘‘opened’’ substrate 1. The structures of 2 and 3
suggested a possible mechanism of this rearrangement—the reaction to a new
aSystematic name: 3,9-dihydro-9-oxo-3-(b-D-ribofuranosyl)-5H-imidazo[1,2-a]purine.

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119
Scheme 1. Reagents and conditions: i, p-TsOH, C6H5Cl, reflux, 3 h; ii, p-TsOH, C6H5Cl,
120°C, 3 h.
cyclonucleoside system could proceed exclusively with a cleavage of the 5’ ,8-oxygen
bridge. Indeed, the reaction repeated at lower temperature (120°C) in the presence of
0.1 molar eq. of p-toluenesulfonic acid afforded a non-fluorescent reaction intermediate,
5’ -(p-toluenesulfonyl)-2,’ 3’ -O-isopropylidene-8-oxo-1,N2-isopropenoguanosine (4; yield
1.4%), in addition to already known 2 and 3 (Scheme 1). The isolated compound 4
underwent a quantitative conversion to cyclonucleoside 2 (but not to the dimer 3!) when
heated in chlorobenzene.
Basing on these experimental data, we have proposed a possible mechanism of the
observed rearrangement (Scheme 2). The starting 5’ ,8-cyclo-8-oxo compound (1) is
protonated at N7 (structure 5), and this facilitates a nucleophilic attack of the tosyl
anion at C5’ , leading to the formation of 4 (route A). Then, the tosyl derivative 4
undergoes a recyclization, which presumably takes place as a result of removal of N2H,
and intramolecular nucleophilic attack of N3 at C5’ . Perhaps the presence of 5’ -tosyl
substituent, a good leaving group, further facilitates the rearrangement. However,
there is another possibility of the ring-opening reaction of 5—an acid-catalyzed
cleavage of the N-glycosylic bond (pathway B). This closely resembles an initiation
step in transglycosylation of ‘‘regular’’ 6-oxopurine nucleosides.[5,8] The resulting
oxocarbenium cation 6 is then attacked by the N7 center of another molecule of 1 to
finally furnish the dimer 3, probably after a similar rearrangement of the cyclonucleo-
side portion as depicted in the pathway A. An alternative mechanism assuming the

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Zandecki and Boryski
Scheme 2. Mechanism of the formation of compounds 2 and 3.
direct reaction of 6 and 2 must be rejected because N7 in compound 2 cannot react
with sugar cations as being already substituted by proton.
To prove this mechanism, we have synthesized cyclonucleoside 7, an N2-methyl
analog of 1 (Scheme 3). Previously, the compound was obtained in methylation of 1
with diazomethane,[13] but in this work its preparation was simplified by using methyl
iodide in the presence of potassium carbonate.[15] Heating of 7 in the presence
of p-toluenesulfonic acid resulted in the formation of a tosyl derivative (8) as
a single reaction product. In the presence of triethylamine in chloroform, the compound
8 was converted to 7 to regain the only possible system of the starting 5’ ,8-cyclo-8-
oxonucleoside. A similar reversible transformation has been observed for 5’ ,8-cyclo-8-
Scheme 3. Reagents and conditions: i, CH3I, K2CO3, DMF, RT, 1 h; ii, p-TsOH, C6H5Cl, reflux,
1.5 h; iii, Et3N, CH3Cl, 48°C, 5 h.

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121
oxo-2’ ,3’ -O-isopropylidene-N2-acetylguanosine.[12] Therefore, the presence of unsubsti-
tuted N2H as well as the tricyclic system of the 1,N2-etheno type are necessary for the so
far unknown isomerization of 5’ ,8-cyclonucleosides into the fluorescent ones of the 5’ ,3-
cyclic structure. These structural features were met in the case of another model
compound, 1,N2-isopropeno-tetrahydro-1,5,3-dioxazepine[3,2-e]guanine (10) which was
obtained from acyclovir via tetrahydro-1,5,3-dioxazepine[3,2-e]guanine (9).[16] The
isomerization reaction (Scheme 4) gave quite similar results to that of 1: a tosyl
intermediate 11 and the fluorescent cyclic compound 12 as a major product. Any dimeric
product of the type 3 was not observed in this reaction. This reflects lower stability of the
N-glycosylic bond of cyclonucleoside 1 in the ribo series in comparison with that of a
corresponding C–N bond of 10.
In conclusion, under acid-catalyzed transglycosylation conditions 5’ ,8’ -cyclo-8-
oxonucleosides of 1,N2-isopropenoguanine undergo a new isomerization reaction to the
5’ ,3-cyclo-8-oxonucleosides, and this may indicate a higher thermodynamic stability of
the latter. In fact, the reaction is related to the cyclization of 4-desmethylwyosine.[1,17]
This is the main difference when compared to the corresponding guanine cyclonucleo-
sides, in which the reaction is stopped at the 5’ -tosyl-8-oxo stage.[12] Removal of the
proton N2H seems to be of a crucial importance for the rearrangement observed in the
1,N2-isopropenoguanine series. Neither isopropenoguanine cyclonucleosides nor
guanine cyclonucleosides undergo the 7>9 transglycosylation. However, the structure
of dimer 3 corresponds to that of 7,9-diglycosylpurine derivatives,[6] the unstable
intermediates in transglycosylation, decomposition of which leads to a mixture of 7-
and 9-regioisomers.[5,8] Unlike 7,9-diglycosylpurines of a quaternary character, dimer 3
is a quite stable reaction product due to the presence of 8-oxo group (no positive charge
in the imidazolium ring). This seems to explain the fact that 8-oxocyclonucleosides of
guanine and related heterocycles do not undergo the 7>9 transglycosylation.
EXPERIMENTAL
Melting points were determined on a Laboratory Devices Mel-Temp II micro-
melting points apparatus and are uncorrected. UV spectra were measured in methanol
on a Beckman DU-65 spectrophotometer. 1H and 13C NMR spectra were recorded
in DMSO-d6 on a Varian Unity 300 FT NMR spectrometer with tetramethysilane as an
internal standard, and chemical shifts are reported in d-values (ppm). Mass spectra were
taken on an AMD-604 spectrometer using the LSIMS technique (Cs+, 12 keV; in
NBA). Elemental analyses were performed on a Perkin–Elmer 240 Elemental Analyzer.
TLC was conducted on Merck silica gel F254 60 plates using the following solvent
systems (measured by volume): A, chloroform—methanol (9:1); B, toluene—ethanol
(4:1). For preparative short-column chromatography Merck TLC gel H 60 was used.
8,5’ -Cyclo-8-oxo-2,’ 3’ -O-isopropylidene-1,N2-isopropenoguanosine (1) was pre-
pared as described previously,[13] and tetrahydro-1,5,3-dioxazepine[3,2-e]guanine (9)
was obtained from acyclovir according to Madre et al.[16]
3,5’ -Cyclo-2,’ 3’ -O-isopropylidene-8-oxo-1,N2-isopropenoguanosine (2).
suspension of cyclonucleoside 1 (359 mg, 1.0 mmol) and p-toluenesulfonic acid
A
monohydrate (47.6 mg, 0.25 mmol) in chlorobenzene (20 mL) was stirred at 150°C for 3 h.

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Zandecki and Boryski
Scheme 4. Reagents and conditions: i, CH3COCH2Br, NaH, DMSO, RT, 1 h, then concd.
NH4OH, RT, 2.5 h; ii, p-TsOH, C6H5Cl, 120°C, 1.5 h.
After this time TLC showed two new fluorescent spots in addition to non-fluorescent
unreacted 1. The solvent was then evaporated, and the residue after evaporation was
applied on a silica gel short column. Separation of products in toluene-ethanol 9:1 gave the
main product, cyclonucleoside 2 as a solid foam (147 mg, 41%). Evaporation of the first
fractions afforded a side-product, the dimer 3 (27.5 mg, 7.7%). Analytical samples of both
compounds were crystallized from 50% aqueous EtOH.
Compound 2: mp > 300°C. Rf0.77(A); 0.56(B). lmax 238 nm (e 32,900), 306
(13,200). 1H NMR: 1.23, 1.45 (2s, 2 ꢀ 3, C > Me2), 2.21 (s, 3, CH3), 4.05 (dd,
Jgem = 17.1 Hz, 1, 5’ b-H), 4.69 (d, J = 5.7 Hz, 1, 3’ -H), 4.87 (d, J = 5.7 Hz, 1, 2’ -H),
4.90 (s, 1, 4’ -H), 5.10 (dd, Jgem = 17.1 Hz, 1, 5’ a-H), 5.92 (s, 1, 1’ -H), 7.37 (d, J = 1.2 Hz,
1, HC = C), 11.49 (s, 1, N7H). 13C NMR: 13.94 (CH3), 21.14, 25.68 (C > Me2), 53.94
(C-5’ ), 80.74 (C-2’ ), 83.30 (C-4’ ), 84.51 (C-3’ ), 88.20 (C-1’ ), 97.44 (C-5), 105.91
(HC = C), 112.05 (OCO), 136.81 (C-4 and C = CCH3), 141.05 (C-2), 146.82 (C-6),
149.39 (C-8). Anal. Calcd. for C16H17N5O5ꢀ 0.5 H2O (368.35): C, 52.18; H, 4.92; N,
19.01. Found: C, 52.74; H, 4.85; N, 19,06.
1
Compound 3: mp >300°C. Rf 0.52(A); 0.44(B). lmax 235, 302 nm. H NMR:
(data for the fragment attached at N7 in italics) 1.20, 1.40 (2s, 2x3, C>Me2), 1.30, 1.46
(2s, 2x3, C>Me2), 2.19 (s, 3, CH3), 2.26 (s, 3, CH3), 4.03 (dd, Jgem=14.9 Hz, 1, 5’b-H),
4.19-4.43 (m, 2, 5’b-H, 4’-H), 4.42 (m, 1, 5’a-H), 4.59 (d, J=6.0 Hz, 1, 3’-H), 4.89 (s, 1,
4’-H), 4.93 (d, J=6.0 Hz, 1, 2’-H), 5.09 (dd, Jgem=15.1 Hz, 1, 5’a-H), 5.13 (t, 1, 3’-H),
5.47 (dd, 1, 2’-H), 5.85 (s, 2, 1’-H, 1’-H), 7.22 (d, J=0.9 Hz, 1, HC=C), 7.37 (d, J=1.2
Hz, 1, HC=C), 10.91 (s, 1, N7H or N9H), 12.52 (s, 1, N2H). 13C NMR: 10.34 (CH3),
13.84 (CH3), 24.05, 25.56 (C>Me2), 25.11, 26.88 (C>Me2), 43.18 (C-5’), 54.00 (C-5’),
80.55 (C-2’), 82.20 (C-3’), 82.74 (C-2’), 83.11 (C-4’), 84.25 (C-3’), 85.60 (C-4’), 85.90
(C-1’), 88.99 (C-1’), 97.74 (C-5), 98.45 (C-5), 103.60 (HC=C), 105.71 (HC=C), 111.94
(OCO), 112.53 (OCO), 125.73 (C=CCH3), 136.53 (C-4), 136.93 (C=CCH3), 140.76

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123
(C-2), 144.03 (C-2), 145.27 (C-4), 145.34 (C-6), 146.95 (C-6), 149.02 (C-8), 151.51
(C-8). LSIMS HR Calcd. for MH+ C32H35N10O10. 719.25378. Found: 719.25395.
5’ -(p-Toluenesulfonyl)-2,’ 3’ -O-isopropylidene-8-oxo-1,N2-isopropenoguanosine
(4). A suspension of 1 (400 mg, 1.11 mmol) and p-toluenesulfonic acid monohydrate
(21.2 mg, 0.111 mmol) in chlorobenzene (12 mL) was stirred at 120°C for 3 h. The
products were separated as described above to provide (in order of elution): 2 (34.8 mg,
8.7%), the tosyl derivative 4 (8.2 mg, 1.4%), and 3 (18.1 mg, 4.1%). Compound 4 was
crystallized from 50% aqueous EtOH. The attempted 13C NMR spectrum failed due to
a partial conversion into 2. Rf: 0.69(A); 0.46(B) (non-fluorescent). lmax 232 nm (e
1
47,100), 258 (10,200), 299 (9700). H NMR: 1.27, 1.48 (2s, 2 ꢀ 3, C > Me2), 2.24 (s,
3, CH3), 2.30 (s, 3, CH3Ph), 4.22–4.32 (m, 3, 4’ -H, 5’ -H), 4.59 (dd, 1, 3’ -H), 5.19 (dd,
1, 2’ -H), 5.84 (d, 1, 1’ -H), 7.11 (d, 2, Ph), 7.39 (s, 1, HC = C), 7.53 (d, 2, Ph), 10.96 (s,
1, N7H), 12.50 (s, 1, N2H). LSIMS HR Calcd. for MH+ C23H26O8N5S 532.15021.
Found: 532.14686. A sample of 4 (3 mg, ca. 0.006 mmol) was refluxed in chloro-
benzene (2 mL) for 5 h, and this resulted in a quantitative conversion of 4 to fluorescent
2 (TLC, UV).
8,5’ -Cyclo-8-oxo-2,’ 3’ -O-isopropylidene-N2-methyl-1,N2-isopropenoguanosine
(7). A solution of 1 (665 mg, 1.85 mmol) in dry DMF (9 mL) was treated with well-
powdered potassium carbonate (394 mg, 2.85 mmol), and after 10 min of stirring with
methyl iodide (394 mg, 2.78 mmol). The resulting suspension was stirred at room
temperature for 1 h, then passed through a layer of Celite. A white precipitate of
inorganic salts was washed with warm DMF. The filtrate was concentrated to an oil
which was coevaporated with water (3 ꢀ 15 mL) and finally with chloroform (2 ꢀ 10
mL) to get a solid foam. The product 7 was purified by silica gel chromatography in
chloroform-methanol 95:5 and crystallized from methanol, mp > 300°C. Yield 247 mg
(36%). Rf0.61(A); 0.40(B) (non-fluorescent, identical with the authentic sample of 7
obtained by methylation with diazomethane[13]). lmax 230 nm (e 35,300) 287 nm
1
(12,000). H NMR: 1.31, 1.48 (2s, 2 ꢀ 3, C > Me2), 2.27 (s, 3, C = CCH3), 3.59 (s, 3,
N2CH3), 4.06 (d, J = 13.0 Hz, 1, 5’ b-H), 4.60 (d, J = 13.0 Hz, 1, 5’ a-H), 4.74 (bs, 1, 4’ -
H), 4.93 (d, J = 5.7 Hz, 1, 3’ -H), 5.11 (d, J = 5.7 Hz, 1, 2’ -H), 6.05 (s, 1, 1’ -H), 7.45 (s,
1, HC = C). 13C NMR: 9.42 (CH3), 24.18, 25.82 (C > Me2), 28.38 (N2CH3), 74.01 (C-
5’ ), 80.97 (C-3’ ), 84.76 (C-2’ ), 85.23 (C-4’ ), 85.77 (C-1’ ), 103.50 (HC = C), 109.78 (C-
5), 111.77 (OCO), 127.64 (C = CCH3), 144.61 (C-2), 147.14 (C-4), 150.18 (C-6),
150.62 (C-8).
5’ -(p-Toluenesulfonyl)-2,’ 3’ -O-isopropylidene-N2-methyl-8-oxo-1,N2-isopropeno-
guanosine (8). Cyclonucleoside 7 (373 mg, 1.0 mmol) and p-toluenesulfonic acid
monohydrate (19 mg, 0.1 mmol) were refluxed in chlorobenzene (10 mL) for 1.5 h.
The solvent was evaporated and the resulting oil was chromatographed on silica gel
column to afford 37 mg (6.8%) of 8 as a white solid. Further fractions contained
unreacted 7 (310 mg, 83%). The tosyl derivative 8 was crystallized from EtOH, mp
221°C. Rf 0.84(A); 0.56(B). lmax 234 nm (e 43,900), 259 (10,300), 302 nm (10,200).
1H NMR: 1.29, 1.50 (2s, 2 ꢀ 3, C > Me2), 2.24 (s, 3, C = CCH3), 2.36 (s, 3, CH3Ph),
3.53 (s, 3, N2CH3), 4.31 (m, 1, 5’ b-H), 4.37–4.42 (m, 2, 4’ -H, 5’ a-H), 4.97 (dd, J = 6.3 Hz,
1, 3’ -H), 5.24 (dd, J = 6.3 Hz, 1, 2’ -H), 5.90 (d, J = 1.2 Hz, 1, 1’ -H), 7.08 (d, J = 8.4

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Zandecki and Boryski
Hz, 2, Ph), 7.49 (d, J = 1.2 Hz, 1, HC = C), 7.52 (d, J = 8.4 Hz, 2, Ph), 11.03 (s, 1,
N7H). 13C NMR: 9.42 (C = CCH3), 20.89 (CH3Ph), 25.00, 26.72 (C > Me2), 28.54
(N2CH3), 70.27 (C-5’ ), 81.05 (C-3’ ), 82.75 (C-2’ ), 84.43 (C-4’ ), 86.28 (C-1’ ), 98.31 (C-
5), 102.93 (HC = C), 112.86 (OCO), 127.84, 127.92, 129.17, 144.22 (Ph), 131.72
(C = CCH3), 143.15 (C-2), 144.64 (C-4), 145.09 (C-6), 151.23 (C-8). Calcd. for
C24H27N5O8S (545.48): C, 52.84; H, 4.99; N, 12.84; S, 5.88. Found: C, 52.66;H, 4.82;
N, 12.74; S: 5.96.
Base-catalyzed conversion of 8 into 7. A solution of the tosyl derivative 8 (52 mg,
0.095 mmol) in chloroform (5 mL) was treated with Et3N (2 mL) and heated at 48°C
for 5 h. After this time, TLC showed a complete conversion to cyclonucleoside 7. The
reaction mixture was evaporated to dryness and the product was purified on a silica gel
column in toluene-ethanol 9:1 to afford 32.9 mg (92%) of a white solid, identical in all
1
respects (TLC, UV, H NMR) to an authentic sample of 7.
1,N2-Isopropeno-tetrahydro-1,5,3-dioxazepine[3,2-e]guanine (10). Sodium hy-
dride (142 mg, 5.90 mmol; 60% suspension in oil) was added to a solution of
tetrahydro-1,5,3-dioxazepine[3,2-e]guanine (9; 1.285 g, 5.76 mmol) in anhydrous
DMSO (25 mL) and this mixture was stirred with exclusion of moisture for 35 min. A
resulting almost clear solution was treated with bromoacetone (790 mg, 5.75 mmol) for
1 h. The reaction mixture was then made basic by addition of concd. NH4OH (25 mL)
and stirred for 2.5 h. The solution was evaporated to an oil which was washed with
water (3 ꢀ 10 mL), and crystallized from 50% aqueous EtOH, mp > 300°C. Yield 916
1
mg (61%). Rf 0.32(A); 0.20(B). lmax 229 nm (e 38,600), 284 (12,700). H NMR: 2.26
(s, 3, CH3), 4.15 (m, 2, CH2), 4.25 (m, 2, CH2), 5.45 (s, 2, OCH2N), 7.34 (d, J = 1.2
Hz, 1, HC = C), 12.41 (s, 1, N2H). 13C NMR: 10.37 (CH3), 72.73 (CH2), 73.30 (CH2),
73.48 (OCH2N), 103.38 (HC = C), 109.87 (C-5), 125.63 (C = CCH3), 145.10 (C-2),
147.64 (C-4), 150.37 (C-6), 152.93 (C-8). LSIMS HR Calcd. for MH+ C11H12O3N5
262.09402. Found: 262.09505.
Rearrangement reaction of 1,N2-isopropeno-tetrahydro-1,5,3-dioxazepine[3,2-
e]-guanine (10). A suspension of 10 (100 mg, 0.383 mmol) and p-toluenesulfonic
acid monohydrate (72.2 mg, 0.383 mmol) in chlorobenzene (10 mL) was stirred at
120°C for 1.5 h. After this time, TLC showed two new spots: a non-fluorescent one of
compound 11, Rf 0.50(A); 0.40(B), and a fluorescent spot of 12, Rf 0.52(A); 0.46(B).
The solvent was evaporated and resulting oil was chromatographed on a silica gel short
column in toluene ethanol 9:1. Evaporation of fractions containing 12 and crystal-
lization of the resulting solid from 50% aqueous EtOH gave 27 mg (27%) of the main
1
product, mp > 300°C. lmax 238 nm (e 32,700), 306 (13,100). H NMR: 2.24 (s, 3,
CH3), 4.26 (m, 2, CH2), 4.57 (m, 2, CH2), 5.35 (s, 2, OCH2N), 7.37 (d, J = 1.2 Hz, 1,
HC = C), 11.34 (s, 1, N7H). 13C NMR: 13.91 (CH3), 50.84 (CH2), 70.07 (CH2), 76.59
(OCH2N), 96.91 (C-5), 105.87 (HC = C), 133.66 (C-4), 138.54 (C = CCH3), 140.67
(C-2), 146.69 (C-6), 150.07 (C-8). LSIMS HR Calcd. for MH+ C11H12N5O3 262.09402.
Found: 262.09510.
Further fractions contained the tosyl derivative 11, yield 12.6 mg (7.6%) of a white
solid, mp 222–224°C. lmax 233 nm (e 45,200), 258 (10,400), 298 (9,600). 1H NMR: 2.26
(s, 3, CH3), 2.39 (s, 3, CH3Ph), 3.71 (m, 2, CH2), 4.11 (m, 2, CH2), 5.09 (s, 2, OCH2N),

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1,N2-Isopropenoguanine Cyclonucleosides
125
7.37 (d, 1 HC = C), 7.40 (d, J = 8.4 Hz, 2, Ph), 7.71 (d, J = 8.4 Hz, 2, Ph), 10.90 (s, 1,
N7H), 12.61 (s, 1, N2H). 13C NMR: 10.33 (CH3), 20.97 (CH3Ph), 66.49 (CH2), 68.77
(CH2), 69.52 (OCH2N), 98.14 (C-5), 103.62 (HC = C), 125.76 (C = CCH3), 127.40,
129.92, 132.25, 144.31 (Ph), 144.78 (C-2), 145.22 (C-4), 146.07 (C-6), 152.37 (C-8).
LSIMS HR Calcd. for MH+ C18H20N5O6S 434.11343. Found: 434.11227.
A sample of 11 (12.0 mg, 0.0277 mmol) was refluxed in chlorobenzene (3 mL),
and after 3 h TLC in solvent B showed a quantitative conversion to fluorescent 12.
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Received August 6, 2003
Accepted October 3, 2003

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