N-oxides of adenosine-type nucleosides undergo pyrimidine ring opening and closure to give 5-amino-4-(1,2,4-oxadiazol-3-yl)imidazole derivatives

Article abstract of DOI:10.1021/ol061715v

Treatment of acylated adenosine N-oxides with carboxylic anhydrides and thiophenol resulted in pyrimidine ring opening followed by exocyclic ring closure. Ammonolysis gave 5-amino-4-(5-substituted-1,2,4-oxadiazol-3-yl)-1- (β-D-ribofuranosyl)imidazole deri

Full text of DOI:10.1021/ol061715v

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4565-4568
N-Oxides of Adenosine-Type
Nucleosides Undergo Pyrimidine Ring
Opening and Closure To Give
5-Amino-4-(1,2,4-oxadiazol-3-yl)imidazole
Derivatives†
Ireneusz Nowak, John F. Cannon, and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602-5700
morris_robins@byu.edu
Received July 12, 2006
ABSTRACT
Treatment of acylated adenosine N-oxides with carboxylic anhydrides and thiophenol resulted in pyrimidine ring opening followed by exocyclic
ring closure. Ammonolysis gave 5-amino-4-(5-substituted-1,2,4-oxadiazol-3-yl)-1-( -ribofuranosyl)imidazole derivatives, whereas iodine in
methanol selectively unmasked the 5-amino group. Related flexible nucleoside analogues can be prepared from adenine-type precursors.
â
-D
Separation of the fused imidazole and pyrimidine rings of
purine nucleosides increases conformational flexibility, and
such shape-modified analogues have been synthesized to
investigate triple helix formation1 and as probes for the study
of enzyme interactions.2 Binding sites on enzymes and other
proteins have varying degrees of freedom, and the inherently
greater flexibility of ring-linked nucleoside analogues2 might
result in enhanced monomer-protein affinity in favorable
cases. Syntheses of such “fleximers” have employed cross-
coupling reactions and multistep linear approaches.
N-oxides into 2-(substituted)adenosines. However, a product
resulting from pyrimidine ring opening and exocyclic ring
closure was isolated upon treatment of an adenosine N-oxide
with acetic anhydride in pyridine. It is known that N-oxides
of purines and pyrimidines undergo ring opening and
rearrangement reactions, many of which have been studied
with stable heterocyclic bases.4 We now report mild condi-
tions with nucleoside derivatives that provide ready access
to new “flexible” ring-linked nucleoside analogues.
Brown and co-workers5 had noted that a number of
intermediates were formed upon treatment of adenine 1-oxide
(1) with acetic anhydride under different reaction conditions
(Scheme 1). The imine enol acetate 3a was postulated to
result from attack of acetate at C2 of intermediate 2.
Heterolytic fission of the C2-N1 bond and closure of the
oxadiazole ring produced 3a. In situ hydrolysis of 3a gave
We attempted to apply chemistry that has been used with
pyridine and quinoline N-oxides3 to convert adenosine
† Nucleic Acid Related Compounds. 138. Paper 137: Zhong, M.; Nowak,
I.; Robins, M. J. J. Org. Chem., 2006, 71, 7773-7779.
(1) (a) Wang, W.; Purwanto, M. G. M.; Weisz, K. Org. Biomol. Chem.
2004, 2, 1194-1198. (b) Lengeler, D.; Weisz, K. Nucleosides Nucleotides
1999, 18, 1657-1658.
(2) (a) Seley, K. L.; Zhang, L.; Hagos, A. Org. Lett. 2001, 3, 3209-
3210. (b) Seley, K. L.; Zhang, L.; Hagos, A.; Quirk, S. J. Org. Chem. 2002,
67, 3365-3373. (c) Seley, K. L.; Salim, S.; Zhang, L. Org. Lett. 2005, 7,
63-66. (d) Seley, K. L.; Salim, S.; Zhang, L.; O’Daniel, P. I. J. Org. Chem.
2005, 70, 1612-1619.
(3) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127-3129.
(4) Brown, G. B. Prog. Nucleic Acid Res. 1968, 8, 209-255.
(5) Stevens, M. A.; Smith, H. W.; Brown, G. B. J. Am. Chem. Soc. 1960,
82, 1148-1152.
10.1021/ol061715v CCC: $33.50
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Published on Web 08/31/2006

Scheme 1. Ring Opening/Closure of Adenine N-Oxide in
Scheme 3. Ring Opening/Closure of Adenosine N-Oxides
Ac2O
with Acid Anhydrides and Thiophenol
for pyridine as solvent. Addition of thiophenol (a softer and
stronger nucleophile than acetate) also permitted milder
conditions.8 An exothermic reaction (7/PhSH/Ac2O) occurred
to give 9a (R′ ) Me) (E and Z isomers, ∼8:1). The 1H NMR
spectrum of the major isomer of 9a had a signal at δ 9.8
ppm (CHdN) and also showed the presence of a phenyl-
sulfanyl group. Treatment with NH3/MeOH at 50 °C
removed the O-acetyl protecting groups as well as the
phenylsulfanylmethylene moiety to give crystalline 12a (R′
) CH3). It is noteworthy that similar treatment of 9a with
aqueous ammonia gave mixtures of poorly differentiated
products that might result from partial hydrolysis of the 1,2,4-
oxadiazole ring. Brief exposure of 9a to I2 (0.5 mol equiv)
in hot MeOH9 caused selective deprotection of the amino
group at C5. Chromatography separated the yellow hydroio-
dide salt of 11a. Evaporation of volatiles followed by
neutralization (Et3N/CH2Cl2) and chromatography gave the
free amine. TLC spots of the UV-sensitive 11a, 11b, and
12a developed deep purple colors. The structures of 11b and
12a were confirmed by X-ray crystallography.
formamido derivative 3b, which underwent amide exchange
to give acetamido derivative 3c. The resulting mixture of
3b and 3c was converted into 4 by treatment with hydro-
chloric acid at reflux.
We subjected N-oxide 5 to Ac2O/pyridine (Scheme 2). The
Scheme 2. Ring Opening/Closure of Adenosine N-Oxide in
Ac2O/Pyridine
Anhydrides derived from aliphatic acids reacted rapidly
with 7 in the presence of excess thiophenol. Deprotected
products 12a-i (Table 1) were obtained by ammonolysis of
intermediates 9a-i. Increases in the steric bulk of the alkyl
groups adjacent to the anhydride carbonyls had little effect
on reaction rates or yields (entries 1-5). The longer-chain
aliphatic and benzoic anhydrides required a solvent (1,2-
dichloroethane) and gave lower yields (entries 6-9). Bz2O
in excess (6 equiv) and longer reaction times (1-2 h) were
required for conversion of 7 into 9i.
dark mixture contained two closely migrating (TLC) prod-
ucts, and treatment of the mixture with superheated MeOH6
gave a major product consistent with structure 6a. Treatment
of the mixture with NH3/MeOH at ambient temperature also
cleaved the O-acetyl groups to give 6b. Prolonged heating
at 80 °C produced an additional UV-absorbing compound
with similar TLC mobility.
Our recent methodology6 was used for the preparation of
2′,3′,5′-tri-O-acyladenosine derivatives. Selection of ap-
propriate acyl groups gave organic-soluble N-oxides and
readily crystallized derivatives. Oxidation7 of 2′,3′,5′-tri-O-
acetyladenosine6 gave the protected adenosine N-oxide 7
(Scheme 3) whose nonpolar solubility circumvented the need
(7) (a) Kikugawa, K.; Suehiro, H.; Yanase, R.; Aoki, A. Chem. Pharm.
Bull. 1977, 25, 1959-1969. (b) Kwong, C. D.; Krauth, C. A.; Shortnacy-
Fowler, A.; Arnett, G.; Hollingshead, M. G.; Shannon, W. M.; Montgomery,
J. A.; Secrist, J. A., III. Nucleosides Nucleotides 1998, 17, 1409-1443.
(8) Other additions [e.g., TMS-N3/Ac2O, TMS-Cl/Ac2O, CH3NO2/
Ac2O, PCl3/Ac2O, SOCl2/Ac2O, and BnN(Et)3Cl/Ac2O] were ineffective,
and addition of phenol or methanol gave lower yields of related intermedi-
ates.
(6) Nowak, I.; Conda-Sheridan, M.; Robins, M. J. J. Org. Chem. 2005,
70, 7455-7458.
(9) Szarek, W. A.; Zamojski, K. N.; Tiwari, K. N.; Ison, E. R.
Tetrahedron Lett. 1986, 27, 3827-3830.
4566
Org. Lett., Vol. 8, No. 20, 2006

Table 1. Conversiona of N-Oxide 7 into 9 and 12
Scheme 5. Ring Opening/Closure of Related N-Oxides
yield (%)b
entry
R′
CH3
C2H5
C3H7
CH(CH3)2
C(CH3)3
C5H11
C7H15
C9H19
Ph
1
2
3
4
5
6
7
8
9
9a (78)
9b (82)
9c (68)
9d (83)
9e (60)
9f (45)
9g (43)
9h (40)
9i (51)
12a (59)
12b (63)
12c (49)
12d (47)
12e (46)
12f (29)
12g (32)
12h (28)
12i (41)
which is typical with aminopyrrole derivatives.10 Standard
treatment of the protected formycin N-oxide 18 gave a
complex mixture that was not investigated further.
a The general procedures were used (Supporting Information). b Isolated
yields beginning with 7 (one step for 9, two steps for 12).
Treatment of the 5-amino compounds 11a and 16 with
Ac2O/pyridine for 1 h at 100 °C resulted in formation of the
5-(N,N-diacetyl) derivatives 20a and 20b, respectively
(Scheme 6). It is noteworthy that 11a was unchanged by
Immediate evolution of gas occurred upon addition of
acetic formic anhydride to 7, and a complex mixture was
formed. Such a mixture also resulted from treatment of 7
with the anhydrides of trifluoroacetic or chloroacetic acid.
Recovery of starting materials after prolonged reflux of a
solution of the N-oxide 7 and phenyl thiobenzoate in 1,2-
dichloroethane indicated that transesterification of the N-
oxide 7 by the thioester did not occur.
Scheme 6. Acetylation of 11a and 16
It is noteworthy that the less-stable 2′-deoxy N-oxide 13
readily underwent conversions to intermediates 14a (70%)
and 14b (79%) [as well as two-step conversions via am-
monolysis to 15a (53%) and 15b (46%)] (Scheme 4).
Scheme 4. Ring Opening/Closure of 2′-Deoxyadenosine
N-Oxide
such treatment at ambient temperature (and ∼10% of 11a
was detected even at 90 °C). Thus, acetylation of the amino
group did not occur under conditions that usually produce
amides, and diacetylation resulted under more forcing
conditions. Steric hindrance and/or delocalization of the lone-
pair electrons into the heteroaromatic ring might seriously
retard the rate of amine acetylation.
We have reported the structures and syntheses of several
6-(heteroaryl)purine nucleosides in which the heteroaryl and
Treatment of intermediate 14a with I2/MeOH gave 16 (93%
from 14a, 65% from 13).
The acetylated tubercidin N-oxide 17 (Scheme 5) and
2′,3′,5′-tri-O-acetylformycin N-oxide (18) were subjected to
our standard conditions. The expected intermediate 19 was
obtained from 17 in low yield (24%), but ammonolysis of
19 (NH3/MeOH) gave an unstable, deeply colored mixture,
Figure 1. X-ray crystal structure of 11b.
Org. Lett., Vol. 8, No. 20, 2006
4567

purine rings approach coplanarity in the solid state.11
Favorable π-π interactions contribute to lower energies in
coplanar conformations.12 Our X-ray crystal structures of
protected 11b (Figure 1) and deprotected 12a (Figure 2) show
the imidazole ring but could undergo acetylation at 100 °C.
Treatment of the 2′-deoxy-5-(N,N-diacetyl) compound 20b
with NH3/MeOH at 50 °C resulted in removal of one N-acetyl
group and cleavage of the glycosyl bond to give 3c. Our
X-ray crystal structure of 3c revealed that its rings are nearly
coplanar (projection angle of ∼5°), but the two rings are
inverted relative to the conformations of 11b and 12a
(Supporting Information).
In conclusion, our treatment of N-oxides of hydroxyl-
protected adenosine, 2′-deoxyadenosine, and tubercidin (7-
deazaadenosine) with carboxylic acid anhydrides in the
presence of thiophenol produced 4-(5-substituted-1,2,4-
oxadiazol-3-yl) nucleoside analogues. Deprotection of the
5-amino group was effected selectively with iodine in hot
methanol, and complete deblocking occurred in methanolic
ammonia at 50 °C. Acylation of the 5-amino group did not
occur at ambient temperature, and 5-(N,N-diacetyl) deriva-
tives were produced at 100 °C. Orientations of the linked
heterocyclic rings approached coplanarity (in the solid state),
which indicates possible constraints of conformational flex-
ibility. However, hydrogen bonding of protein amino acid
residues with acceptors and donors in the fleximer analogues
might outweigh such stereoelectronic effects. Evaluations of
biological response properties are underway.
Figure 2. X-ray crystal structure of 12a.
the 1,2,4-oxadiazole and imidazole rings approaching co-
planarity (∼8° projection angle for the rings of 11b; ∼11°
for 12a). Steric and/or conjugative electron donation effects
might retard nucleophilic attack by the 5-amino group at the
electrophilic carbonyl groups of carboxylic anhydrides.
Elevated temperatures would change rotamer populations,
which might make amine acetylation more favorable. The
5-acetamido group would be a weaker electron donor into
Acknowledgment. We gratefully acknowledge NIH grant
GM029332, pharmaceutical company unrestricted gift funds
(M.J.R.), and Brigham Young University for support of this
research.
Supporting Information Available: Experimental pro-
cedures, data, NMR spectra, and X-ray crystal structures with
CIF data for 3c, 11b, and 12a. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) Cirrincione, G.; Almerico, A. M.; Aiello, E.; Dattolo, G. In Pyrroles,
Part 2; Jones, R. A., Ed.; Wiley: New York, 1992; Chapter 3.
(11) Zhong, M.; Nowak, I.; Cannon, J. F.; Robins, M. J. J. Org. Chem.
2006, 71, 4216-4221.
(12) Carra, C.; Bally, T.; Albini, A. J. Am. Chem. Soc. 2005, 127, 5552-
5562.
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