An unusual occurrence on attempted purine C-8 electrophilic fluorination of 5′-noraristeromycin

Article abstract of DOI:10.1021/ol051297e

(Chemical Equation Presented) Reaction of the in situ generated purine C-8 carbanion of a protected 5′-noraristeromycin derivative with N-fluorobenzenesulfonimide gave 8-phenylsulfonyl-5′-noraristeromycin rather than the expected 8-fluoro derivative. A si

Full text of DOI:10.1021/ol051297e

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3889-3891
An Unusual Occurrence on Attempted
Purine C-8 Electrophilic Fluorination of
5′-Noraristeromycin
Atanu Roy and Stewart W. Schneller*
Department of Chemistry and Biochemistry, Auburn UniVersity,
Auburn, Alabama 36849-5312
schnest@auburn.edu
Received June 2, 2005
ABSTRACT
Reaction of the in situ generated purine C-8 carbanion of a protected 5
8-phenylsulfonyl-5 -noraristeromycin rather than the expected 8-fluoro derivative. A single electron transfer (SET) mechanism is proposed for
this occurrence. The phenylsulfonyl product offers a structural feature common to some anti-HIV agents.
′-noraristeromycin derivative with N-fluorobenzenesulfonimide gave
′
Significant effort has been directed toward the synthesis of
base-modified nucleosides for their potential biological
activities, specifically within the context of antiviral thera-
peutic agents.1-3 The least studied modification has been at
the C-8 position of the purine-based nucleosides, although,
in some cases, interesting antiviral and anticancer properties
have been reported.4-6 In our laboratory, we have found that
5′-noraristeromycin (1) has provided a fruitful foundation
to a wealth of structural entities with potentially significant
antiviral properties.7 Therefore, it was of interest to prepare
C-8-substituted 5′-noraristeromycin derivatives to expand
upon this latter observation.
Barton and co-workers8 reported that regioselective lithia-
tion at purine C-8 made possible substitution reactions by
various electrophiles, for example, halonium ions5b,9 (X+ )
Cl+, Br+, I+ except F+), alkyl (R+) halides,10 and carbonyl
compounds11 (such as PhCHO, EtCHO, Ph2CO, Et2CO) to
(1) (a) McGuigan, C.; Yarnold, C. J.; Jones, G.; Velazquez, S.; Barucki,
H.; Brancale, A.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J.
Med. Chem. 1999, 42, 4479. (b) Brancale, A.; McGuigan, C.; Andrei, G.;
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(2) (a) Kifli, N.; De Clercq, E.; Balzarini, J.; Simons, C. Bioorg. Med.
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S. W. J. Med. Chem. 1995, 38, 1035. (c) Kitade, Y.; Kozaki, A.; Miwa, T.;
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(3) (a) Van Aerschot, A. A.; Mamos, P.; Weyns, N. J.; Ikeda, S.; De
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K.; Smith, K. M. J. Chem. Soc., Perkin Trans. 1 1996, 1607.
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Chem. 1985, 28, 1481. (b) Secrist, J. A., III; Bennett, L. L., Jr.; Allan, P.
W.; Rose, L. M.; Chang, C.-H. J. Med. Chem. 1986, 29, 2069.
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A. V.; Herdewijn, P.; Hannaert, V.; Michels, P. A. M.; Opperdoes, F. R.;
Hol, W. G. J. J. Med. Chem. 1994, 37, 3605. (b) Gudmundsson, K. S.;
Daluge, S. M.; Condreay, L. D.; Johnson, L. C. Nucleosides Nucleotides
2002, 21. 891. (c) Pope, B. L.; Chourmouzis, E.; Lee, S.; Goodman, M. G.
Can. J. Immunol. with Emphasis on Tumor Immunology 1995, 17, 98.
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10.1021/ol051297e CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/04/2005

Scheme 1. Synthesis of 8-Phenylsulfonyl-5′-noraristeromycin
provide the corresponding halo, alkyl, and carbinol deriva-
tives. Nothing could be found in the literature regarding the
electrophilic fluorination reactions involving in situ generated
C-8 purine carbanions. In this paper, we describe an
interesting observation that the reaction between such a
carbanion and an electrophilic fluorinating agent, N-fluo-
robenzenesulfonimide (NFSI), proceeded by an apparent
single electron transfer (SET) pathway and furnished the
novel 8-phenylsulfonyl-5′-noraristeromycin 2.
Figure 1. Single electron transfer (SET) mechanism.
and carbon electrophiles.10,11 Failure to detect 6 may be due
to the instability of the 8-fluoro purine derivative.13
The diol 312 was treated with tert-butyldimethylsilyl
chloride in N,N-dimethylformamide (DMF) containing imid-
azole at room temperature to produce the 2′,3′,4′-tris O-tert-
butyldimethylsilyl derivative 4 (Scheme 1). When 4 was
subjected to reaction with n-butyllithium (3 equiv) at -78
°C followed by quenching with NFSI (3 equiv), 5 (78.2%)
was the only product obtained with no trace of the expected
8-fluoro derivative 6 (Figure 1). The structure of 5 was
The formation of 5 can be rationalized by assuming that
the in situ generated carbanion 7 followed a single electron
transfer mechanism rather than participating in the expected
nucleophilic substitution reaction (route A, Figure 1). It is
with this in mind that we postulate the reaction mechanism
between 7 and NFSI shown in Figure 1 (route B), which
follows from literature precedent.14 In this direction, a single
electron is transferred from carbanion 7 to NFSI to produce
a C-8 radical 8 and a reduced derivative of NFSI 9
[•NF-(SO2Ph)2] (route B). Radical anion 9 would be highly
unstable and, thus, would dissociate to 10 [•N(SO2Ph)2] with
loss of the fluoride ion (F-). Due to the steric bulkiness of
the radical 10, it would not be expected to combine with 8
to produce 11. Instead, radical 10 underwent homolytic N-S
bond cleavage to give the phenylsulfonyl radical 12 and the
phenylsulfonyl nitrene 13. The phenylsulfonyl radical 12
would then combine with 8 to provide the fully protected
8-phenylsulfonyl carbocyclic nucleoside, 5. Because of the
limited reactivity of the phenylsulfonyl nitrene,15 no product
was observed through its radical recombination.
1
unequivocally identified by H and 13C NMR spectroscopy
and elemental analysis. The 1H NMR spectrum of 5 (CDCl3)
showed the disappearance of the C-8 hydrogen singlet of 4
at δ 8.33 ppm and the concomitant appearance of five
aromatic (phenyl) protons in the δ 7.52-8.08 ppm region
[7.52 (t, 2H, J ) 7.64 Hz), 7.63 (t, 1H, J ) 7.48 Hz), 8.08
(d, 2H, J ) 7.76 Hz)], confirming reaction at the C-8 of the
purine ring. This experimental observation was in contrast
to the other halonium ions9 (X+ ) Cl+, Br+, I+ except F+)
(9) (a) Kato, K.; Hayakawa, H.; Tanaka, H.; Kumamoto, H.; Shindoh,
S.; Shuto S.; Miyasaka, T. J. Org. Chem. 1997, 62, 6833. (b) Hayakawa,
H.; Tanaka, H.; Sasaki, K.; Haraguchi, K.; Saitoh, T.; Takai, F.; Miyasaka,
T. J. Heterocycl. Chem. 1989, 26, 189. (c) Hayakawa, H.; Tanaka, H.;
Haraguchi, K.; Mayumi, M.; Nakajima, M.; Sakamaki, T.; Miyasaka, T.
Nucleosides Nucleotides 1988, 7. 121.
(10) (a) Hayakawa, H.; Haraguchi, K.; Tanaka, H.; Miyasaka, T. Chem.
Pharm. Bull. 1987, 35, 72. (b) Cong-Danh, N.; Pichat, L.; Beaucourt, J.-P.
Tetrahedron Lett. 1979, 20, 2385.
(13) See, for example: (a) Kobayashi, Y.; Kumadaki, I.; Ohsawa, A.;
Murakami, S.-I. J. Chem. Soc., Chem. Commun. 1976, 430. (b) Barrio, J.
R.; Namavari, M.; Phelps, M. E.; Satyamurthy, N. J. Am. Chem. Soc. 1996,
118, 10408. (c) Barrio, J. R.; Namavari, M.; Keen, R. E.; Satyamurthy, N.
Tetrahedron Lett. 1998, 39, 7231.
(11) Tanaka, H.; Uchida, Y.; Shinozaki, M.; Hayakawa, H.; Matsuda,
A.; Miyasaka, T. Chem. Pharm. Bull. 1983, 31, 787.
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1997, 24, 3601.
(14) Differding, E.; Wehrli, M. Tetrahedron Lett. 1991, 32, 3819.
(15) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 5th ed.; Wiley-Interscience: New
York, 2001; p 253.
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Org. Lett., Vol. 7, No. 18, 2005

A similar result was obtained when the ammonolysis
product of 4 (that is, 14) was allowed to react with 5 equiv
of lithium diisopropylamide (LDA) at low temperature (-78
°C) followed by quenching with NFSI. In addition to the
8-phenylsulfonyl derivative 15 (46% yield), a recovery of
30% of the starting material was found (no starting material
was observed from 4). Compound 5 was efficiently trans-
formed into 15 using saturated NH3 in MeOH at 120 °C.
Desilylation of 15 was carried out with NH4F in MeOH at
reflux temperature to yield the novel 8-phenylsulfonyl-5′-
noraristeromycin 2.
Compound 2 is important to our ongoing antiviral drug
discovery research program because the presence of a
phenylsulfonyl moiety on a heterocyclic ring is known to
be relevant to inhibition of the HIV-1 reverse transcriptase,16-18
an important enzyme for the HIV infection. The phenylsul-
fonyl moiety is believed to cause its effects via two enzyme
binding modes: (1) the phenyl unit fits in the enzyme
hydrophobic pocket, and (2) the sulfonyl oxygen atoms offer
hydrogen bonding opportunities to amino acid residues of
the enzyme that could stabilize the inhibitor enzyme complex.
A similar fate for 2 is under investigation in our laboratory.
In conclusion, a single electron transfer mechanism is
proposed to be responsible for the formation of 8-phenyl-
sulfonyl-5′-noraristeromycin19 in high and reproducible
yield20 under conditions expected to yield the 8-fluoro
derivative. Application of this experiment to the synthesis
of other 8-substituted purine analogues of related carbocyclic
purine nucleosides is of interest to our antiviral studies.
Acknowledgment. This research was supported by funds
from the Department of Health and Human Services (AI
56540), and this is appreciated.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 2, 4, 5, 14,
and 15. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL051297E
(16) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.; Rooney, C.
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(19) We appreciate a referee calling to our attention a similar occurrence
with a substituted imidazole (Collman, J. P.; Zhong, M.; Boulatov, R. J.
Chem. Res. 2000, 230).
(20) 8-Phenylsulfonyladenine derivatives have heretofore not been
conveniently accessible. See: (a) Llauger, L.; He, H.; Chiosis, G.
Tetrahedron Lett. 2004, 45, 9549. (b) Llauger, L.; He, H.; Kim, J.; Aguirre,
J.; Rosen, N.; Peters, U.; Davies, P.; Chiosis, G. J. Med. Chem. 2005, 48,
2892.
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