A methylareal derivative of 5'-noraristeromycin

Full text of DOI:10.1021/jo970515h

J . Org. Chem. 1997, 62, 5645-5646
5645
Sch em e 1
A Meth yla ted Der iva tive of
5′-Nor a r ister om ycin
Katherine L. Seley and Stewart W. Schneller*
Department of Chemistry, Auburn University,
Auburn, Alabama 36849-5312
Erik De Clercq
Sch em e 2
Rega Institute for Medical Research, Katholieke Universiteit
Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Received March 20, 1997
5′-Noraristeromycin in the D-like configuration 1 has
been reported by us1 to possess potent, selective antiviral
activity, which correlated with its ability to inhibit
S-adenosyl-L-homocysteine hydrolase. To determine if a
free hydroxyl hydrogen at C-4′ was necessary for the
biological properties of 1, its methyl derivative 2 was
sought. The results of this effort are described here.
Success to 7 was achieved using the tedious series of
steps presented in Scheme 28 beginning with silylation
of the known 92 (the enantiomer of 8) to 10. Hydrolysis
of 10 provided 11, which was not susceptible to elimina-
tion when treated with standard base-promoted methy-
lation to 12. Desilylation of 12 gave 13, which was
acetylated to 7. With the requisite 7 available, the
synthesis of 2 was then accomplished by, first, its
palladium-catalyzed coupling with N6-benzoyladenine (6)
to afford 3. Subsequent debenzoylation of 3 using am-
monium hydroxide in methanol to 14 was followed by
glycolization with osmium tetraoxide to give 2.
The plan to 2 was to employ a standard glycolization2
of the 2′,3′-dideoxy-2′,3′-didehydro precursor 3 followed
by debenzoylation. The first approach to 3 was to explore
direct methylation of compound 4.2 Simple base-pro-
moted methylation3 led to elimination of the heterocyclic
base (Scheme 1) while application of less common me-
thylation procedures (for example, using trimethylsilyl
diazomethane4,5) were unsuccessful.
A second approach to 3 was to consider the pal-
ladium(0)-catalyzed coupling of the allylic acetate 5
(obtained from 4) with methoxide ion.6 In that effort only
compound 4 resulted due to simple deacetylation of 5 by
methoxide.
With these difficulties in preparing 3 from 4, attention
turned to the palladium-promoted coupling of 67 and 7.
The initial attempt to compound 7 via a simple methy-
lation of the known2 (+)-(1R,4S)-4-hydroxy-2-cyclopenten-
1-yl acetate (8) resulted in the base-catalyzed elimination
of acetic acid to give cyclopentadiene monoepoxide, in a
manner likely to be similar to Scheme 1.
Compound 2 was much less effective against those
viruses that were most susceptible to 1 and lacked the
potent inhibitory property of 1 toward S-adenosyl-L-
homocysteine (AdoHcy) hydrolase.10 Possible reasons for
the decreased activity of 2 may be attributed to (1) the
steric interference exhibited by the newly introduced
methyl group when 2 interacts with the hydrolase and/
or (2) loss of the biologically necessary proton from the
4′-hydroxyl of 1. Regardless, this data indicates that
(6) Deardorff, D. R.; Linde, R. G., II; Martin, A. M.; Shulman, M. J .
J . Org. Chem. 1989, 54, 2759.
(7) Ness, R. K. In Synthetic Procedures in Nucleic Acid Chemistry;
Zorbach, W. W., Tipson, R. S., Eds.; J ohn Wiley and Sons: New York,
1968; Vol. 1, p. 185.
(8) For related work see: Nokami, J .; Matsuura, H.; Nakasima, K.;
Shibata, S. Chem. Lett. 1994, 1071.
(9) Siddiqi, S. M.; Chen, X.; Rao, J .; Schneller, S. W.; Ikeda, S.;
Snoeck, R.; Andrei, G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1995,
38, 1035.
(1) Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda, S.; Snoeck, R.;
Andrei, G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1994, 37, 551.
(2) Siddiqi, S. M.; Chen, X.; Schneller, S. W. Nucleosides Nucleotides
1993, 12, 267.
(3) J ohnstone, R. A.; Rose, M. E. Tetrahedron 1979, 35, 2169.
(4) Aoyama, T.; Shiroiri, T. Tetrahedron Lett. 1990, 31, 5507.
(5) Aoyama, T.; Terasawa, S.; Sudo, K.; Shioiri, T. Chem. Pharm.
Bull. 1984, 32, 3759.
(10) These assays were conducted using methods previously de-
scribed by us (Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda, S.;
Snoeck, R.; Andrei, G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1994,
37, 1382).
S0022-3263(97)00515-X CCC: $14.00 © 1997 American Chemical Society

5646 J . Org. Chem., Vol. 62, No. 16, 1997
Notes
mixture was stirred overnight at rt, at which point it was treated
with saturated NaHCO3 solution (50 mL) and stirred vigorously
for 15 min. The organic layer was separated, washed with ice-
cold 1 N HCl (50 mL) and brine (2 × 50 mL), dried (MgSO4),
and evaporated under reduced pressure. The residue was
purified via column chromatography, eluting with hexane/EtOAc
(19:1) to give 1.2 g (58%) of 7 as a yellow syrup: 1H NMR (CDCl3)
δ 1.57 (dt, 1H), 1.97 (s, 3H), 2.66 (m, 1H), 3.30 (s, 3H), 4.24 (t,
1H), 5.44 (t, 1H), 6.05 (dd, 2H); 13C NMR (CDCl3) δ 21.0, 36.8,
56.1, 76.5, 82.9, 132.9, 135.7, 170.7. Anal. Calcd for C8H12O3:
C, 61.70; H, 7.71. Found: C, 61.60, H, 7.68.
preservation of the proton on the 4′-hydroxyl of 1 is
important for its antiviral activity and inhibition of the
hydrolase.
Exp er im en ta l Section
Gen er a l. Melting points were recorded on a Meltemp II
melting point apparatus and are uncorrected. Combustion
analyses were performed by M-H-W Laboratories, Phoenix, AZ.
1H and 13C spectra were recorded on a Bruker AC 250 spec-
trometer (operated at 250 and 62.5 MHz, respectively) all
referenced to internal tetramethylsilane (TMS) at 0.0 ppm. The
spin multiplicities are indicated by the symbols s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), and br (broad).
Optical rotations were measured on a J ASCO DIP-370 polarim-
eter. Reactions were monitored by thin-layer chromatography
(TLC) using 0.25 mm Whatman Diamond silica gel 60-F254
precoated plates with visualization by irradiation with a Min-
eralight UVGL-25 lamp or exposure to iodine vapor. Column
chromatography was performed on Whatman silica, 230-400
mesh, 60 Å, and elution with the indicated solvent system.
Yields refer to chromatographically and spectroscopically (1H
and 13C NMR) homogeneous materials.
(1R,4S)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-4-m et h oxycy-
clop en t-2-en e (12). A solution of (-)-(1S,4R)-4-hydroxy-2-
cyclopenten-1-yl acetate2 (24.66 g, 0.17 mol) in anhydrous DMF
(300 mL) was treated with imidazole (29.5 g, 0.43 mol) and
TBDMSCl (31.45 g, 0.21 mol) and the clear solution stirred at
rt for 6 h under N2.8 The reaction mixture was treated with
300 mL of ice-water and 300 mL of ether and the organic layer
separated, washed with brine (3 × 500 mL), dried (Na2SO4), and
evaporated under reduced pressure. The residue was purified
by flash column chromatography eluting with hexane/EtOAc (4:
1) to afford 44.0 g of 10 as a colorless oil: 1H NMR (CDCl3) δ
-0.08 (s, 6H), 0.86 (s, 9H), 1.57 (dt, 1H), 2.06 (s, 3H), 2.83 (dt,
1H), 4.72 (t, 1H), 5.48 (t, 1H), 5.87 (d), 5.98 (d, 1H); 13C NMR
(CDCl3) δ -4.7, 18.1, 25.7, 41.1, 74.8, 76.89, 131.1, 138.8, 170.8.
To a suspension of K2CO3 (5.4 g, 39.0 mmol) in MeOH (100
mL) was added 10 (10.0 g, 39.0 mmol) and stirred at rt for 30
min.8 The solvent was removed under reduced pressure and the
residue dissolved in ether (300 mL) and washed with brine (300
mL). The organic layers were combined, dried (Na2SO4), and
evaporated to afford 11 (7.7 g crude) as a colorless syrup which
was used immediately in the next step.
To a suspension of crushed KOH (8.06 g, 61.70 mmol) in
DMSO (50 mL) that had been stirring at rt for 15 min was added
11, obtained in the previous step, followed immediately by the
dropwise addition of MeI (10.21 g, 71.94 mmol).3 The reaction
mixture was then stirred at rt for 4 h, after which it was poured
onto ice and extracted with CH2Cl2 (3 × 200 mL). The organic
layers were combined and washed with brine, dried (MgSO4),
and evaporated. The residue was purified via column chroma-
tography eluting with hexane/EtOAc (10:1, followed by 4:1) to
afford 5.1 g (62%) of 12 as a colorless syrup: 1H NMR (CDCl3)
δ -0.08 (s, 6H), 0.86 (s, 9H), 1.57 (dt, 1H), 2.65 (dt, 1H), 3.33 (s,
3H), 4.26 (t, 1H), 4.67 (t, 1H), 5.93 (m, 2H); 13C NMR (CDCl3) δ
-4.7, 18.1, 25.8, 40.8, 55.7, 74.8, 83.0, 132.4, 137.5. Anal. Calcd
for C12H24O2Si: C, 63.28; H, 10.54. Found: C, 63.13, H, 10.61.
(1R,4S)-4-Meth oxy-2-cyclop en ten -1-yl Aceta te (7). A so-
lution of 12 (5.1 g, 22.2 mmol) and Bu4NF (1.0 M sol in THF, 47
mL, 47 mmol) was stirred at rt for 3 h. The solvent was
evaporated under reduced pressure and the residue was purified
via column chomatography eluting with hexane/EtOAc (5:1,
followed by 2:1) to afford 1.5 g (59%) of 13 as a colorless syrup,
which was used directly in the next step: 1H NMR (CDCl3) δ
1.57 (dt, 1H), 2.65 (dt, 1H), 3.06 (br, 1H), 3.34 (s, 3H), 4.24 (q,
1H), 4.60 (q, 1H), 6.01 (d, 2H); 13C NMR (CDCl3) δ 40.1, 56.1,
74.5, 83.3, 133.2, 137.4.
(1R,4S)-4-Meth oxy-1-(6-a m in o-9H-p u r in -9-yl)cyclop en t-
2-en e (14). To a solution of N6-benzoyladenine7 (2.02 g, 8.41
mmol) in dry DMSO (30 mL) was added NaH (0.23 g, 8.62 mmol,
95%). The mixture was stirred at rt under an argon atmosphere
for 30 min. Tetrakis(triphenylphosphine)palladium (0.61 g, 0.53
mmol), Ph3P (0.23 g, 0.88 mmol), and a solution of 7 (1.2 g, 7.65
mmol) in dry THF (30 mL) was added.2 The mixture was stirred
at 55 °C for 2 days. The volatiles evaporated under reduced
pressure, and the residue was slurried in CH2Cl2 and filtered.
The filtrate was washed with brine and evaporated. The residue
was purified via column chromatography eluting with EtOAc/
MeOH (19:1, followed by 9:1) to afford 2.2 g of 3 as a gum, which
was used directly in the next reaction, without further purifica-
tion.
A solution of 3 (2.2 g, 4.09 mmol) in NH4OH/H2O (1:1, 100
mL) was sealed in a steel vessel and heated at 110 °C for 2 days.
The vessel was cooled to 0 °C, and the solvents were removed
under reduced pressure. The residue was then purified via
column chromatography, eluting with EtOAc/MeOH (19:1, fol-
lowed by 10:1). Fractions containing product were combined and
evaporated to give 0.69 g (39% from N6-benzoyladenine) of 14
as a white crystalline solid: mp 155-156 °C; 1H NMR (DMSO-
d6) δ 1.80 (dt, 1H), 2.87 (m, 1H), 3.27 (s, 3H), 4.45 (t, 1H), 5.48
(t, 1H), 6.20 (dd, 2H), 7.25 (br, 2H), 7.95 (s, 1H), 8.15 (s, 1H);
13C NMR (DMSO-d6) δ 37.9, 55.9, 56.5, 83.1, 118.8, 132.8, 135.8,
138.6, 149.1, 152.4, 156.0. Anal. Calcd for C11H13N5O: C, 57.31;
H, 5.64; N, 30.16. Found: C, 57.06; H, 5.60; N, 30.35.
(1R,2R,3R,4S)-4-Met h oxy-1-(6-a m in o-9H -p u r in -9-yl)cy-
clop en ta n e-2,3-d iol (2). To a solution of 14 (0.50 g, 2.15 mmol)
in THF/H2O/acetone (75 mL, 1:1:1) were added OsO4 (0.03 g)
and 4-methylmorpholine N-oxide (1 mL).2 The mixture was
stirred at rt overnight until TLC (EtOAc/MeOH, 5:1) showed
no remaining starting material. The solvent was evaporated,
and the residue was purified via column chromatography,
eluting with EtOAc/MeOH (9:1). Fractions containing product
were combined and evaporated to afford 0.17 g (30%) of 2 as a
white solid: mp 230-231 °C; [R]23D 37.6° (c 0.20, DMF); 1H NMR
(DMSO-d6/D2O) δ 1.99 (m, 1H), 2.61 (m, 1H), 3.31 (s, 3H), 3.64
(d, 1H), 3.91 (d, 1H), 4.42 (q, 1H), 4.63 (q, 1H), 8.14 (s, 1H), 8.17
(s, 1H); 13C NMR (DMSO-d6) δ 33.1, 56.5, 58.1, 73.3, 74.3, 84.0,
119.3, 140.1, 149.8, 152.2, 156.0. Anal. Calcd for C11H15N5O3:
C, 49.98; H, 5.68; N, 26.31. Found: C, 49.85; H, 5.65; N, 26.14.
Ack n ow led gm en t. This research was supported by
funds from the Department of Health and Human
Services (U19-AI31718) and this is appreciated. We
would like to thank Dr. J iri Zemlicka of the School of
Medicine, Wayne State University, for the optical rota-
tion determination. These investigations were also
supported by the Biomedical Research Programme of
the European Commission and by grants from the
Belgian Fonds voor Geconcerteerde Onderzoeksacties
(project number 95/5). We thank Anita Van Lierde,
Frieda De Meyer, Anita Camps, Lizette van Berckelaer,
Ann Absillis, and Ria Van Berwaer for excellent techni-
cal assistance.
To a chilled stirring solution of 13 (1.5 g, 13.1 mmol) in dry
CH2Cl2 (30 mL) were added pyridine (1.5 g, 19.5 mmol), DMAP
(0.05 g), and acetic anhydride (1.9 g, 19.5 mmol).9 The reaction
J O970515H