The 3-deaza and 7-deaza derivatives of 5′-amino-5′-deoxy- 5′-noraristeromycin

Article abstract of DOI:10.1135/cccc20061122

The 3-deaza and 7-deaza derivatives of 5′-amino-5′-deoxy- 5′-noraristeromycin (6 and 7, respectively) have been prepared from the common starting material (+)-(1R,4S)-4-hydroxy-cyclopent-2-en-1-yl acetate (8). Two Pd(0)-catalyzed allylic substitution reac

Full text of DOI:10.1135/cccc20061122

1122
Yang, Serbessa, Schneller:
THE 3-DEAZA AND 7-DEAZA DERIVATIVES OF
5′-AMINO-5′-DEOXY-5′-NORARISTEROMYCIN
1,
Minmin YANG, Tesfaye SERBESSA and Stewart W. SCHNELLER *
Department of Chemistry and Biochemistry, Auburn University,
1
Auburn, AL 36849, U.S.A.; e-mail: schnest@auburn.edu
Received April 3, 2006
Accepted Jun e 6, 2006
Dedicated to Professor Antonín Holý on the occasion of his 70th birthday in recognition of his
outstanding contributions to the area of nucleosides and nucleic acid chemistry.
Th e 3-deaza an d 7-deaza derivatives of 5′-am in o-5′-deoxy-5′-n oraristerom ycin (6 an d 7, re-
spectively) h ave been prepared from th e com m on startin g m aterial (+)-(1R,4S)-4-h ydroxy-
cyclopen t-2-en -1-yl acetate (8). Two Pd(0)-catalyzed allylic substitution reaction s afforded
th e desired azide in term ediates, 12 an d 16, wh ich were tran sform ed to target com poun ds by
stan dard procedures. Th ese com poun ds were evaluated again st a large n um ber of viruses an d
foun d to be in active except for weak effect again st h epatitis B virus: 6, EC50 4.7 µM (3TC
EC50 0.056 µM); 7, EC50 4.8 µM (3TC EC50 0.063 µM).
Keyw ord s: Deazapurin es; Carban ucleosides; Im idazo[4,5-c]pyridin es; Allylic substitution ;
Pyrrolo[2,3-d]pyrim idin es; Carbocyclic n ucleosides; An tivirals.
From a decades lon g study in our laboratory to im prove upon th e an tiviral
poten tial of aristerom ycin 1 (1), 5′-n oraristerom ycin (2) con tin ues to be on e
of th e an alogs with th e m ost prom ise2. It acts by in h ibitin g S-aden osyl-
h om ocystein e h ydrolase, con sisten t with th e paren t 1. To build upon th is
3
4
observation , we h ave con sidered various 4′-an alogs (for exam ple, 3 , 4 ,
5
an d 5 ; Ch art 1); th is study is n ow bein g exten ded to varyin g th e h etero-
NH2
N
NH2
N
NH2
N
X
N
N
N
N
N
Y
N
H2N
N
X
HO
OH
OH
HO
OH
HO
HO
1
6; X=N,Y=CH
7; X=CH,Y=N
2; X=OH
3a; X=NH2
3b; X=NHR
4; X=SH
5; X=F
CHART 1
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 7, pp. 1122–1129
© 2006 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20061122

Derivatives of 5′-Amino-5′-deoxy-5′-noraristeromycin
1123
cyclic base of th ese C-4′ altered agen ts. For th is purpose, th e 3-deaza- an d
7-deazaaden in e bases were selected because of th eir presen ce in related
com poun ds th at h ave dem on strated in h ibitory effects on th e aforem en -
tion ed h ydrolase6,7. Th is m an uscript presen ts th e results for th e 4′-am in o
represen tatives (6 an d 7).
Chemistry
Syn th esis of 5′-am in o-5′-deoxy-5′-n or-3-deazaaristerom ycin (6) com m en ced
with th e palladium (0)-catalyzed allylic substitution reaction of (+)-(1R,4S)-
4-h ydroxycyclopen t-2-en -1-yl acetate8 (8) with 4-ch loro-1H-im idazo[4,5-c]-
pyridin e (6-ch loro-3-deazapurin e)9 to afford an in separable m ixture of N-1
an d N-3 coupled isom ers (Sch em e 1). Th is m ixture was treated with ben zoic
an h ydride. Th e desired ben zoate 9 was easily separated from th e N-3 com -
poun d 10 by colum n ch rom atograph y. Th e isom ers were distin guish ed by
th e ch aracteristic 13C NMR peak at δ 105.8 ppm for th e N-1 product (9) an d
th e peak at δ 114.8 ppm for th e N-3 isom er10
.
Cl
N
N
N
N
a
N
X
N
HO
OAc
BzO
1
3
+
Cl
8
10
9, X=OBz
11, X=N3
b
(ref. 8)
c
NH2
N
Cl
N
N
N
N
N
e
X
H2N
on 13
OH
HO
OH
HO
12, X=N3
13, X=NH2
6
d
Reaction conditions: a, (i) 4-chloro-1H-imidazo[4,5-c]pyridine9, [Pd(Ph3P)4], PPh
NaH, DMF/THF; (ii) Bz2O, DMAP, pyridine, CH2Cl2, 9 (31%, 2 steps), 10 (15%
2 steps); b, NaN3, [Pd2(dba)3]·CHCl3, dppp, THF/H2O, 90%; c, OsO4, NMO,
CH2Cl2/H2O, 78%; d, Ph3P, THF/H2O, 85%; e, (i) NH2NH2; (ii) Ra-Ni, H2O, 70%
SCHEME 1
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Yang, Serbessa, Schneller:
Subjectin g 9 to an oth er Pd(0)-catalyzed allylic substitution with sodium
azide (to 11) was followed by dih ydroxylation with osm ium tetroxide to
provide 12 in good yield. A Staudin ger reaction of 12 with triph en yl-
ph osph in e clean ly provided th e am in o com poun d 13. Con version of 13
in to 6 was accom plish ed by, first, reaction with h ydrazin e to displace th e
h eterocyclic ch loro substituen t followed by Ran ey n ickel reduction .
Th e syn th esis of 5′-am in o-5′-deoxy-5′-n or-7-deazaaristerom ycin (7) began
with 14, wh ich is available from 8 by our previous procedure8 but with im -
proved yields, by ch an gin g th e solven t from DMF to THF (Sch em e 2).
Ben zoylation of 14 with ben zoic an h ydride afforded 15, wh ich was sub-
jected to a Pd(0)-catalyzed allylic azidation with sodium azide to give 16.
Dih ydroxylation of 16 to 17 followed by stan dard am m on olysis (to 18) an d
h ydrolysis gave th e desired 7.
Cl
X
N
N
HO
OAc
a
d
X
N
N3
N
N
N
on 16
8
14, X=OH
15, X=OBz
16, X=N3
b
c
OH
HO
(ref. 8)
17, X=Cl
e
18, X = NH2
f
NH2
N
Reaction conditions: a, ref8; b, Bz2O, pyridine, DMAP,
CH2Cl2, rt, 12 h, 88 %; c, NaN3, [Pd2(dba)3]·CHCl3, dppp,
THF/H2O, 85%; d, OsO4, NMO, CH2Cl2/H2O, 65%; e,
NH3/MeOH, 100 °C, 48 h, 90%; f, H2, Pd/C, 81%.
N
N
H2N
OH
HO
7
SCHEME 2
Antiviral Analysis11
Viruses subjected to 6 an d 7 were respiratory syn cytial virus, h erpes sim plex
virus 1 an d 2, h erpes sim plex 1 TK–, h um an cytom egalovirus, varicella
zoster virus, vaccin ia virus, cowpox virus, aden ovirus type 1, Pun ta Toro vi-
rus, h um an coron avirus, yellow fever, m easles, parain fluen za-3, in fluen za A
(H1N1 an d H3N2), in fluen za B, Ven ezuelan equin e en ceph alitis, h epatitis B
an d C, rh in ovirus type 2 an d West Nile. In addition , 6 was evaluated to-
wards vesicular stom atitis, reo, Den gue, an d Coxsackie B4 viruses wh ile 7
was screen ed versus m on keypox, Ebola, an d pich in de viruses. Th e on ly ac-
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Derivatives of 5′-Amino-5′-deoxy-5′-noraristeromycin
1125
tivity foun d was again st h epatitis B in 2.2.15 cells an d th at was weak:
for 6, EC50 4.7 µM (3TC EC50 0.056 µM) an d for 7, EC50 4.8 µM (3TC EC50
0.063 µM). Th e paren t am in o derivative 3a was devoid of effects versus
HBV 3a
.
Am on g th e h ost cells for th e assays, on ly weak to m oderate cytotoxicity
was seen for 6 towards CV-1, HeLa Oh io-1, HEL an d Huh 7 cells an d for 7
towards MA-104. No oth er cytotoxicity was observed.
EXPERIMENTAL
Gen eral Meth ods
Meltin g poin ts were recorded on a Meltem p II m eltin g poin t apparatus an d th e values were
un corrected. Th e com bustion an alysis was perform ed at Atlan tic Microlab, Norcross, GA. 1H
an d 13C NMR spectra (δ, ppm ; J, Hz) were recorded on eith er a Bruker AC 250 spectrom eter
(250 MHz for 1H an d 62.9 MHz for 13C) or Bruker AV 400 spectrom eter (400 MHz for 1H
an d 100 MHz for 13C), all referen ced to in tern al tetram eth ylsilan e (TMS) at 0.0 ppm . Th e
reaction s were m on itored by th in -layer ch rom atograph y (TLC) usin g 0.25 m m Wh atm an
Diam on d silica gel 60-F254 precoated plates with visualization by irradiation with
a
Min eraligh t UVGL-25 lam p. Colum n ch rom atograph y was perform ed on Wh atm an silica,
230–400 m esh , 60 Å an d elution with th e in dicated solven t system . Yields refer to ch rom a-
tograph ically an d spectroscopically (1H an d 13C NMR) h om ogen eous m aterials.
(1S,4R)-4-(4-Ch loro-1H-im idazo[4,5-c]pyridin -1-yl)cyclopen t-2-en -1-yl Ben zoate (9) an d
(1S,4R)-4-(4-Ch loro-1H-im idazo[4,5-c]pyridin -3-yl)cyclopen t-2-en -1-yl Ben zoate (10)
To a solution of 4-ch loro-1H-im idazo[4,5-c]pyridin e (6-ch loro-3-deazapurin e)9 (10.0 g, 64.0
m m ol) in dry DMF (90 m l) was added NaH (1.75 g, 69.0 m m ol). Th e reaction m ixture was
stirred at room tem perature for 3 h , followed by th e addition of tetrakis(triph en ylph os-
ph in e)palladium (3.70 g, 3.20 m m ol), triph en ylph osph in e (2.50 g, 9.50 m m ol) an d a solu-
tion of (+)-(1R,4S)-4-h ydroxycyclopen t-2-en -1-yl acetate8 (8; 11.0 g, 77.5 m m ol) in dry THF
(90 m l). Th is m ixture was stirred at 55 °C for 24 h . Th e solven t was rem oved an d th e residue
purified by colum n ch rom atograph y (CH2Cl2/EtOAc, 3:1) to afford a m ixture (14.01 g) of
4-ch loro-1H-im idazo[4,5-c]pyridin e an d N-1 an d N-3 coupled products as in dicated by NMR
an alysis10. Th is m ixture was used directly in th e n ext step.
Th e above m ixture was dissolved in CH2Cl2 (200 m l) con tain in g pyridin e (7.0 m l, 89 m m ol)
an d 4-(dim eth ylam in o)pyridin e (200 m g, 1.65 m m ol). To th is solution was added Bz2O
(13.50 g, 59.73 m m ol), an d th is m ixture was stirred at room tem perature overn igh t. Th e sol-
ven t was rem oved an d th e residue purified by colum n ch rom atograph y (CH2Cl2/EtOAc, 3:1)
to afford 9 (6.70 g, 31%) an d 10 (3.26 g, 15%) in yields based on 4-ch loro-1H-im idazo[4,5-c]-
pyridin e (6-ch loro-3-deazapurin e).
Com poun d 9 (wh ite solid); m .p. 140–141 °C. 1H NMR (250 MHz, CDCl3): 8.17 (s, 1 H);
8.15 (d, J = 5.5, 1 H); 8.00 (m , 2 H); 7.55 (m , 4 H); 6.53 (m , 1 H); 6.31 (m , 1 H); 6.00 (m ,
1 H); 5.57 (m , 1 H); 3.29 (ddd, J = 15.3, 8.1, 8.1, 1 H); 2.17 (dt, J = 15.2, 3.7, 1 H). 13C NMR
(62.9 MHz, CDCl3): 165.7, 143.2, 142.8, 141.2, 139.1, 138.1, 136.1, 133.5, 133.3, 129.4,
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 7, pp. 1122–1129

1126
Yang, Serbessa, Schneller:
128.5, 105.810, 76.7, 60.2, 59.8, 38.1. For C18H14ClN3O2 (339.8) calculated: 63.63% C,
4.15% H, 12.37% N; foun d: 63.63% C, 4.14% H, 12.45% N.
Com poun d 10 (colorless oil). 1H NMR (250 MHz, CDCl3): 8.21 (s, 1 H); 8.20 (d, J = 5.6,
1 H); 7.93 (m , 2 H); 7.65 (d, J = 5.6, 1 H); 7.57 (m , 1 H); 7.51 (m , 2 H); 6.57 (ddd, J = 7.5,
2.0, 2.0, 1 H); 6.39 (dd, J = 5.6, 2.2, 1 H); 6.23 (dd, J = 5.6, 2.3, 1.0, 1 H); 6.00 (ddd, J = 9.8,
2.5, 2.5, 1 H); 3.29 (ddd, J = 15.4, 8.3, 7.8, 7.8, 1 H); 2.09 (dt, J = 15.3, 3.1, 1 H). 13C NMR
(62.9 MHz, CDCl3): 165.7, 151.2, 150.5, 144.4, 140.9, 136.3, 133.3, 133.2, 133.0, 129.2,
128.2, 127.6, 114.8 10, 76.5, 59.6, 40.1. For C18H14ClN3O2 (339.8) calculated: 63.63% C,
4.15% H, 12.37% N; foun d: 63.26% C, 4.34% H, 11.98% N.
1-[(1R,4S)-4-Azidocyclopen t-2-en -1-yl]-4-ch loro-1H-im idazo[4,5-c]pyridin e (11)
To a solution of ben zoate 9 (0.65 g, 1.91 m m ol) in THF (15 m l) was added [Pd2(dba)3]·
CHCl3 (80 m g, 0.078 m m ol) an d 1,3-diph en ylph osph in epropan e (dppp) (0.13 g, 0.32 m m ol).
After th e m ixture was stirred for 30 m in (color ch an ged from deep-red to yellow), a solution
of NaN3 (0.32 g, 4.9 m m ol) in H2O (4 m l) was added. Th e reaction was stirred at room tem -
perature un der N2 for 4 h . Th e resultin g solid was rem oved by filtration an d th e filtrate was
separated. Th e aqueous layer was extracted with CH2Cl2 (2 × 30 m l). Th e com bin ed organ ic
ph ases were dried (an h ydrous MgSO4) an d con cen trated. Th e residue was purified by
colum n ch rom atograph y (EtOAc/h exan es, 1:2) to afford 11 (0.45 g, 85%) as a foam ; m .p.
68–70 °C. 1H NMR (250 MHz, CDCl3): 8.15 (d, J = 5.6, 1 H); 8.06 (s, 1 H); 7.41 (d, J = 5.6,
1 H); 6.35 (m , 1 H); 6.20 (m , 1 H); 5.51 (m , 1 H); 4.70 (m , 1 H); 3.15 (ddd, J = 14.9, 8.1, 8.1,
1 H); 2.00 (ddd, J = 14.8, 3.8, 3.8, 1 H). 13C NMR (62.9 MHz, CDCl3): 143.2, 142.8, 141.3,
139.1, 138.2, 135.9, 132.4, 105.9, 65.0, 60.3, 38.0. For C11H9ClN6·0.18EtOAc (276.6) calcu-
lated: 50.90% C, 3.77% H, 30.81% N; foun d: 51.29% C, 3.55% H, 30.81% N.
(1S,2R,3S,5R)-3-Azido-5-(4-ch loro-1H-im idazo[4,5-c]pyridin -1-yl)-
cyclopen tan e-1,2-diol (12)
N-Meth ylm orph olin e oxide (2.13 g, 18.2 m m ol) was added to a solution of 11 (2.53 g, 9.15
m m ol) in CH2Cl2 (50 m l) con tain in g a sm all am oun t of H2O (0.8 m l). After th e solution was
cooled to 0 °C, a catalytic am oun t of solid osm ium tetroxide (90 m g, 0.36 m m ol) was added
an d th e solution stirred at room tem perature for 12 h . Th e reaction m ixture was quen ch ed
by addition of NaHSO3. Th e solven t was rem oved an d th e residue purified by flash colum n
ch rom atograph y (EtOAc) to afford 12 as a wh ite solid (2.22 g, 78%); m .p. 95–96 °C. 1H NMR
(400 MHz, DMSO-d6): 8.54 (s, 1 H); 8.10 (d, J = 5.5, 1 H); 7.70 (d, J = 5.5, 1 H); 5.43 (d, J =
4.8, 1 H, OH); 5.31 (d, J = 6.4, 1 H, OH); 4.69 (q, J = 8.3, 1 H); 4.20 (q, J = 7.3, 1 H); 3.95
(m , 2 H); 2.63 (m , 1 H); 1.90 (m , 1 H). 13C NMR (100 MHz, DMSO-d6): 145.0, 141.1, 140.8,
140.0, 137.3, 107.1, 74.5, 74.3, 63.9, 60.0, 31.7. For C11H11ClN6O2·0.2H2O (298.3) calcu-
lated: 44.25% C, 3.82% H, 28.16% N; foun d: 44.33% C, 3.82% H, 27.90% N.
(1S,2R,3S,5R)-3-Am in o-5-(4-ch loro-1H-im idazo[4,5-c]pyridin -1-yl)-
cyclopen tan e-1,2-diol (13)
Triph en ylph osph in e (1.50 g, 5.72 m m ol) was added to a solution of 12 (1.47 g, 4.99 m m ol)
in THF (10 m l) an d H2O (10 m l). After th e reaction m ixture was brough t to reflux for 6 h ,
th e volatiles were rem oved un der reduced pressure. Th e residue was purified by colum n
ch rom atograph y (EtOAc/MeOH/NH4OH, 9:3:1) to afford 13 as a pale yellow foam (1.14 g,
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Derivatives of 5′-Amino-5′-deoxy-5′-noraristeromycin
1127
85%). 1H NMR (250 MHz, DMSO-d6): 8.59 (s, 1 H); 8.15 (d, J = 5.6, 1 H); 7.98 (d, J = 5.6,
1 H); 4.71 (dd, J = 8.6, 17.7, 1 H); 4.47 (dd, J = 4.8, 8.4, 1 H); 3.68 (m , 1 H); 3.23 (m , 1 H);
2.57 (m , 1 H); 1.73 (m , 1 H). 13C NMR (62.9 MHz, DMSO-d6): 145.5, 141.0, 140.4, 139.9,
137.5, 107.5, 77.2, 75.6, 60.9, 55.3, 35.2. For C11H13ClN4O2 (284.7) calculated: 49.17% C,
4.88% H, 20.85% N; foun d: 49.12% C, 4.80% H, 20.52% N.
(1S,2R,3S,5R)-3-Am in o-5-(4-am in o-1H-im idazo[4,5-c]pyridin -1-yl)-
cyclopen tan e-1,2-diol (6)
A solution of 13 (0.54 g, 2.0 m m ol) in h ydrazin e (20 m l) was brough t to reflux for 4 h . After
coolin g to room tem perature, th e solution was con cen trated. Th e residue was dissolved in
distilled H2O (40 m l) an d fresh ly prepared Ran ey Ni W2 (prepared from 30 g of alloy) was
added. Th e reaction m ixture was h eated to reflux for 1 h . Th e h ot reaction m ixture was
filtered an d wash ed with h ot H2O (3 × 10 m l). Th e com bin ed filtrates were evaporated to
dryn ess. Th e residue was purified via colum n ch rom atograph y (EtOAc/MeOH/NH4OH, 7:3:1)
to afford 6 as wh ite solid (0.35 g, 70%); m .p. 221–222 °C. 1H NMR (250 MHz, DMSO-d6):
8.21 (s, 1 H); 7.65 (d, J = 5.8, 1 H); 6.97 (d, J = 5.8, 1 H); 6.17 (br, 2 H); 4.60 (dd, J = 8.9,
17.6, 1 H); 4.46 (dd, J = 5.3, 8.0, 1 H); 3.87 (m , 1 H); 3.32 (m , 1 H); 2.57 (m , 1 H); 1.88 (m ,
1 H). 13C NMR (62.9 MHz, DMSO-d6): 152.4, 140.6, 140.0, 138.0, 127.0, 97.3, 74.8, 74.2,
59.7, 54.3, 32.8. For C11H15N5O2·0.8H2O (263.67) calculated: 50.11% C, 6.30% H, 26.58% N;
foun d: 50.13% C, 6.42% H, 26.29% N.
(1S,4R)-4-(4-Ch loro-7H-pyrrolo[2,3-d]pyrim idin -7-yl)cyclopen t-2-en -1-yl Ben zoate (15)
8
To a solution of 14 (1.59 g, 6.77 m m ol), pyridin e (0.82 m l, 10 m m ol) an d DMAP (40 m g,
0.33 m m ol) in CH2Cl2 (50 m l) was added ben zoic an h ydride (1.55 g, 6.86 m m ol). After th e
reaction m ixture was stirred at room tem perature for 12 h , th e solven t was rem oved un der
reduced pressure an d th e residue purified by colum n ch rom atograph y (EtOAc/h exan es, 1:3)
to afford 15 (2.02 g, 88%) as a wh ite solid; m .p. 74–75 °C. 1H NMR (400 MHz, CDCl3): 8.66
(s, 1 H); 8.05 (m , 2 H); 7.60 (m , 1 H); 7.47 (m , 2 H); 7.39 (d, J = 3.8, 1 H); 6.65 (d, J = 3.8,
1 H); 6.44 (dt, J = 5.6, 2.0, 1 H); 6.19 (ddd, J = 5.6, 2.3, 1.0, 1 H); 6.06 (m , 1 H); 5.99 (m ,
1 H); 3.21 (ddd, J = 15.9, 8.3, 7.6, 1 H); 2.02 (dt, J =15.3, 3.3, 1 H). 13C NMR (100 MHz,
CDCl3): 166.4, 152.6, 151.1, 151.1, 135.6, 135.4, 133.7, 130.2, 130.0, 128.9, 126.8, 118.2,
100.8, 78.2, 57.7, 39.0. For C18H14ClN3O2 (339.8) calculated: 63.63% C, 4.15% H, 12.37% N;
foun d: 63.45% C, 4.09% H, 12.37% N.
7-[(1R,4S)-(4-Azidocyclopen t-2-en -1-yl)]-4-ch loro-7H-pyrrolo[2,3-d]pyrim idin e (16)
To a solution of 15 (1.70 g, 5.00 m m ol) in THF (40 m l) was added [Pd2(dba)3]·CHCl3 (0.20 g,
0.19 m m ol) an d dppp (0.32 g, 0.78 m m ol). After th e m ixture was stirred for 30 m in (color
ch an ged from deep-red to yellow), a solution of NaN3 (0.90 g, 15 m m ol) in H2O (12 m l) was
added. Th e reaction m ixture was stirred at room tem perature un der N2 for 8 h . Th e resultin g
solid was rem oved by filtration an d th e filtrate recovered an d extracted with EtOAc (2 ×
50 m l). Th e com bin ed organ ic ph ases were dried (MgSO4) an d con cen trated. Th e residue was
purified by colum n ch rom atograph y (EtOAc) to give 16 as a colorless oil (1.10 g, 85%).
1H NMR (400 MHz, CDCl3): 8.67 (s, 1 H); 7.35 (d, J = 3.7, 1 H); 6.67 (d, J = 3.7, 1 H); 6.27
(m , 1 H); 6.13 (m , 1 H); 5.01 (m , 1 H); 4.63 (m , 1 H); 3.12 (ddd, J = 15.7, 8.2, 7.7, 1 H); 1.88
(dt, J = 15.2, 3.2, 1 H). 13C NMR (100 MHz, CDCl3): 152.4, 150.8, 150.1, 134.8, 134.2, 126.6,
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1128
Yang, Serbessa, Schneller:
118.0, 100.6, 65.2, 57.9, 38.5. For C11H9ClN6 (260.7) calculated: 50.68% C, 3.48% H,
32.24% N; foun d: 50.78% C, 3.56% H, 32.02% N.
(1S,2R,3S,5R)-3-Azido-5-(4-ch loro-7H-pyrrolo[2,3-d]pyrim idin -7-yl)-
cyclopen tan e-1,2-diol (17)
N-Methylm orpholine oxide (0.99 g, 8.5 m m ol) was added to a solution of 16 (1.10 g, 4.23 m m ol)
in CH2Cl2 (20 m l) con tain in g a sm all am oun t of H2O (0.8 m l). After th e solution was cooled
to 0 °C, a catalytic am oun t of solid osm ium tetroxide (40 m g, 0.16 m m ol) was added an d
th e solution stirred at room tem perature for 8 h . Th e reaction was quen ch ed by addition of
NaHSO3. Th e solven t was rem oved an d th e residue purified by flash colum n ch rom atogra-
ph y (EtOAc/h exan es, 3:1) to afford 17 as a wh ite solid (0.81 g, 65%); m .p. 73–74 °C.
1H NMR (400 MHz, DMSO-d6): 8.63 (s, 1 H); 7.89 (d, J = 3.7, 1 H); 7.70 (d, J = 3.7, 1 H); 5.37
(d, J = 5.2, 1 H); 5.20 (d, J = 6.1, 1 H); 4.99 (dq, J = 1.8, 9.0, 1 H); 4.28 (q, J = 6.9, 1 H); 3.97
(m , 2 H); 2.57 (m , 1 H); 1.90 (m , 1 H). 13C NMR (100 MHz, DMSO-d6): 150.8, 150.6, 150.1,
129.7, 117.1, 99.0, 74.6, 74.3, 63.8, 59.0, 32.1. For C11H11ClN6O2·0.1EtOAc (303.5) calcu-
lated: 45.07% C, 3.89% H, 27.68% N; foun d: 45.39% C, 3.87% H, 27.51% N.
(1R,2S,3R,5S)-3-(4-Am in o-7H-pyrrolo[2,3-d]pyrim idin -7-yl)-
5-azidocyclopen tan e-1,2-diol (18)
Com poun d 17 (0.80 g, 2.7 m m ol) was dissolved in saturated m eth an olic am m on ia solution
(40 m l) in a stain less steel pressure vessel an d th is sealed an d h eated at 100 °C for 48 h . Af-
ter coolin g to 0 °C, th e reaction vessel was open ed an d NH3 an d MeOH rem oved to dryn ess.
Colum n ch rom atograph y (EtOAc/MeOH, 6:1) of th e residue afforded 18 as a wh ite solid
(0.68 g, 90%); m .p. 149–151 °C. 1H NMR (400 MHz, DMSO-d6): 8.04 (s, 1 H); 7.23 (d, J = 3.5,
1 H); 6.98 (br, 2 H); 6.56 (d, J = 3.5, 1 H); 5.28 (d, J = 5.3, 1 H); 5.13 (br, 1 H); 4.81 (dq, J =
2.5, 8.9, 1 H); 4.19 (m , 1 H); 4.00 (q, J = 5.1, 1 H); 3.91 (dq, J = 2.2, 7.6, 1 H); 2.48 (m , 1 H);
1.79 (m , 1 H). 13C NMR (100 MHz, DMSO-d6): 158.2, 152.1, 150.6, 123.2, 103.6, 99.9, 75.8,
75.3, 64.8, 59.2, 33.3. For C11H13N7O2·0.7H2O (287.9) calculated: 45.85% C, 5.00% H,
34.04% N; foun d: 45.91% C, 4.84% H, 33.97% N.
(1S,2R,3S,5R)-3-Am in o-5-(4-am in o-7H-pyrrolo[2,3-d]pyrim idin -7-yl)-
cyclopen tan e-1,2-diol (7)
To a solution of 18 (0.68 g, 2.5 m m ol) in MeOH (50 m l) was added Pd/C (0.21 g), an d th e
m ixture placed un der 40 psi of H2 an d sh aken for 12 h . Th e m ixture was filtered th rough
a Celite pad an d th e filtrate was evaporated un der reduced pressure. Th e residue was th en
purified via colum n ch rom atograph y (EtOAc/MeOH/NH4OH, 7:3:1) to afford 7 as a wh ite
solid (0.56 g, 90%); m .p. > 184 °C (dec). 1H NMR (400 MHz, DMSO-d6): 8.03 (s, 1 H); 7.28
(d, J = 3.3, 1 H); 6.93 (br, 2 H); 6.55 (d, J = 3.3, 1 H); 4.83 (dd, J = 16.9, 8.3, 1 H); 4.36 (dd,
J = 7.1, 5.3, 1 H); 3.67 (t, J = 4.0, 1 H); 3.13 (m , 1 H); 2.42 (dt, J = 8.1, 13.1, 1 H); 1.50 (ddd,
J = 6.1, 8.3, 14.1, 1 H). 13C NMR (100 MHz, DMSO-d6): 158.3, 152.1, 150.7, 123.2, 103.6,
99.5, 78.6, 76.2, 59.4, 56.2, 37.4. For C11H15N5O2·0.3H2O (254.7) calculated: 51.83% C,
6.13% H, 27.49% N; foun d: 51.96% C, 6.09% H, 27.31% N.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 7, pp. 1122–1129

Derivatives of 5′-Amino-5′-deoxy-5′-noraristeromycin
1129
An tiviral Assays
Th e an tiviral an d toxicity an alyses were perform ed followin g stan dard procedures reported
previously by us11
.
This research was supported by funds from the Department of Health and Human Services
(AI 56540), which is appreciated. We would also like to thank Dr E. De Clercq, the Rega Institute,
Leuven, Belgium; Dr E. Kern, University of Alabama at Birmingham, Birmingham, AL, U.S.A.;
Dr B. Korba, Georgetown University, W ashington, DC, U.S.A.; and Dr R. Sidwell, Utah State
University, Ogden, UT, U.S.A. for the antiviral testing.
REFERENCES AND NOTES
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Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 7, pp. 1122–1129