Synthesis of novel racemic carbocyclic nucleosides derived from 5,6-disubstituted norbornene

Article abstract of DOI:10.1135/cccc2009116

Novel class of the carbocyclic nucleosides based on bicyclo[2.2.1]heptene/ heptane was prepared by two approaches. Thymine analogues were synthesized starting from methyl (1R,4S)-bicyclo[2.2.1]hepta-2,5-diene-2-carboxylate 1 by Michael addition of the thy

Full text of DOI:10.1135/cccc2009116

Novel Racemic Carbocyclic Nucleosides
1
SYNTHESIS OF NOVEL RACEMIC CARBOCYCLIC NUCLEOSIDES
DERIVED FROM 5,6-DISUBSTITUTED NORBORNENE
a3
Michal ŠÁLAa1, Hubert HŘEBABECKÝa2,*, Martin DRAČÍNSKÝ
,
Milena MASOJÍDKOVÁa4, Armando M. DE PALMAb1, Johan NEYTS and
b2
a5
Antonín HOLÝ
a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i,
Gilead Sciences and IOCB Research Center, 166 10 Prague 6, Czech Republic;
e-mail: sala@uochb.cas.cz, hubert@uochb.cas.cz, dračínský@uochb.cas.cz,
masojid@uochb.cas.cz, holy@uochb.cas.cz
Rega Institute for Medical Research, Minderbroedersstraat 10, BE-3000, Leuven, Belgium;
e-mail: armando.depalma@rega.kuleuven.be, johan.neyts@rega.kuleuven.be
1
2
3
4
5
b
1
2
Received Septem ber 4, 2009
Accepted October 6, 2009
Publish ed on lin e Novem ber 28, 2009
Novel class of th e carbocyclic n ucleosides based on bicyclo[2.2.1]h epten e/h eptan e was pre-
pared by two approach es. Th ym in e an alogues were syn th esized startin g from m eth yl
(1R*,4S*)-bicyclo[2.2.1]h epta-2,5-dien e-2-carboxylate 1 by Mich ael addition of th e th ym in e
salt to th e double bon d as th e key step. Th e yield an d ratio of th e isom ers of th is reaction
depen ded on th e used base (DBU, K2CO3). Purin e n ucleoside an alogues were syn th esized by
th e lin ear syn th esis, th e purin e n ucleobase was build-up on th e am in o group. Th e am in o
groups (exo/endo con figuration ) were in troduced to th e scaffold by th e Curtius rearran ge-
m en t. Norborn en e an alogues were con verted to saturated an d cis-h ydroxylated n ucleoside
derivatives. [(1R*,2S*,3S*,4S*)-3-(6-Ch loro-9H-purin -9-yl)bicyclo[2.2.1]h ept-5-en -2-yl]m eth a-
n ol (13a) an d [(1R*,2R*,3R*,4S*)-3-(6-ch loro-9H-purin -9-yl)bicyclo[2.2.1]h ept-5-en -2-yl]m eth -
an ol (13b) sh owed m oderate activity again st Coxsackie virus CVB3.
Keyw ord s: Carban ucleosides; Carbocyclic n ucleosides; Nucleosides; Norborn en es; Purin es;
Coxsackie virus; Mich ael addition ; Am in o alcoh ols; Curtius rearran gem en t.
Carbocyclic n ucleosides are in terestin g group of com poun ds in wh ich th e
en docyclic oxygen of th e n ucleoside sugar rin g h as been replaced by a
m eth ylen e group1. Th is m odification in creases th e en zym atic stability
again st ph osporylases an d also in creases th e absorption an d pen etration of
th is com poun d th rough th e cell m em bran e due th e en h an ced lipoph ilicity.
Th is group of com poun ds represen ts an extrem ely im portan t class of poten -
tially active th erapeutic agen ts, e.g. abacavir2 h as been approved by th e
Collect. Czech. Chem. Commun. 2010, Vol. 75, No. No. 1, pp. 1–20
© 2010 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2009116

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Šála et. al.:
FDA as a drug for th e treatm en t of HIV in fection s an d en tecavir3 for th e
treatm en t of ch ron ic h epatitis B virus in fection s.
In our on goin g research we h ave syn th esized a series of th e n ovel racem ic
con form ation ally-locked carbocyclic purin e n ucleoside an alogues derived
from 4-oxatricyclo[4.2.1.03,7]n on an e-6-m eth an ol4, 4-oxatricyclo[4.2.1.03,7]-
n on an e-9-m eth an ol an d th eir Pro-Tides5, 5,5- an d 6,6-bis(h ydroxym eth yl)-
bicyclo[2.2.1]heptan-2-ols6, 3-(hydroxym ethyl)bicyclo[2.2.1]heptane-2,5-diol7,
2- an d 3-(h ydroxym eth yl)bicyclo[2.2.1]h eptan es8, 5- or 6-(h ydroxym eth yl)-
bicyclo[2.2.1]h ept-5-en -2-ol9, 4,8-dioxatricyclo[4.2.1.03,7]n on an e-9-m eth an ol
an d 4-oxatricyclo[4.3.1.03,7]decan e-10-m eth an ol10, 7-oxabicyclo[2.2.1]-
h eptan e-2-m eth an ol11 an d an alogues with a bicyclo[2.2.1]h epten e or
-h eptan e rin g system substituted with n ucleobase at position 7 with syn-
con figuration 12 an d also anti-con figuration 13
.
Th is study con cern s a syn th esis of n ovel racem ic con form ation ally locked
n ucleoside an alogues con tain in g bicyclo[2.2.1]h ept-2-en e or h eptan e rin g
substituted with base an d h ydroxym eth yl group at th e 5,6-trans position s.
Carbocyclic n ucleosides with th is un usual 1,2-position s of base an d
h ydroxym eth yl group were also descibed14. Gen eral form ulae of target
com poun ds are sh own in Ch art 1.
CHART 1
Syn th etic strategy was origin ally based on Mich ael addition of th e
n ucleobase to th e activated double bon d (see ref.15 for acyclic n ucleosides
an d ref.16 for th e carbocyclic n ucleosides). Addition of th ym in e to ester 1
(ref.17) in th e presen ce of th e base (DBU, K2CO3) gave m oderate yields of
isom ers 2a an d 2b (Sch em e 1). On ly isom ers with trans-con figuration were
observed in reaction m ixture. Th ese isom ers were easily separated by
colum n ch rom atograph y. Th e ratio of th e exo-2a an d endo-2b depen ded on
th e used base. In th e case of DBU th e ratio 2a/2b was 3.5:1 (total yield
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Novel Racemic Carbocyclic Nucleosides
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46%), wh ereas wh en potassium carbon ate was used, th e ratio was alm ost
com pletely con versely – 1:2.5 (total yield 56%). However, th is con jugate
addition is n ot suitable for preparin g purin e n ucleoside derivatives. Addi-
tion of aden in e, N6-ben zoyl aden in e an d 6-ch loropurin e led to com plicated
reaction m ixtures. In case of aden in e (or protected aden in e) addition , th e
pair (exo/endo) of th e 3-substituted aden in e derivatives was detected as a by-
product. Th e sam e reaction with 6-ch loropurin e as a n ucleobase gave pair
of th e 7-isom ers followed th e desired 9-isom ers. Th e yields of th ese addi-
tion s were also low an d isolation of th e pure isom ers was n ot successful.
SCHEME 1
Target th ym in e n ucleosides were prepared by stan dard reaction proce-
dures (Sch em e 2). Ester group on un saturated esters 2a an d 2b was reduced
with lith ium alum in ium h ydride (2.5 equivalen ts) in tetrah ydrofuran e to
afford h ydroxym eth yl group (54% for 5a an d 69% for 5b). Saturated n u-
cleosides were prepared in sim ple two steps: th e double bon d was h ydroge-
n ated on palladium h ydroxide (86% of 3a an d 84% of 3b) an d th en th e
ester group was reduced to h ydroxym eth yl group with lith ium alum in ium
h ydride un der th e sam e con dition s as for un saturated com poun ds givin g 6a
(55%) an d 6b (70%). Th e esters with two cis-h ydroxy groups at th e skeleton
were prepared in excellen t yields (98% of 4a an d 91% of 4b) by osm ium
tetroxide catalyzed cis-h ydroxylation in aceton e–water m ixture with
N-m eth ylm orph olin e-N-oxide (NMMO) as a recoverin g agen t for osm ium
catalytic cycle. Treatm en t of th e cis-h ydroxyesters 4a an d 4b with lith ium
alum in ium h ydride led to cis-h ydroxy n ucleoside derivatives 7a (39%) an d
7b (58%).
Wh en th e Mich ael addition strategy was aban don ed, it was n ecessary to
fin d a n ew route leadin g to th e purin e n ucleosides. We h ave ch osen Curtius
rearran gem en t for th e in troduction of th e am in o fun ction . Th e purin e
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Šála et. al.:
SCHEME 2
n ucleobase was th en built up by stan dard procedures12 at th is am in o fun c-
tion . Th e syn th esis started by reaction of cyclopen tadien e 8 an d fum aric
acid m on oeth yl ester (Sch em e 3). Th e Diels–Alder adducts were treated with
iodin e an d sodium bicarbon ate in th e presen ce of potassium iodide18. Two
products were obtain ed – iodoacid 9a (41%) an d iodoester 9b (31%). Th is
step allowed th e separation of th ese crucial in term ediates by sim ple
acid/base extraction . Both in dividuals were utilized for preparation of th e
isom eric am in oalcoh ols 11a an d 11b in four steps. Iodoacid 9a was firstly
con verted to Boc-protected am in e 10a (51%) by Curtius rearran gem en t.
Double bon d was restored with zin c in refluxin g eth an ol–water solution .
Protected am in o acid was im m ediately deprotected un der acidic con dition s
an d carboxylic acid was subsequen tly reduced with lith ium alum in ium
h ydride in THF to am in oalcoh ol 11a (total yield of th ree steps from 10a
is 61%). Syn th esis of th e am in oalcoh ol 11b was realized in th e sim ilar way,
on ly th e reaction sequen ce was differen t. Iodoester 9b was firstly con verted
to acid 10b by th e zin c deiodolacton ization (quan titative) an d th e carbox-
ylic group was th en degraded by th e Curtius reaction . Boc-protected am in e
was n ot prepared in th is case an d th e form ed carbam ic acid was directly
decom posed to am in o fun ction un der acidic con dition s (reflux with aque-
ous 2 M HCl in THF). Th is am in o acid in term ediate was th en reduced with
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Novel Racemic Carbocyclic Nucleosides
5
lith ium alum in ium h ydride in THF to th e am in oalcoh ol 11b (total yield
from 10b is 67%). Both am in es were used crude for th e n ext step an d th e
com poun ds were fully ch aracterized as acetyl derivatives 12a (80%) an d
12b (92%).
SCHEME 3
Th e am in oalcoh ols 11a an d 11b were used to build th e target n ucleoside
an alogues usin g stan dard an d described syn th etic procedure (Sch em e 4).
Am in o group was coupled with 4,6-dich loropyrim idin -5-am in e in eth an ol
in th e presen ce of trieth ylam in e an d purin e rin g was closed with trieth yl
orth oform ate in th e presen ce of con cen trated h ydroch loric acid to give
ch loropurin e derivatives 13a (60%) an d 13b (55%). Am m on olysis of th e
ch lorin e atom with liquid am m on ia at 75 °C led to aden in e derivatives
14a (83%) an d 14b (82%). Nucleoph ilic substitution of th e ch lorin e atom
with cyclopropylam in e gave cyclopropylam in o n ucleosides 15a (89%) an d
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Šála et. al.:
15b (94%). Double bon d in n ucleosides 14 an d 15 was utilized in two ways
usin g th e sam e m eth ods as described above for preparation of saturated an d
cis-h ydroxy th ym in e n ucleosides (Sch em e 4). As it was observed previ-
ously13, it was n ot n ecessary to protect th e free h ydroxy group. Hydrogen a-
tion of th e com poun ds 14 an d 15 gave saturated com poun ds 16 an d 17
an d cis-h ydroxylation of 14 an d 15 led to diols 18 an d 19.
SCHEME 4
In con clusion , we h ave syn th esized a n ovel series of carbocyclic n ucleo-
sides based on th e n orborn en e or n orborn an e skeleton , in wh ich th e
n ucleobase an d th e h ydroxym eth yl group h ave a trans-1,2-relation sh ip. We
used two m eth odologies, direct addition of th e n ucleobase by con jugate ad-
dition for th e th ym in e n ucleosides an d build-up strategy for purin e n ucleo-
sides. Th e target com poun ds were tested for in h ibition of cell growth of th e
followin g cell cultures: m ouse leukem ia L1210 cells (ATCC CCL 240), h u-
m an cervix carcin om a HeLaS3 cells (ATCC CCL 2.2), h um an prom yelocytic
leukem ia HL60 cells (ATCC CCL 240), an d h um an T lym ph oblastoid
CCRF-CEM cell lin e (ATCC CCL 119). Non e of th e com poun ds exh ibited
a con siderable activity19. Th e com poun ds were also tested for an ti-HIV-1
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Novel Racemic Carbocyclic Nucleosides
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an d an ti-HIV-2 activity in h um an T-lym ph ocyte (CEM) cells an d for th e
activity again st Coxsackie virus (CVB3) in Vero cells. Prelim in ary data
sh owed th at on ly com poun ds 13a an d 13b exh ibit a weak activity (13a:
EC50 = 20.2 µM, TC50 > 361 µM; 13b: EC50 = 43.3 µM, TC50 > 361 µM) again st
Coxsackie virus (CVB3).
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Büch i B-540 apparatus an d are un corrected. NMR spec-
tra (δ, ppm ; J, Hz) were m easured on a Bruker Avan ce II-600 an d/or Bruker Avan ce II-500
in strum en ts (600.1 or 500.0 MHz for 1H an d 150.9 or 125.7 MHz for 13C) in h exadeutero-
dim eth yl sulfoxide an d referen ced to th e solven t sign al (δ 2.50 an d 39.70, respectively).
Mass spectra were m easured on a ZAB-EQ (VG An alytical) spectrom eter usin g th e FAB ion iza-
tion (ion ization with Xe, acceleratin g voltage 8 kV, th ioglycerol–glycerol 3:1 or bis-
(2-h ydroxyeth yl) disulfide m atrix) or LTQ Orbitrap XL (Th erm o Fish er Scien tific) for ESI.
Colum n ch rom atograph y was perform ed on Silica gel 60 (Fluka) an d th in -layer ch rom atog-
raph y (TLC) on Silufol Silica gel 60 F254 foils (Merck). Solven ts were evaporated at 2 kPa
an d bath tem perature 30–60 °C; th e com poun ds were dried at 50 °C/13 Pa.
Meth yl (1R*,2S*,3S*,4S*)-3-(5-Meth yl-2,4-dioxo-3,4-dih ydropyrim idin -
1(2H)-yl)bicyclo[2.2.1]h ept-5-en e-2-carboxylate (2a) an d
Meth yl (1R*,2R*,3R*,4S*)-3-(5-Meth yl-2,4-dioxo-3,4-dih ydropyrim idin -
1(2H)-yl)bicyclo[2.2.1]h ept-5-en e-2-carboxylate (2b)
Method A: A m ixture of th ym in e (340 m g, 2.70 m m ol), m eth yl bicyclo[2.2.1]h epta-
2,5-dien e-2-carboxylate 1 (600 m g, 4 m m ol) an d DBU (0.2 m l, 1.35 m m m ol) in DMF (10 m l)
was stirred at 75 °C for 72 h in an argon atm osph ere, th en AcOH (0.1 m l) was added
an d m ixture was evaporated. Th e residue was adsorbed on silica gel an d ch rom atograph ed
on silica gel colum n (200 g) in eth yl acetate–toluen e (20:1). Mixed fraction s were re-
ch rom atograph ed. It was obtain ed 260 m g (35%) of product 2a an d 75 m g (10%) of product
2b. An alytical sam ples were obtain ed by crystallization from eth yl acetate.
Method B: A m ixture of th ym in e (340 m g, 2.70 m m ol), m eth yl bicyclo[2.2.1]h epta-
2,5-dien e-2-carboxylate 1 (600 m g, 4 m m ol) an d potassium carbon ate (550 m g, 4 m m ol) in
DMF (10 m l) was stirred at 75 °C for 72 h in an argon atm osph ere an d m ixture was evapo-
rated. Th e residue was adsorbed on silica gel an d ch rom atograph ed on silica gel colum n
(200 g) in eth yl acetate–toluen e (20:1). Mixed fraction s were rech rom atograph ed. It was ob-
tain ed 120 m g (16%) of product 2a an d 292 m g (40%) of product 2b.
Methyl (1R*,2S*,3S*,4S*)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (2a): M.p. 178–181 °C. 1H NMR: 1.55 dq, 1 H, J(7b,1) ~ J(7b,3) ~
J(7b,4) ~ 1.7, Jgem = 9.3 (H-7b); 1.79 brdt, 1 H, J(7a,1) ~ J(7a,4) ~ 1.2 (H-7a); 1.79 d, 3 H,
J(CH3,6′) = 1.0 (CH3); 3.01 brdq, 1 H, J(4,1) ~ 1.5, J(4,5) = 3.3 (H-4); 3.11 brt, 1 H, J(2,1) =
3.6, J(2,3) = 4.2 (H-2); 3.12 m , 1 H (H-1); 3.55 s, 3 H (OCH3); 4.24 brdd, 1 H, J(3,4) < 1.0
(H-3); 6.13 dd, 1 H, J(6,1) = 2.6, J(6,5) = 5.6 (H-6); 6.30 dd, 1 H, J(5,4) = 3.3 (H-5); 7.68 q,
1 H (H-6′); 11.26 s, 1 H (NH). 13C NMR: 12.30 (CH3); 45.30 (C-1); 46.91 (C-4); 46.93 (C-7);
48.38 (C-2); 51.74 (OCH3); 59.96 (C-3); 108.68 (C-5′); 136.25 (C-5); 136.80 (C-6); 137.56
(C-2′); 163.92 (C-4′); 172.94 (CO). FAB MS, m/z (rel.%): 277 (91) [M + H], 245 (20), 127 (61),
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Šála et. al.:
91 (100). For C14H16N2O4 (276.3) calculated: 60.86% C, 5.84% H, 10.14% N; foun d: 60.66% C,
5.81% H, 9.91% N.
Methyl (1R*,2R*,3R*,4S*)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (2b): M.p. 198–201 °C. 1H NMR: 1.43 dq, 1 H, J(7b,1) = 1.8, J(7b,2) =
J(7b,4) = 2.2, Jgem = 9.2 (H-7b); 1.71 brdt, 1 H, J(7a,1) ~ J(7a,4) ~ 1.1 (H-7a); 1.73 d, 3 H,
J(CH3,6′) = 1.2 (CH3); 2.59 dd, 1 H, J(2,3) = 4.8 (H-2); 3.04 m , 1 H (H-1); 3.13 m , 1 H (H-4);
3.64 s, 3 H (OCH3); 5.10 dd, 1 H, J(3,4) = 3.4 (H-3); 6.14 dd, 1 H, J(5,4) = 2.2, J(5,6) = 5.6
(H-5); 6.49 dd, 1 H, J(6,1) = 3.2 (H-6); 7.22 q, 1 H (H-6′); 11.27 s, 1 H (NH). 13C NMR: 12.28
(CH3); 45.66 (C-4); 46.10 (C-7); 47.22 (C-1); 47.76 (C-2); 52.13 (OCH3); 59.41 (C-3); 108.08
(C-5′); 133.64 (C-5); 137.74 (C-6′); 138.86 (C-6); 151.69 (C-2′); 163.88 (C-4′); 173.95 (CO).
FAB MS, m/z (rel.%): 277 (100) [M + H], 245 (17), 127 (36), 91 (80). For C14H16N2O4 (276.3)
calculated: 60.86% C, 5.84% H, 10.14% N; foun d: 60.74% C, 5.70% H, 9.96% N.
Meth yl (1R*,2R*,3R*,4S*)-3-(5-Meth yl-2,4-dioxo-3,4-dih ydropyrim idin -
1(2H)-yl)bicyclo[2.2.1]h eptan e-2-carboxylate (3a) an d
Meth yl (1R*,2S*,3S*,4S*)-3-(5-Meth yl-2,4-dioxo-3,4-dih ydropyrim idin -
1(2H)-yl)bicyclo[2.2.1]h eptan e-2-carboxylate (3b)
A m ixture of un saturated ester 2 (280 m g, 1 m m ol) an d palladium on ch arcoal (100 m g) in
m eth an ol (30 m l) was stirred in atm osph ere of h ydrogen for 5 h . Th e catalyst was filtered
off an d wash ed with m eth an ol an d filtrate was evaporated. Th e residue was ch rom atog-
raph ed on silica gel (10 g) in eth yl acetate–toluen e (10:1).
Methyl (1R*,2R*,3R*,4S*)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)bicyclo[2.2.1]-
heptane-2-carboxylate (3a): Yield 246 m g (86%) as a foam . 1H NMR: 1.25 dddd, 1 H, J(5en ,7a) =
2.2, J(5en ,6ex) = 4.6, J(5en ,6en ) = 8.8, Jgem = 12.2 (H-5en ); 1.28 ttd, 1 H, J(6ex,2) = 1.7,
J(6ex,1) = 4.5, J(6ex,5ex) = 12.2 (H-6ex); 1.36 dq, 1 H, J(7b,1) ~ J(7b,3) ~ J(7b,4) = 1.6, Jgem
=
10.6 (H-7b); 1.41 dddd, 1 H, J(6en ,7a) = 1.8, J(6en ,5ex) = 4.4 (H-6en ); 1.62 tt, 1 H, J(5ex,4) =
4.5 (H-5ex); 1.75 brdpen t, 1 H, J(7a,1) ~ J(7a,4) = 1.7 (H-7a); 1.78 d, 3 H, J(CH3,6′) = 1.1
(CH3); 2.43 brdq, 1 H, J(4,1) = 4.5 (H-4); 2.54 brtq, 1 H, J(1,2) = 4.5 (H-1); 2.99 brdt, 1 H,
J(2,3) = 5.0 (H-2); 3.61 s, 3 H (OCH3); 4.37 dd, 1 H (H-3); 7.61 q, 1 H (H-6′); 11.23 s, 1 H
(NH). 13C NMR: 12.30 (CH3); 23.56 (C-6); 27.35 (C-5); 37.54 (C-7); 40.03 (C-1); 41.00 (C-4);
51.72 (C-2); 53.15 (OCH3); 61.21 (C-3); 108.43 (C-5′); 137.50 (C-6′); 151.33 (C-2′); 163.91
(C-4′); 172.63 (CO). FAB MS, m/z (rel.%): 279 (100) [M + H], 247 (15), 153 (10), 127 (54),
121 (30). For C14H18N2O4 (278.3) calculated: 60.42% C, 6.52% H, 10.07% N; foun d: 60.29% C,
6.63% H, 9.84% N.
Methyl (1R*,2S*,3S*,4S*)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)bicyclo[2.2.1]-
heptane-2-carboxylate (3b): Yield 236 m g (84%). M.p. 212–215 °C (eth yl acetate). 1H NMR:
1.25 dddd, 1 H, J(5en ,7a) = 2.0, J(5en ,6ex) = 4.3, J(5en ,6en ) = 8.8, Jgem = 12.2 (H-5en );
1.30 dq, 1 H, J(7b,1) ~ J(7b,2) ~ J(7b,4) = 1.7, Jgem = 10.7 (H-7b); 1.42 tddd, 1 H, J(5ex,3) =
1.7, J(5ex,4) = 4.4, J(5ex,6en ) = 4.9, J(5ex,6ex) = 12.0 (H-5ex); 1.57 brdpen t, 1 H, J(7a,1) ~
J(7a,4) ~ J(7a,4) ~ 1.5 (H-7a); 1.60 m , 2 H (H-6en , H-6ex); 1.79 d, 3 H, J(CH3,6′) = 1.0 (CH3);
2.49 m (H-1); 2.51 m , 1 H (H-4); 2.84 dd, 1 H, J(2,3) = 6.0 (H-2); 3.61 s, 3 H (OCH3);
4.81 dd, 1 H, J(3,4) = 3.9 (H-3); 7.51 q, 1 H (H-6′); 11.29 s, 1 H (NH). 13C NMR: 12.22 (CH3);
21.00 (C-5); 27.96 (C-6); 36.17 (C-7); 40.20 (C-4); 41.41 (C-1); 47.32 (C-2); 52.07 (OCH3);
60.46 (C-3); 108.18 (C-5′); 138.33 (C-6′); 151.69 (C-2′); 163.86 (C-4′); 173.98 (CO). FAB MS,
m/z (rel.%): 279 (100) [M + H], 247 (23), 153 (10), 127 (29), 121 (44). For C14H18N2O4
(278.3) calculated: 60.42% C, 6.52% H, 10.07% N; foun d: 60.29% C, 6.54% H, 9.97% N.
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Novel Racemic Carbocyclic Nucleosides
9
Meth yl (1R*,2R*,3R*,4S*,5S*,6R*)-5,6-Dih ydroxy-3-(5-m eth yl-2,4-dioxo-
3,4-dih ydropyrim idin -1(2H)-yl)bicyclo[2.2.1]h eptan e-2-carboxylate (4a) an d
Meth yl (1R*,2S*,3S*,4S*,5S*,6R*)-5,6-Dih ydroxy-3-(5-m eth yl-2,4-dioxo-
3,4-dih ydropyrim idin -1(2H)-yl)bicyclo[2.2.1]h eptan e-2-carboxylate (4b)
Ester 2 (250 m g, 0.90 m m ol) was dissolved in m ixture of aceton e (25 m l) an d water (2.5 m l).
Solution of NMMO (50%, 1.6 m l) an d aqueous solution of osm ium tetroxide (30 µl, 20%)
was added an d th e reaction m ixture was stirred at r.t. for 3 h an d taken down . Th e product
was isolated by colum n ch rom atograph y on silica gel (50 g) in eth yl acetate–aceton e–eth an ol–
water (105:15:3:2).
Methyl (1R*,2R*,3R*,4S*,5S*,6R*)-5,6-dihydroxy-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)bicyclo[2.2.1]heptane-2-carboxylate (4a): Yield 275 m g (98%). M.p. 206–209 °C (eth a-
n ol). 1H NMR: 1.33 brdpen t, 1 H, J (7a,1) ~ J(7a,4) ~ J(7a,5) ~ J(7a,6) ~ 1.5, Jgem = 10.9
(H-7a); 1.77 d, 3 H, J(CH3,6′) = 1.1 (CH3); 1.87 dq, 1 H, J(7b,1) ~ J(7b,3) ~ J(7b,4) = 1.7
(H-7b); 2.23 brq, 1 H, J(4,1) = 1.6 (H-4); 2.31 brdq, 1 H, J(1,2) = 4.6 (H-1); 2.97 dd, 1 H,
J(2,3) = 5.3 (H-2); 3.61 s, 3 H (OCH3); 3.65 m , 2 H (H-5, H-6); 4.30 dd, 1 H (H-3); 4.79 d,
1 H, J(OH,5) = 4.5 (OH-5); 4.83 d, 1 H, J(OH,6) = 4.5 (OH-6); 7.58 brq, 1 H (H-6′); 11.23 s,
1 H (NH). 13C NMR: 12.25 (CH3); 31.45 (C-7); 46.36 (C-2); 48.50 (C-1); 49.96 (C-5); 51.88
(OCH3); 57.77 (C-3); 68.86 (C-6); 71.87 (C-5); 108.65 (C-5′); 137.48 (C-6′); 151.32 (C-2′);
163.89 (C-4′); 173.13 (CO). FAB MS, m/z (rel.%): 311 (32) [M + H], 279 (10), 153 (10), 127
(100). For C14H18N2O6 (310.3) calculated: 54.19% C, 5.85% H, 9.03% N; foun d: 53.94% C,
6.00% H, 8.86% N.
Methyl (1R*,2S*,3S*,4S*,5S*,6R*)-5,6-dihydroxy-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)bicyclo[2.2.1]heptane-2-carboxylate (4b): Yield 255 m g (91%). M.p. 219–221 °C (eth a-
n ol). 1H NMR: 1.33 brdpen t, 1 H, J(7a,1) ~ J(7a,4) ~ J(7a,5) ~ J(7a,6) ~ 1.5, Jgem = 10.6 (H-7a);
1.78 dq, 1 H, J(7b,1) ~ J(7b,2) ~ J(7b,4) ~ 1.7 (H-7b); 1.79 d, 3 H, J(CH3,6′) = 1.1 (CH3);
2.25 brq, 1 H, J(1,4) ~ 1.2, J(1,6) < 1.0 (H-1); 2.34 brdq, 1 H, J(4,3) = 4.0 (H-4); 2.82 dd, 1 H,
J(2,3) = 6.5 (H-2); 3.62 s, 3 H (OCH3); 3.66 brdt, 1 H, J(5,6) ~ J(5,OH) ~ 5.2 (H-5); 3.96 brtt,
1 H, J(6,OH) ~ 5.0 (H-6); 4.63 dd, 1 H (H-3); 4.71 d, 1 H (OH-6); 4.83 d, 1 H (OH-5);
7.47 brq, 1 H (H-6′); 11.24 s, 1 H (NH). 13C NMR: 12.19 (CH3); 29.90 (C-7); 43.79 (C-2);
47.16 (C-4); 48.17 (C-1); 52.20 (OCH3); 58.78 (C-3); 67.25 (C-5); 71.98 (C-6); 108.46 (C-5′);
138.44 (C-6′); 151.67 (C-2′); 163.82 (C-4′); 173.58 (CO). FAB MS, m/z (rel.%): 311 (100) [M +
H], 293 (21), 127 (80). For C14H18N2O6 (310.3) calculated: 54.19% C, 5.85% H, 9.03% N;
foun d: 54.10% C, 5.93% H, 8.65% N.
Reduction of th e Meth yl Esters 2, 3 an d 4. Gen eral Procedure
Solution of m eth yl ester 2, 3 or 4 (1 m m ol) in an h ydrous THF (10 m l) was added dropwise
to a 1 M solution of LiAlH4 in THF (2.5 m l, 2.5 equiv.) at r.t. in an argon atm osph ere. Reac-
tion m ixture was stirred at r.t. for 4 h . After addin g eth yl acetate (5 m l), eth an ol (5 m l) an d
water (5 m l), reaction m ixture was filtered th rough diatom aceous earth an d residual solids
were wash ed with h ot water–eth an ol (1:1). Glacial AcOH (3 m l) an d CH2Cl2 (10 m l) were
added to th e residual solids. Th is m ixture was filtered, com bin ed filtrates were evaporated
an d th e crude product was purified by colum n ch rom atograph y on silica gel (35 g).
1-[(1R*,2R*,3R*,4S*)-3-(Hydroxymethyl)bicyclo[2.2.1]hept-5-en-2-yl]-5-methylpyrimidine-
2,4(1H,3H)-dione (5a): Ch rom atograph y in eth yl acetate–aceton e–eth an ol–water (100:15:6:4)
afforded 134 m g (54%) of 5a as an oily residue, wh ich slowly crystallized upon stan din g in
aceton e–m eth an ol (10:1) in refrigerator. M.p. 200–203 °C (decom p.). 1H NMR: 1.54 dq, 1 H,
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10
Šála et. al.:
J(7b,1) ~ J(7b,2) ~ J(7b,4) ~ 1.6, Jgem = 9.2 (H-7b); 1.79 d, 3 H, J(CH3,6′) = 1.0 (CH3);
1.80 brdq, 1 H, J ~ 1.2 (3 ×) (H-7a); 2.22 dddd, 1 H, J(3,4) = 3.3, J(3,2) = 4.9, J(3,CHa) = 6.2,
J(3,CHb) = 8.8 (H-3); 2.76 brdq, 1 H, J(1,4) = 1.5, J(1,7a) = 1.8, J(1,6) = 3.2 (H-1); 2.93 m , 1 H
(H-4); 3.10 ddd, 1 H, J(CHa,OH) = 5.2, Jgem = 10.8 (CHa); 3.42 ddd, 1 H, J(CHb,OH) = 5.2
(CHb); 3.67 dd, 1 H (H-2); 4.56 t, 1 H (OH); 6.21 dd, 1 H, J(5,4) = 2.7, J(5,6) = 5.6 (H-5);
6.27 brdd, 1 H, J(6,7a) = 0.7 (H-6); 7.67 q, 1 H (H-6′); 11.25 s, 1 H (NH). 13C NMR: 12.31
(CH3); 43.13 (C-3); 46.53 (C-7); 47.48 (C-4); 47.55 (C-1); 59.09 (C-2); 64.28 (OCH2); 108.82
(C-5′); 136.25 (C-6); 137.27 (C-5); 137.71 (C-6′); 151.88 (C-2′); 163.83 (C-4′). FAB MS, m/z
(rel.%): 249 (67) [M + H], 201 (20), 127 (64), 91 (100). For C13H16N2O4 (248.3) calculated:
62.89% C, 6.20% H, 11.28% N; foun d: 62.64% C, 6.50% H, 10.92% N.
1-[(1R*,2S*,3S*,4S*)-3-(Hydroxymethyl)bicyclo[2.2.1]hept-5-en-2-yl]-5-methylpyrimidine-
2,4(1H,3H)-dione (5b): Ch rom atograph y in eth yl acetate–aceton e–eth an ol–water (100:15:6:4)
afforded 170 m g (68.5%) of 5b as an oily residue, wh ich slowly crystallized upon stan din g
in aceton e–m eth an ol (10:1) in refrigerator. M.p. 209–211 °C. 1H NMR: 1.34 dq, 1 H, J(7b,1) ~
J(7b,3) ~ J(7b,4) ~ 2.0, Jgem = 9.0 (H-7b); 1.68 brdt, 1 H, J(7a,1) ~J(7a,4) ~ 1.5 (H-7a); 1.72 d,
3 H, J(CH3,6′) = 1.2 (CH3); 1.83 brdddd, 1 H, J(3,2) = 4.8, J(3,CHa) = 6.2, J(3,CHb) = 7.6
(H-3); 2.78 m , 1 H, J(4,1) = 2.0, J(4,5) = 3.1 (H-4); 2.91 m , 1 H (H-1); 3.49 ddd, 1 H,
J(CHa,OH) = 5.1, Jgem = 10.6 (CHa); 3.56 ddd, 1 H, J(CHb,OH) = 5.1 (CHb); 4.63 dd, 1 H,
J(2,1) = 3.4 (H-2); 4.77 t, 1 H (OH); 5.97 dd, 1 H, J(6,1) = 2.8, J(6,5) = 5.7 (H-6); 6.51 dd, 1 H
(H-5); 7.16 q, 1 H (H-6′); 11.23 brs, 1 H (NH). 13C NMR: 12.36 (CH3); 44.33 (C-4); 45.38
(C-1); 45.81 (C-7); 46.30 (C-3); 58.02 (C-2); 63.91 (OCH2); 104.62 (C-5′); 132.34 (C-6);
139.59 (C-5); 137.61 (C-6′); 151.77 (C-2′); 163.85 (C-4′). FAB MS, m/z (rel.%): 249 (67) [M +
H], 201 (20), 127 (27), 91 (100). For C13H16N2O4·1/4H2O (252.8) calculated: 61.77% C,
6.58% H, 11.08% N; foun d: 61.89% C, 6.81% H, 10.65% N.
1 -[(1 R*,2 S*,3 S*,4 S*)-3 -(Hydroxym eth yl)bicyclo[2 .2 .1 ]h ept-2 -yl]-5 -m eth ylpyrim idin e-
2,4(1H,3H)-dione (6a): Ch rom atograph y in eth yl acetate–toluen e–aceton e–eth an ol–water
(85:20:15:3:2) yielded 138 m g (55%) of 6a as a viscous oil, slowly crystallized from aceton e–
m eth an ol (10:1). M.p. 197–199 °C. 1H NMR: 1.26 dq, 1 H, J(7b,1) ~ J(7b,2) ~ J(7b,3) ~
J(7b,4) = 1.5, Jgem = 10.6 (H-7b); 1.32 ttd, 1 H, J(5ex,3) = 1.3 J(5ex,4) ~ J(5ex,6en ) ~ 4.2,
J(5ex,6ex) ~ Jgem = 12.2 (H-5ex); 1.47 dddd, 1 H, J(5en ,7a) = 2.0, J(5en ,6ex) = 4.4, J(5en ,6en ) =
8.9, Jgem = 12.2 (H-5en ); 1.54 tt, 1 H, J(6ex,1) = 4.5 (H-6ex); 1.75 brdpen t, 1 H, J(7a,1) ~
J(7a,4) ~ J(7a,6en ) ~ 1.7 (H-7a); 1.79 d, 3 H, J(CH3,6′) = 1.1 (CH3); 2.12 m , 1 H (H-3);
2.16 brdq, 1 H, J(1,4) =1.5 (H-1); 2.37 brtq, 1 H, J(4,7b) ~ 1.3, J(4,3) = 4.0 (H-4); 3.38 ddd,
1 H, J(CHa,OH) = 5.0, J(CHa,3) = 8.9, Jgem = 10.7 (CHa); 3.55 ddd, 1 H, J(CHb,OH) = 5.2,
J(CHb,3) = 6.2 (CHb); 3.76 dd, 1 H, J(2,3) = 6.1 (H-2); 4.48 t, 1 H (OH); 7.61 q, 1 H (H-6′);
11.20 s, 1 H (NH). 13C NMR: 12.31 (CH3); 21.33 (C-5); 28.88 (C-6); 37.16 (C-7); 37.72 (C-4);
42.32 (C-1); 50.93 (C-3); 61.00 (OCH2); 61.11 (C-2); 108.78 (C-5′); 137.69 (C-6′); 151.62
(C-2′); 163.80 (C-4′). FAB MS, m/z (rel.%): 251 (100) [M + H], 127 (30). For C13H18N2O4
(250.3) calculated: 62.38% C, 7.25% H, 11.19% N; foun d: 62.11% C, 7.31% H, 10.97% N.
1 -[(1 R*,2 R*,3 R*,4 S*)-3 -(Hydroxym eth yl)bicyclo[2 .2 .1 ]h ept-2 -yl]-5 -m eth ylpyrim idin e-
2,4(1H,3H)-dione (6b ): Ch rom atograph y in eth yl acetate–toluen e–aceton e–eth an ol–water
(85:15:15:6:4) yielded 175 m g (70%) of 6b as a viscous oil, slowly crystallized from aceton e.
M.p. 178–180 °C. 1H NMR: 1.20 dq, 1 H, J(7b,1) ~ J(7b,3) ~ J(7b,4) = 1.7, Jgem = 10.4 (H-7b);
1.21 dddd, 1 H, J(6en ,7a) = 2.0 J(6en ,5ex) = 4.2, J(6en ,5en ) = 9.0, Jgem = 12.2 (H-6en ); 1.35 m ,
1 H (H-6ex); 1.56 m , 2 H (H-5en , H-5en ); 1.61 brdpen t, 1 H, J(7a,1) ~ J(7a,4) ~ J(7a,5en ) ~
1.5 (H-7a); 1.81 d, 3 H, J(CH3,6′) = 1.0 (CH3); 1.94 brqd, 1 H, J(3,2) ~ J(3,CH2) ~ 7.0 (H-3);
2.18 m , 1 H (H-4); 2.16 brtq, 1 H, J(1,4) ~ 1.0, J(1,2) ~ J(1,6ex) ~ 4.0 (H-1); 3.20 ddd, 1 H,
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Novel Racemic Carbocyclic Nucleosides
11
J(CHa,OH) = 5.5, J(CHa,3) = 6.6, Jgem = 10.5 (CHa); 3.34 ddd, 1 H, J(CHb,OH) = 4.6,
J(CHb,3) = 7.6 (CHb); 4.21 ddd, 1 H, J(2,6ex) = 1.8 (H-2); 4.48 dd, 1 H, J(OH,CHa) = 5,
J(OH,CHb) = 4.6 (OH); 7.50 brq, 1 H (H-6′); 11.24 s, 1 H (NH). 13C NMR: 12.30 (CH3); 21.40
(C-6); 28.30 (C-5); 35.79 (C-7); 38.55 (C-4); 40.61 (C-1); 44.88 (C-3); 61.15 (C-2); 63.86
(OCH2); 107.68 (C-5′); 138.44 (C-6′); 151.80 (C-2′); 163.88 (C-4′). FAB MS, m/z (rel.%): 251
(100) [M + H], 127 (30). For C13H18N2O4 (250.3) calculated: 62.38% C, 7.25% H, 11.19% N;
foun d: 62.11% C, 7.31% H, 10.51% N.
1-[(1R*,2R*,3S*,4S*,5S*,6R*)-5,6-Dihydroxy-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-
5-methylpyrimidine-2,4(1H,3H)-dione (7a): Ch rom atograph y in eth yl acetate–aceton e–eth an ol–
water (36:6:5:3) yielded 110 m g (39%) of 7a as a viscous oil, slowly crystallized from
2-propan ol. M.p. 225–227 °C. 1H NMR: 1.55 brdpen t, 1 H, J(7a,1) ~ J(7a,4) ~ J(7a,5) ~ J(7a,6) ~
1.6, Jgem = 10.9 (H-7a); 1.76 dq, 1 H, J(7b,1) ~ J(7b,2) ~ J(7b,4) ~ 1.2 (H-7b); 1.79 d, 3 H,
J(CH3,6′) = 1.0 (CH3); 1.99 brdq, 1 H, J(1,4) ~ 1.5, J(1,6) < 1.0 (H-1); 2.07 dtd, 1 H, J(3,4) =
4.0, J(3,2) = 6.2, J(3,CHa) = 6.2, J(3,CHb) = 8.7 (H-3); 2.17 brdq, 1 H, J(4,1) = 1.8 (H-4);
3.38 ddd, 1 H, J(CHa,OH) = 5.3, Jgem = 10.5 (CHa); 3.50 ddd, 1 H, J(CHb,OH) = 4.8 (CHb);
3.60 brtd, 1 H, J(6,5) ~ J(6,OH) ~ 5.0 (H-6); 3.77 dd, 1 H (H-2); 3.87 brtd, 1 H, J(5,OH) = 5.2,
J(5,4) ~ 1.0 (H-5); 4.56 dd, 1 H (CH2OH); 4.68 d, 1 H (OH-5); 4.70 d, 1 H (OH-6); 7.56 brq,
1 H (H-6′); 11.22 s, 1 H (NH). 13C NMR: 12.27 (CH3); 31.15 (C-7); 44.92 (C-3); 44.48 (C-4);
49.64 (C-1); 57.29 (C-2); 60.00 (OCH2); 67.62 (C-6); 72.39 (C-5); 108.99 (C-5′); 137.67 (C-6′);
151.58 (C-2′); 163.79 (C-4′). FAB MS, m/z (rel.%): 283 (60) [M + H], 265 (10) [M + H – H2O],
181 (6), 127 (100), 91 (31). For C13H18N2O5 (282.3) calculated: 55.31% C, 6.43% H, 9.92% N;
foun d: 55.09% C, 6.53% H, 9.50% N.
1-[(1R*,2S*,3R*,4S*,5S*,6R*)-5,6-Dihydroxy-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-
5-methylpyrimidine-2,4(1H,3H)-dione (7b): Ch rom atograph y in eth yl acetate–aceton e–eth an ol–
water (36:6:5:3) yielded 164 m g (58%) of 7b as a viscous oil, slowly crystallized from
2-propan ol–water (10:1). M.p. 232–234 °C. 1H NMR: 1.35 brdpen t, 1 H, J(7a,1) ~ J(7a,4) ~
J(7a,5) ~ J(7a,6) ~ 1.5, Jgem = 10.6 (H-7a); 1.69 dq, 1 H, J(7b,1) ~ J(7b,3) ~ J(7b,4) ~ 1.7
(H-7b); 1.80 d, 3 H, J(CH3,6′) = 1.1 (CH3); 1.94 brqd, 1 H, J(3,2) ~ J(3,CH2) ~ 6.6 (H-3);
2.00 brq, 1 H, J(4,1) = 1.3, J(4,5) = 1.0 (H-4); 2.19 brdq, 1 H, J(1,2) ~ 4.0 (H-1); 3.25 ddd,
1 H, J(CHa,OH) = 5.4, J(CHa,3) = 6.6, Jgem = 10.5 (CHa); 3.36 ddd, 1 H, J(CHb,OH) = 4.8,
J(CHb,3) = 7.4 (CHb); 3.60 brdt, 1 H, J(6,5) ~ J(6,OH) ~ 5.2 (H-6); 3.94 brtt, 1 H, J(5,OH) ~
5.2 (H-5); 4.08 dd, 1 H (H-2); 4.59 d, 1 H (OH-5); 4.70 d, 1 H (OH-6); 4.75 t, 1 H (CH2OH);
7.47 brq, 1 H (H-6′); 11.29 s, 1 H (NH). 13C NMR: 12.17 (CH3); 29.36 (C-7); 40.47 (C-3);
45.79 (C-4); 47.65 (C-1); 59.10 (C-2); 63.33 (OCH2); 67.60 (C-6); 72.49 (C-5); 107.96 (C-5′);
138.48 (C-6′); 151.77 (C-2′); 163.83 (C-4′). FAB MS, m/z (rel.%): 283 (27) [M + H], 265 (8)
[M + H – H2O], 215 (10), 127 (15), 91 (100). For C13H18N2O5 (282.3) calculated: 55.31% C,
6.43% H, 9.92% N; foun d: 55.32% C, 6.68% H, 9.75% N.
(1R*,2R*,3R*,6S*,7S*,9R*)-2-Iodo-5-oxo-4-oxatricyclo[4.2.1.03,7]nonane-9-carboxylic Acid (9a) and
Ethyl (1R*,2R*,3R*,6S*,7S*,9R*)-2-Iodo-5-oxo-4-oxatricyclo[4.2.1.03,7]nonane-9-carboxylate (9b)
Mixture of th e fum aric acid m on oeth yl ester (7.5 g, 52 m m ol), cyclopen tadien e 8 (5.2 m l,
62 m m ol, fresh ly distilled) an d dioxan e (25 m l) was h eated at 60 °C for 1 h . Reaction m ix-
ture was evaporated an d dissolved in saturated Na2CO3 aqueous solution (200 m l) an d water
ph ase was wash ed with h exan e (75 m l). Water ph ase was diluted with water (100 m l) an d
ch loroform (100 m l). Iodin e (13.2 g, 52 m m ol), potassium iodide (5 g) an d sodium bicar-
bon ate (26 g) were added an d reaction m ixture was vigorously stirred overn igh t. Solid
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Šála et. al.:
Na2S2O3 was added un til th e brown color disappeared an d th e organ ic ph ase was separated.
Water ph ase was wash ed with CHCl3 (2 × 100 m l). Organ ic ph ases were dried over an -
h ydrous sodium sulfate an d evaporated. Recrystallization of th e crude product from eth yl
acetate gave 7.1 g (41%) of 9b. NMR spectrum was in agreem en t with previously publish ed
data17. pH of th e water ph ase was adjusted to 4 an d water ph ase was extracted with CHCl3
(4 × 100 m l). Organ ic ph ases were dried over an h ydrous sodium sulfate an d evaporated.
Crude product was purified by ch om atograph y on silica gel (250 g) in toluen e–eth yl acetate
(4:1) to afford 6.1 g of 9a (31%). NMR spectrum was in agreem en t with previously publish ed
data20
.
tert-Butyl [(1R*,2R*,3R*,6S*,7S*,9R*)-2-Iodo-5-oxo-4-oxatricyclo[4.2.1.03,7]non-9-yl]carbamate (10a)
To a solution of th e carboxylic acid 9a (3.42 g, 11.1 m m ol) an d trieth ylam in e (1.9 m l,
13.5 m m ol) in aceton e (45 m l) at 0 °C, eth yl ch loroform ate (1.1 m l, 11.5 m m ol) was added
dropwise over several m in utes. After th e addition was com plete th e solution was stirred at
0 °C for 1 h . A solution of sodium azide (2.17 g, 33.4 m m ol) in water (35 m l) was th en
added an d th e reaction m ixture was stirred at 0 °C for an addition al 1 h . Th e solution was
th en poured in ice water (100 m l) an d th e resultin g m ixture was extracted with eth yl acetate
(4 × 100 m l). Th e com bin ed organ ic ph ases were wash ed with saturated solution of sodium
bicarbon ate (2 × 100 m l), dried over an h ydrous sodium sulfate an d evaporated. Residue was
redissolved in dry toluen e (50 m l), h eated un der reflux for 1.5 h an d evaporated. tert-Butyl
alcoh ol (45 m l) was th en added to th e residue an d th e solution was refluxed for 2.5 h . Reac-
tion m ixture was evaporated an d ch rom atograph ed on a colum n of silica gel (250 g) in tolu-
en e–eth yl acetate (7:1) to afford 2.14 g (50.9%) of carbam ate 10a as a wh ite solid. M.p.
169–170 °C. 1H NMR: 1.39 s, 9 H (CH3); 2.01 bd, 1 H, Jgem = 11.9 (H-8a); 2.07 bd, 1 H, Jgem
= 11.9 (H-8b); 2.38 bd, 1 H, J(6,7) = 4.7 (H-6); 2.49 m , 1 H (H-1); 3.16 tq, 1 H, J(7,3) = J(7,6)
= 4.9, J(7,8) = J(7,1) = 1.5 (H-7); 3.72 bd, 1 H, J(9,NH) = 6.8 (H-9); 4.05 bd, 1 H, J(2,8b) = 2.3
(H-2); 5.06 dm , 1 H, J(3,7) = 5.1 (H-3); 7.44 bd, 1 H, J(NH,9) = 6.8 (NH). 13C NMR: 27.54
(C-2); 28.39 (CH3); 34.03 (C-8); 45.61 (C-7); 46.12 (C-6); 53.30 (C-1); 55.64 (C-9); 78.80
(C(CH3)3); 87.83 (C-3); 154.68 (CON); 177.03 (COO). FAB MS, m/z (rel.%): 380 (1) [M + H],
324 (48), 57 (100). For C13H18INO4 (379.2) calculated: 41.18% C, 4.78% H, 33.47% I, 3.69% N;
foun d: 41.20% C, 4.84% H, 33.56% I, 3.58% N.
(1R*,2S*,3S*,4S*)-3-(Eth oxycarbon yl)bicyclo[2.2.1]h ept-5-en e-2-carboxylic Acid (10b)
A m ixture of iodoester 9b (3.36 g, 10 m m ol) an d zin c dust (2.62 g, 40 m m ol) in eth an ol–
water (60 m l, 5:1) was refluxed for 1 h . Th e reaction m ixture was cooled an d filtered
th rough celite pad. Th e filtrate was evaporated, dissolved in eth yl acetate (250 m l) an d
organ ic ph ase was wash ed with brin e (50 m l). Water ph ase was th en extracted with eth yl ac-
etate (100 m l). Com bin ed organ ic ph ases were dried over an h ydrous sodium sulfate an d
evaporated. Crude product (2.1 g, 100%) was used in th e n ext step with out purification .
An alytical sam ple was ch rom atograph ed on silica gel colum n in toluen e–eth yl acetate (7:1).
1H NMR: 1.20 t, 3 H, J(CH3,CH2) = 7.1 (CH3); 1.34 dm , 1 H, Jgem = 8.6 (H-7a); 1.51 dm , 1 H,
Jgem = 8.7 (H-7b); 2.47 m , 1 H (H-3); 3.02 m , 1 H (H-4); 3.16–3.18 m , 2 H (H-1, H-2);
4.06–4.12 m , 2 H (CH2CH3); 6.07 bdd, 1 H, J(6,5) = 5.8, J(6,1) = 2.2 (H-6); 6.29 dd, 1 H,
J(5,6) = 5.7, J(5,4) = 3.1 (H-5). 13C NMR: 14.34 (CH3); 45.22 (C-1); 46.80 (C-3); 47.27 (C-4);
47.28 (C-7); 47.77 (C-2); 60.67 (CH2CH3); 135.34 (C-6); 137.62 (C-5); 174.12, 174.17 (COO).
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Novel Racemic Carbocyclic Nucleosides
13
ESI MS, m/z (rel.%): 233 (100) [M + Na], 211 (20) [M + H]. For C11H14O4 (210.2) calculated:
62.85% C, 6.71% H; foun d: 62.66% C, 6.68% H.
[(1R*,2S*,3S*,4S*)-3-Am in obicyclo[2.2.1]h ept-5-en -2-yl]m eth an ol (11a)
A m ixture of iodolacton e 10a (2.14 g, 5.64 m m ol) an d zin c dust (1.5 g, 23.1 m m ol) in eth a-
n ol (140 m l) was refluxed for 2 h . Th e reaction m ixture was cooled an d filtered th rough
celite pad. Th e filtrate was evaporated, dissolved in eth yl acetate (250 m l) an d organ ic ph ase
was wash ed with brin e (50 m l). Water ph ase was th en extracted with eth yl acetate (100 m l).
Com bin ed organ ic ph ases were dried over an h ydrous sodium sulfate an d evaporated. Th e
residue was dissolved in m eth an ol (120 m l), aqueous HCl was added (3 m l, 1:1), reaction
m ixture was stirred for 4 days an d evaporated. Th e residue was redissolved in water (150 m l).
Water ph ase was extracted with eth er (100 m l) an d evaporated. Th e residue (from water
ph ase) was th en dried in vacuum oven at 60 °C for 1 day an d suspen ded in dry THF (50 m l).
LiAlH4 (powder, 1 g, 26.3 m m ol) was carefully added to th e suspen sion . Th e reaction m ix-
ture was refluxed un der argon for 12 h . After slowly addin g eth yl acetate (15 m l), eth an ol
(15 m l), water (25 m l) an d aqueous KOH (20 m l, 10%), th e reaction m ixture was filtered
th rough diatom aceous earth an d residual solids were wash ed with m eth an ol. Filtrate was
evaporated an d dissolved in water–m eth an ol (30 m l, 2:1) an d pH was adjusted to n eutral
with aqueous HCl (10%). Solution was applied on to a Dowex 50 (H+ form , 200 m l). Colum n
was eluted with water (400 m l), m eth an ol (300 m l) an d th en with 3.5 M m eth an olic am m o-
n ia. Fraction s con tain in g product were evaporated to yield 480 m g (61%) of th e crude de-
sired am in e 11a. ESI MS, m/z (rel.%): 140 (100) [M + H].
[(1R*,2R*,3R*,4S*)-3-Am in obicyclo[2.2.1]h ept-5-en -2-yl]m eth an ol (11b)
To a solution of th e acid 10b (2.10 g, 10 m m ol) an d trieth ylam in e (1.7 m l, 12 m m ol) in
aceton e (30 m l) at 0 °C, eth yl ch loroform ate (1.1 m l, 11.5 m m ol) was added dropwise over
several m in utes. After th e addition was com plete th e solution was stirred at 0 °C for 1 h .
A solution of sodium azide (2.17 g, 33.4 m m ol) in water (35 m l) was th en added an d th e re-
action m ixture was stirred at 0 °C for an addition al 1 h . Th e solution was th en poured in ice
water (100 m l) an d th e resultin g m ixture was extracted with eth yl acetate (3 × 100 m l). Th e
com bin ed organ ic ph ases were wash ed with saturated solution of sodium bicarbon ate (2 ×
100 m l), dried over an h ydrous sodium sulfate an d evaporated. Th e residue was redissolved
in m ixture of THF (20 m l) an d 2 M aqueous HCl (20 m l), an d h eated un der reflux for 13 h .
Th e reaction m ixture was extracted with eth er (50 m l) an d water ph ase was evaporated. Res-
idue (from water ph ase) was th en dried in vacuum oven at 60 °C for on e day an d suspen ded
in dry THF (50 m l). LiAlH4 (powder, 1.5 g, 39.5 m m ol) was slowly added to th e suspen sion .
Th e reaction m ixture was refluxed un der argon for 12 h . After slowly addin g eth yl acetate
(25 m l), eth an ol (25 m l), water (25 m l) an d aqueous KOH (20 m l, 10%), reaction m ixture
was filtered th rough diatom aceous earth an d residual solids were wash ed with m eth an ol.
Filtrate was evaporated an d th e residue was dissolved in water–m eth an ol (30 m l, 2:1). Th e
solution was applied on to a Dowex 50 (H+ form , 200 m l). Colum n was eluted with water
(400 m l), m eth an ol (300 m l) an d th en with 3.5 M m eth an olic am m on ia. Fraction s con tain -
in g product were evaporated to yield 940 m g (67%) of th e crude desired am in e 11b. ESI MS,
m/z (rel.%): 140 (100) [M + H].
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14
Šála et. al.:
[(1R*,2S*,3S*,4S*)-3-(Acetylam in o)bicyclo[2.2.1]h ept-5-en -2-yl]m eth yl Acetate (12a) an d
[(1R*,2R*,3R*,4S*)-3-(Acetylam in o)bicyclo[2.2.1]h ept-5-en -2-yl]m eth yl Acetate (12b)
Acetic an h ydride (0.5 m l) was added to a stirred ice-cooled solution of am in e 11 (140 m g,
1 m m ol) in pyridin e (4 m l) an d th e m ixture was left overn igh t. Meth an ol (2 m l) was added
an d, after 10 m in , th e m ixture was evaporated. Th e residue was codistilled with toluen e an d
ch rom atograph ed on a silica gel colum n (35 g) in eth yl acetate → eth yl acetate–toluen e–
aceton e–eth an ol (17:4:3:1).
[(1R*,2S*,3S*,4S*)-3-(Acetylamino)bicyclo[2.2.1]hept-5-en-2-yl]methyl acetate (12a): Yield 178 m g
(80%) as an oil. 1H NMR: 1.48 dq, 1 H, Jgem = 8.6, J(7a,1) = J(7a,4) = J(7a,3) = 1.8 (H-7a);
1.62 dm , 1 H, Jgem = 8.6 (H-7b); 1.80 s, 3 H (CH3CON); 1.98 s, 3 H (CH3COO); 2.03 m , 1 H
(H-2); 2.57 m , 1 H (H-4); 2.76 m , 1 H (H-1); 3.06 bddd, 1 H, J(3,NH) = 7.3, J(3,2) = 4.0,
J(3,7a) = 1.8 (H-3); 3.64 dd, 1 H, Jgem = 10.9, J(CH2,2) = 9.9 (CH2Oa); 3.96 dd, 1 H, Jgem
=
10.9, J(CH2,2) = 6.3 (CH2Ob); 6.09 dd, 1 H, J(6,5) = 5.7, J(6,1) = 2.8 (H-6); 6.20 dd, 1 H,
J(5,6) = 5.7, J(5,4) = 3.2 (H-5); 8.05 bd, 1 H, J(NH,3) = 7.3 (NH). 13C NMR: 20.97 (CH3COO);
22.92 (CH3CON); 42.87 (C-1); 46.25 (C-2); 46.67 (C-7); 48.37 (C-4); 52.82 (C-3); 66.47
(CH2O); 135.69 (C-6); 136.39 (C-5); 169.16 (CON); 170.54 (COO). ESI MS, m/z (rel.%): 246
(100) [M + Na], 224 (5) [M + H].
[(1R*,2R*,3R*,4S*)-3-(Acetylamino)bicyclo[2.2.1]hept-5-en-2-yl]methyl acetate (12b): Yield 206 m g
(92%) as an oil. 1H NMR: 1.31 dq, 1 H, Jgem = 9.0, J(7a,1) = J(7a,4) = J(7a,2) = 2.0 (H-7a);
1.38 m , 1 H (H-2); 1.53 dm , 1 H, Jgem = 9.0 (H-7b); 1.74 s, 3 H (CH3CON); 2.00 s, 3 H
(CH3COO); 2.62 m , 1 H (H-1); 2.86 m , 1 H (H-4); 3.77 dt, 1 H, J(3,NH) = 7.1, J(3,2) = J(3,4) =
3.9 (H-3); 3.97 dd, 1 H, Jgem = 11.0, J(CH2,2) = 9.5 (CH2Oa); 4.27 dd, 1 H, Jgem = 11.0,
J(CH2,2) = 5.7 (CH2Ob); 6.07 dd, 1 H, J(5,6) = 5.7, J(5,4) = 2.8 (H-5); 6.36 dd, 1 H, J(6,5) =
5.7, J(6,1) = 3.2 (H-6); 7.47 bd, 1 H, J(NH,3) = 7.2 (NH). 13C NMR: 21.01 (CH3COO); 22.69
(CH3CON); 44.09 (C-1); 44.90 (C-7); 45.78 (C-4); 46.76 (C-2); 53.00 (C-3); 66.49 (CH2O);
133.96 (C-5); 138.88 (C-6); 169.62 (CON); 170.65 (COO). ESI MS, m/z (rel.%): 246 (100)
[M + Na], 224 (8) [M + H]. For C12H17NO3 (223.3) calculated: 64.55% C, 7.67% H, 6.27% N;
foun d: 64.20% C, 8.03% H, 6.14% N.
[(1R*,2S*,3S*,4S*)-3-(6-Ch loro-9H-purin -9-yl)bicyclo[2.2.1]h ept-5-en -2-yl]m eth an ol (13a) an d
[(1R*,2R*,3R*,4S*)-3-(6-Ch loro-9H-purin -9-yl)bicyclo[2.2.1]h ept-5-en -2-yl]m eth an ol (13b)
A m ixture of am in e 11 (840 m g, 6 m m ol), 4,6-dich loropyrim idin -5-am in e (1.48 g, 9 m m ol)
an d trieth ylam in e (3.6 m l) in eth an ol (18 m l) was h eated in a pressure vessel at 105 °C for
6 days, an d, after coolin g, was evaporated. Th e residue was ch rom atograph ed on a colum n
of silica gel (200 g) in eth yl acetate–toluen e–eth an ol–water (17:4:3:1). To a suspen sion of
pyrim idin e in trieth yl orth oform ate (130 m l), con cen trated h ydroch loric acid (2.3 m l) was
added an d th e reaction m ixture was vigorously stirred at room tem perature for 3 days
(suspen sion dissolved). Solution was evaporated, residue was redissolved in a m ixture of
tetrah ydrofuran (17 m l) an d 0.5 M h ydroch loric acid (17 m l) an d stirred at room tem pera-
ture for 4 h . After n eutralization with solid sodium h ydrogen carbon ate, th e m ixture was
evaporated to a on e fourth of origin al volum e an d adsorbed on silica gel. Th e silica gel was
placed on th e top of a silica gel colum n (200 g) an d n ucleosides were isolated by ch rom atog-
raph y.
[(1R*,2S*,3S*,4S*)-3-(6-Chloro-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-yl]methanol (13a ):
Ch rom atograph y in eth yl acetate–toluen e–aceton e–eth an ol (17:4:3:1) afforded 995 m g (60%)
of th e ch loropurin e n ucleoside 13a. Sam ple was crystallized from water. M.p. 158–159 °C.
Collect. Czech. Chem. Commun. 2010, Vol. 75, No. 1, pp. 1–20

Novel Racemic Carbocyclic Nucleosides
15
1H NMR: 1.63 dq, 1 H, J(7b,1) ~ J(7b,3) ~ J(7b,4) ~ 1.7, Jgem = 9.2 (H-7b); 2.03 brdt, 1 H,
J(7a,1) ~ J(7a,4) ~ 1.5 (H-7a); 2.79 dddd, 1 H, J(2,1) = 3.2, J(2,3) = 4.5, J(2,CHa) = 7.2,
J(2,CHa) = 8.2 (H-2); 3.03 m , 1 H (H-1); 3.10 brdq, 1 H, J(4,1) ~ 1.7, J(4,5) = 3.2 (H-4);
3.33 ddd, 1 H, J(CHa,OH) = 4.9, Jgem = 10.5 (CHa); 3.44 ddd, 1 H, J(CHb,OH) = 5.5 (CHb);
4.01 dd, 1 H (H-3); 4.65 t, 1 H (OH); 6.30 dd, 1 H, J(6,1) = 2.7, J(6,5) = 5.7 (H-6); 6.34 dd,
1 H (H-5); 8.78 s, 1 H an d 8.96 s, 1 H (H-2′, H-8′). 13C NMR: 43.35 (C-1); 47.09 (C-7); 48.33
(C-2); 48.53 (C-4); 59.35 (C-3); 63.94 (OCH2); 131.47 (C-5′); 135.20 (C-6); 137.38 (C-5);
146.27 (C-8′); 149.16 (C-6′); 151.42 (C-2′); 152.46 (C-4′). FAB MS, m/z (rel.%): 277/279 (10/5)
[M + H], 155 (15) 57 (100). For C13H13ClN4O (276.7) calculated: 56.42% C, 4.74% H, 12.81% Cl,
20.25% N; foun d: 56.25% C, 4.76% H, 12.74% Cl, 19.96% N.
[(1R*,2R*,3R*,4S*)-3-(6-Chloro-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-yl]methanol (13b ):
Ch rom atograph y in eth yl acetate–toluen e–aceton e–eth an ol (17:5:3:1) afforded 913 m g (55%)
of th e ch loropurin e n ucleoside 13b. Sam ple was crystallized from eth er–m eth an ol (10:1).
M.p. 156–157 °C. 1H NMR: 1.49 dq, 1 H, J(7b,1) ~ J(7b,2) ~ J(7b,4) ~ 2.0, Jgem = 9.2 (H-7b);
1.84 brdt, 1 H, J(7a,1) ~ J(7a,4) ~ 1.5 (H-7a); 2.23 tdd, 1 H, J(2,3) = 4.4, J(2,CHa) = 7.2,
J(2,CHa) = 7.2 (H-2); 2.87 m , 1 H (H-1); 3.30 m , 1 H (H-4); 3.64 ddd, 1 H, J(CHa,OH) = 4.8,
Jgem = 10.7 (CHa); 3.70 ddd, 1 H, J(CHb,OH) = 5.5 (CHb); 4.84 brt, 1 H, J(3,4) = 4.0 (H-3);
4.84 t, 1 H (OH); 5.88 dd, 1 H, J(5,4) = 2.8, J(5,6) = 5.6 (H-5); 6.59 dd, 1 H, J(6,1) = 3.2 (H-6);
8.52 s, 1 H an d 8.80 s, 1 H (H-2′, H-8′). 13C NMR: 44.41 (C-1); 45.31 (C-7); 46.79 (C-4);
48.24 (C-2); 58.84 (C-3); 63.77 (OCH2); 131.19 (C-5′); 132.79 (C-5); 140.82 (C-6); 145.72
(C-8′); 149.08 (C-6′); 151.48 (C-2′); 152.57 (C-4′). FAB MS, m/z (rel.%): 277/279 (15/7)
[M + H], 121 (100). For C13H13ClN4O·1/4H2O (281.2) calculated: 55.52% C, 4.84% H,
12.61% Cl, 19.92% N; foun d: 55.50% C, 4.69% H, 12.42% Cl, 19.73% N.
[(1R*,2S*,3S*,4S*)-3-(6-Am in o-9H-purin -9-yl)bicyclo[2.2.1]h ept-5-en -2-yl]m eth an ol (14a) an d
[(1R*,2R*,3R*,4S*)-3-(6-Am in o-9H-purin -9-yl)bicyclo[2.2.1]h ept-5-en -2-yl]m eth an ol (14b)
Ch loropurin e derivative 13 (560 m g, 2 m m ol) was h eated with liquid am m on ia (35 m l) an d
m eth an ol (6 m l) in an autoclave at 75 °C for 48 h . Am m on ia was th en evaporated, th e prod-
uct was purified by ch rom atograph y on silica gel (150 g) in eth yl acetate–aceton e–eth an ol–
water (95:15:9:6) an d crystallized from eth an ol.
[(1R*,2S*,3S*,4S*)-3-(6-Amino-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-yl]methanol (14a): Yield
428 m g (83%). M.p. 198.5–200 °C. 1H NMR: 1.61 dq, 1 H, Jgem = 9.0, J(7a,1) = J(7a,4) =
J(7a,3) = 1.7 (H-7a); 1.99 dm , 1 H, Jgem = 9.0 (H-7b); 2.66 m , 1 H (H-2); 2.98–3.02 m , 2 H
(H-1, H-4); 3.28 ddd, 1 H, Jgem = 10.5, J(CH2,2) = 8.2, J(CH2,OH) = 5.1 (CH2Oa); 3.43 ddd,
1 H, Jgem = 10.4, J(CH2,2) = 7.1, J(CH2,OH) = 5.1 (CH2Ob); 3.84 dd, 1 H, J(3,2) = 4.4, J(3,7b) =
1.7 (H-3); 4.79 t, 1 H, J(OH,CH2) = 5.2 (OH); 6.27 dd, 1 H, J(6,5) = 5.7, J(6,1) = 2.8 (H-6);
6.32 dd, 1 H, J(5,6) = 5.7, J(5,4) = 3.2 (H-5); 7.24 bs, 2 H (NH2); 8.13 s, 1 H (H-2′); 8.37 s,
1 H (H-8′). 13C NMR: 43.47 (C-1); 47.14 (C-7); 48.65, 48.70 (C-2, C-4); 58.28 (C-3); 64.17
(CH2O); 119.37 (C-5′); 135.49 (C-6); 137.17 (C-5); 139.42 (C-8′); 150.08 (C-4′); 152.42 (C-2′);
156.25 (C-6′). FAB MS, m/z (rel.%): 258 (100) [M + H]. For C13H15N5O (257.3) calculated:
60.69% C, 5.88% H, 27.22% N; foun d: 60.36% C, 5.78% H, 26.96% N.
[(1R*,2R*,3R*,4S*)-3-(6-Amino-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-yl]methanol (14b): Yield
423 m g (82%). M.p. 251.5–253 °C (decom p.). 1H NMR: 1.45 dq, 1 H, Jgem = 9.2, J(7a,1) =
J(7a,4) = J(7a,2) = 2.0 (H-7a); 1.75 dm , 1 H, Jgem = 9.2 (H-7b); 2.07 tdd, 1 H, J(2,CH2) = 7.3,
J(2,3) = 4.5, J(2,7a) = 2.2 (H-2); 2.82 m , 1 H (H-1); 3.20 m , 1 H (H-4); 3.59 ddd, 1 H, Jgem
=
10.7, J(CH2,2) = 7.4, J(CH2,OH) = 4.9 (CH2Oa); 3.65 ddd, 1 H, Jgem = 10.7, J(CH2,2) = 7.0,
Collect. Czech. Chem. Commun. 2010, Vol. 75, No. No. 1, pp. 1–20

16
Šála et. al.:
J(CH2,OH) = 5.4 (CH2Ob); 4.65 bt, 1 H, J(3,2) ~ J(3,4) ~ 3.9 (H-3); 5.10 t, 1 H, J(OH,CH2) =
5.2 (OH); 5.85 dd, 1 H, J(5,6) = 5.7, J(5,4) = 2.8 (H-5); 6.55 dd, 1 H, J(6,5) = 5.7, J(6,1) = 3.2
(H-6); 7.18 bs, 2 H (NH2); 7.93 s, 1 H (H-8′); 8.14 s, 1 H (H-2′). 13C NMR: 44.79 (C-1); 45.80
(C-7); 47.25 (C-4); 48.84 (C-2); 58.27 (C-3); 64.43 (CH2O); 119.20 (C-5′); 133.38 (C-5);
139.60 (C-8′); 140.92 (C-6); 150.44 (C-4′); 152.86 (C-2′); 156.35 (C-6′). ESI MS, m/z (rel.%):
280 (100) [M + Na], 258 (20) [M + H]. For C13H15N5O·1/6 H2O (260.9) calculated: 59.85% C,
5.95% H, 26.84% N; foun d: 59.94% C, 5.93% H, 26.82% N.
{(1R*,2S*,3S*,4S*)-3-[6-(Cyclopropylam in o)-9H-purin -9-yl]-
bicyclo[2.2.1]h ept-5-en -2-yl}m eth an ol (15a) an d
{(1R*,2R*,3R*,4S*)-3-[6-(Cyclopropylam in o)-9H-purin -9-yl]-
bicyclo[2.2.1]h ept-5-en -2-yl}m eth an ol (15b)
Mixture of ch loropurin e derivative 13a or 13b (330 m g, 1.2 m m ol), cyclopropylam in e (2 m l)
an d m eth an ol (2 m l) was set aside overn igh t an d evaporated. Product was purified by ch ro-
m atograph y on silica gel (50 g) in eth yl acetate–aceton e–eth an ol–water (100:15:6:4).
{(1R*,2S*,3S*,4S*)-3-[6-(Cyclopropylamino)-9H-purin-9-yl]bicyclo[2.2.1]hept-5-en-2-yl}methanol
(15a): Yield 292 m g (89%). M.p. 145.5–146.5 °C (aceton e). 1H NMR: 0.61 m , 2 H, 0.72 m ,
2 H an d 3.05 m , 1 H (cyclopropyl); 1.61 dq, 1 H, J(7b,1) ~ J(7b,3) ~ J(7b,4) ~ 1.7, Jgem = 9.0
(H-7b); 1.99 brdt, 1 H, J(7a,1) ~ J(7a,4) ~ 1.5 (H-7a); 2.66 dddd, 1 H, J(2,1) = 3.2, J(2,3) = 4.5,
J(2,CHa) = 7.2, J(2,CHa) = 8.2 (H-2); 3.00 m , 1 H (H-1); 3.02 m , 1 H (H-4); 3.28 ddd, 1 H,
J(CHa,OH) = 5.4, Jgem = 10.6 (CHa); 3.44 ddd, 1 H, J(CHb,OH) = 5.0 (CHb); 4.75 t, 1 H (OH);
5.79 brdd, 1 H, J(3,4) = 1.0 (H-3); 6.27 dd, 1 H, J(6,1) = 2.8, J(6,5) = 5.7 (H-6); 6.32 dd, 1 H,
J(5,4) = 3.2 (H-5); 7.88 brs, 1 H (NH); 8.23 s, 1 H an d 8.37 s, 1 H (H-2′, H-8′). 13C NMR:
6.56, 2 C (2 × CH2); 24.00 (NCH); 43.41 (C-1); 47.07 (C-7); 48.62 (C-4); 48.62 (C-2); 58.21
(C-3); 64.10 (OCH2); 119.70 (C-5′); 135.40 (C-6); 137.10 (C-5); 139.15 (C-8′); 149.00 (C-4′);
151.21 (C-2′); 155.73 (C-6′). FAB MS, m/z (rel.%): 298 (10) [M + H], 176 (20), 133 (50), 56
(100). For C16H19ClN5O (297.4) calculated: 64.63% C, 6.44% H, 23.55% N; foun d: 64.46% C,
6.52% H, 23.38% N.
{(1R*,2R*,3R*,4S*)-3-[6-(Cyclopropylamino)-9H-purin-9-yl]bicyclo[2.2.1]hept-5-en-2-yl}methanol
(15b): Yield 310 m g (94%) as a foam . 1H NMR: 0.59 m , 2 H an d 0.71 m , 2 H (CH2 of
cyclopropyl); 1.46 dq, 1 H, Jgem = 9.1, J(7a,1) = J(7a,4) = J(7a,2) = 1.9 (H-7a); 1.79 dm , 1 H,
Jgem = 9.1 (H-7b); 2.10 m , 1 H (H-2); 2.84 m , 1 H (H-1); 2.99 bs, 1 H (CH of cyclopropyl);
3.23 m , 1 H (H-4); 3.60 m , 1 H an d 3.67 m , 1 H (CH2O); 4.68 bt, 1 H, J(3,2) ~ J(3,4) ~ 3.9
(H-3); 4.93 m , 1 H (OH); 5.88 bdd, 1 H, J(5,6) = 5.7, J(5,4) = 2.8 (H-5); 6.56 bdd, 1 H, J(6,5) =
5.7, J(6,1) = 3.1 (H-6); 7.86 bs, 1 H (NH); 7.93 s, 1 H (H-8′); 8.24 s, 1 H (H-2′). 13C NMR:
6.63 (CH2 of cyclopropyl); 44.48 (C-1); 45.42 (C-7); 46.86 (C-4); 48.46 (C-2); 57.76 (C-3);
64.03 (CH2O); 119.46 (C-5′); 133.16 (C-5); 138.86 (C-8′); 140.43 (C-6); 149.41 (C-4′); 152.36
(C-2′); 155.74 (C-6′). FAB MS, m/z (rel.%): 298 (100) [M + H]. For C16H19ClN5O·1/4H2O
(301.9) calculated: 63.66% C, 6.51% H, 23.20% N; foun d: 63.91% C, 6.74% H, 22.96% N.
Preparation of th e Saturated Nucleosides 16a, 16b, 17a an d 17b. Gen eral Procedure
A m ixture of un saturated com poun d 14 or 15 (0.6 m m ol) an d palladium on ch arcoal (20 m g)
in m eth an ol (10 m l) was stirred in atm osph ere of h ydrogen overn igh t. Th e catalyst was fil-
tered off, wash ed with m eth an ol an d filtrate was evaporated. Th e residue was ch rom atog-
raph ed on silica gel colum n (10 g) in eth yl acetate–aceton e–eth an ol–water (100:15:6:4).
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Novel Racemic Carbocyclic Nucleosides
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[(1R*,2R*,3R*,4S*)-3-(6-Amino-9H-purin-9-yl)bicyclo[2.2.1]hept-2-yl]methanol (16a): Yield
133 m g (86%) after crystallization from eth an ol. M.p. 200.5–202 °C. 1H NMR: 1.27–1.40 m ,
3 H (H-5en do, H-6exo, H-7a); 1.53 m , 1 H (H-6en do); 1.61 tt, 1 H, Jgem = J(5ex,6ex) = 11.9,
J(5ex,6en ) = J(5ex,4) = 4.5 (H-5exo); 1.91 dm , 1 H, Jgem = 10.2 (H-7b); 2.38 bd, 1 H,
J(4,5ex) = 4.8 (H-4); 2.41–2.48 m , 2 H (H-1, H-2); 3.48 ddd, 1 H, Jgem = 10.7, J(CH2,2) = 8.0,
J(CH2,OH) = 5.2 (CH2Oa); 3.63 ddd, 1 H, Jgem = 10.6, J(CH2,2) = 6.5, J(CH2,OH) = 4.8
(CH2Ob); 3.90 dd, 1 H, J(3,2) = 4.9, J(3,7a) = 1.2 (H-3); 4.71 t, 1 H, J(OH,CH2) = 5.0 (OH);
7.22 bs, 2 H (NH2); 8.13 s, 1 H (H-2′); 8.30 s, 1 H (H-8′). 13C NMR: 21.69 (C-6); 27.63 (C-5);
37.24 (C-7); 38.13 (C-1); 43.32 (C-4); 51.00 (C-2); 60.98 (C-3); 61.44 (CH2O); 119.27 (C-5′);
139.08 (C-8′); 149.69 (C-4′); 152.37 (C-2′); 156.22 (C-6′). FAB MS, m/z (rel.%): 260 (100)
[M + H], 136 (60). For C13H17N5O·1/6H2O (262.3) calculated: 59.52% C, 6.66% H, 26.70% N;
foun d: 59.49% C, 6.61% H, 26.41% N.
[(1R*,2S*,3S*,4S*)-3-(6-Amino-9H-purin-9-yl)bicyclo[2.2.1]hept-2-yl]methanol (16b): Yield 121 m g
(78%) after crystallization from eth an ol. M.p. 244–245 °C. 1H NMR: 1.01 m , 1 H (H-5en do);
1.28–1.35 m , 2 H (H-5exo, H-7a); 1.52–1.62 m , 2 H (H-6); 1.71 dm , 1 H, Jgem = 10.2 (H-7b);
2.22 m , 1 H (H-1); 2.30 m , 1 H (H-2); 2.66 m , 1 H (H-4); 3.31 ddd, 1 H, Jgem = 10.7,
J(CH2,2) = 7.2, J(CH2,OH) = 5.4 (CH2Oa); 3.45 ddd, 1 H, Jgem = 10.5, J(CH2,2) = 7.4,
J(CH2,OH) = 4.7 (CH2Ob); 4.37 ddd, 1 H, J(3,2) = 5.4, J(3,4) = 4.0, J(3,5ex) = 1.8 (H-3);
4.73 t, 1 H, J(OH,CH2) = 5.1 (OH); 7.19 bs, 2 H (NH2); 8.12 s, 1 H (H-2′); 8.27 s, 1 H (H-8′).
13C NMR: 21.52 (C-5); 28.97 (C-6); 35.25 (C-7); 38.64 (C-1); 41.28 (C-4); 47.01 (C-2); 60.05
(C-3); 63.80 (CH2O); 119.45 (C-5′); 139.87 (C-8′); 150.43 (C-4′); 152.35 (C-2′); 156.13 (C-6′).
ESI MS, m/z (rel.%): 282 (100) [M + Na], 260 (48) [M + H]. For C13H17N5O·1/6H2O (262.3)
calculated: 59.52% C, 6.66% H, 26.70% N; foun d: 59.59% C, 6.58% H, 26.64% N.
{(1R*,2R*,3R*,4S*)-3-[6-(Cyclopropylamino)-9H-purin-9-yl]bicyclo[2.2.1]hept-2-yl}methanol
(17a): Yield 135 m g (75%) after crystallization from aceton e. M.p. 165–166 °C. 1H NMR:
0.59 m , 2 H an d 0.71 m , 2 H (CH2 of cyclopropyl); 1.27–1.40 m , 3 H (H-5en do, H-6exo,
H-7a); 1.53 m , 1 H (H-6en do); 1.61 tt, 1 H, Jgem = J(5ex,6ex) = 11.7, J(5ex,6en ) = J(5ex,4) =
4.5 (H-5exo); 1.90 dm , 1 H, Jgem = 10.1 (H-7b); 2.37 bd, 1 H, J(4,5ex) = 4.6 (H-4);
2.41–2.48 m , 2 H (H-1, H-2); 3.00 bs, 1 H (CH of cyclopropyl); 3.48 ddd, 1 H, Jgem = 10.6,
J(CH2,2) = 7.8, J(CH2,OH) = 5.1 (CH2Oa); 3.63 ddd, 1 H, Jgem = 10.5, J(CH2,2) = 6.4,
J(CH2,OH) = 4.9 (CH2Ob); 3.92 dd, 1 H, J(3,2) = 4.9, J(3,7a) = 1.2 (H-3); 4.70 t, 1 H,
J(OH,CH2) = 5.0 (OH); 7.88 bs, 1 H (NH); 8.23 s, 1 H (H-2′); 8.30 s, 1 H (H-8′). 13C NMR:
6.67 (CH2 of cyclopropyl); 21.69 (C-6); 27.64 (C-5); 37.23 (C-7); 38.13 (C-1); 43.33 (C-4);
51.01 (C-2); 60.96 (C-3); 61.44 (CH2O); 119.66 (C-5′); 138.92 (C-8′); 149.10 (C-4′); 152.26
(C-2′); 155.77 (C-6′). FAB MS, m/z (rel.%): 300 (100) [M + H], 176 (30). For C16H21N5O
(299.4) calculated: 64.19% C, 7.07% H, 23.39% N; foun d: 63.91% C, 7.12% H, 23.12% N.
{(1R*,2S*,3S*,4S*)-3-[6-(Cyclopropylamino)-9H-purin-9-yl]bicyclo[2.2.1]hept-2-yl}methanol
(17b): Yield 140 m g (78%) as a foam . 1H NMR: 0.60 m , 2 H an d 0.71 m , 2 H (CH2 of
cyclopropyl); 0.99 m , 1 H (H-5en do); 1.27–1.35 m , 2 H (H-5exo, H-7a); 1.53–1.59 m , 2 H
(H-6); 1.71 dm , 1 H, Jgem = 10.2 (H-7b); 2.21 m , 1 H (H-1); 2.30 m , 1 H (H-2); 2.66 m , 1 H
(H-4); 2.99 bs, 1 H (CH of cyclopropyl); 3.31 ddd, 1 H, Jgem = 10.7, J(CH2,2) = 7.0,
J(CH2,OH) = 5.4 (CH2Oa); 3.46 ddd, 1 H, Jgem = 10.8, J(CH2,2) = 7.4, J(CH2,OH) = 4.4
(CH2Ob); 4.38 m , 1 H (H-3); 4.75 t, 1 H, J(OH,CH2) = 5.1 (OH); 7.88 bs, 1 H (NH); 8.22 s,
1 H (H-2′); 8.28 s, 1 H (H-8′). 13C NMR: 6.65 (CH2 of cyclopropyl); 21.58 (C-5); 29.01 (C-6);
35.33 (C-7); 38.67 (C-1); 41.34 (C-4); 47.06 (C-2); 60.08 (C-3); 63.85 (CH2O); 119.90 (C-5′);
139.78 (C-8′); 149.77 (C-4′); 152.34 (C-2′); 155.78 (C-6′). FAB MS, m/z (rel.%): 300 (100)
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18
Šála et. al.:
[M + H], 176 (20). For C16H21N5O (299.4) calculated: 64.19% C, 7.07% H, 23.39% N; foun d:
64.19% C, 7.26% H, 23.11% N.
Preparation of th e cis-Hydroxylated Com poun ds 18a, 18b, 19a an d 19b. Gen eral Procedure
Un saturated n ucleoside 14 or 15 (0.6 m m ol) was dissolved in a m ixture of aceton e–water
(27.5 m l, 10:1). Solution of NMMO (50% in water, 0.9 m l) an d water solution of osm ium
tetroxide (30 µl, 100 m g/5 m l) was added, th e reaction m ixture was stirred at r.t. for 2 days
an d evaporated. Th e product was isolated by colum n ch rom atograph y on silica gel.
(1R*,2R*,3S*,4S*,5S*,6R*)-5-(6-Amino-9H-purin-9-yl)-6-(hydroxymethyl)bicyclo[2.2.1]heptane-
2,3-diol (18a): Ch rom atograph y on silica gel (50 g) in eth yl acetate–aceton e–eth an ol–water
(17:3:3:2). Yield 109 m g (62%) after crystallization from eth an ol. M.p. 258.5–260.5 °C
(decom p.). 1H NMR: 1.71 dm , 1 H, Jgem = 10.7 (H-7a); 1.84 dm , 1 H, Jgem = 10.6 (H-7b);
2.21 m , 1 H (H-4); 2.25 m , 1 H (H-1); 2.43 m , 1 H (H-6); 3.48 ddd, 1 H, Jgem = 10.9,
J(CH2,6) = 7.9, J(CH2,OH) = 5.2 (CH2Oa); 3.58 ddd, 1 H, Jgem = 11.0, J(CH2,6) = 7.0,
J(CH2,OH) = 4.5 (CH2Ob); 3.75 m , 1 H (H-3); 3.92–3.96 m , 2 H (H-2, H-5); 4.74–4.79 m , 3 H
(OH); 7.23 bs, 2 H (NH2); 8.13 s, 1 H (H-2′); 8.28 s, 1 H (H-8′).13C NMR: 31.24 (C-7); 45.37
(C-1); 48.61 (C-6); 50.77 (C-4); 57.22 (C-5); 60.24 (CH2O); 67.73 (C-2); 71.90 (C-3); 119.29
(C-5′); 139.25 (C-8′); 149.72 (C-4′); 152.41 (C-2′); 156.24 (C-6′). FAB MS, m/z (rel.%): 292
(100) [M + H]. For C13H17N5O·1/2H2O (301.3) calculated: 51.99% C, 6.04% H, 23.32% N;
foun d: 52.12% C, 5.98% H, 23.07% N.
(1R*,2R*,3S*,4S*,5R*,6S*)-5-(6-Amino-9H-purin-9-yl)-6-(hydroxymethyl)bicyclo[2.2.1]heptane-
2,3-diol (18b): Ch rom atograph y on silica gel (50 g) in eth yl acetate–aceton e–eth an ol–water
(17:3:3:2). Yield 168 m g (95%) after crystallization from eth an ol. M.p. 258.5–260 °C
(decom p.). 1H NMR: 1.46 dm , 1 H, Jgem = 10.7 (H-7a); 1.76 dm , 1 H, Jgem = 10.7 (H-7b);
2.04 m , 1 H (H-1); 2.31 m , 1 H (H-6); 2.48 m , 1 H (H-4); 3.33–3.49 m , 3 H (CH2O, H-3);
3.94 bt, 1 H, J(2,3) = J(2,OH) = 5.1 (H-2); 4.28 dd, 1 H, J(5,6) = 5.9, J(5,4) = 4.1 (H-5);
4.65–4.67 m , 2 H (2-OH, 3-OH); 4.81 t, 1 H, J(OH,CH2) = 5.2 (CH2OH); 7.24 bs, 2 H (NH2);
8.14 bs, 1 H (H-2′); 8.24 s, 1 H (H-8′). 13C NMR: 29.36 (C-7); 42.40 (C-6); 45.92 (C-1); 48.35
(C-4); 57.65 (C-5); 63.32 (CH2O); 68.13 (C-3); 72.87 (C-2); 119.55 (C-5′); 140.17 (C-8′);
150.44 (C-4′); 152.52 (C-2′); 156.23 (C-6′). ESI MS, m/z (rel.%): 314 (100) [M + Na], 292 (86)
[M + H]. For C13H17N5O (291.3) calculated: 53.60% C, 5.88% H, 24.04% N; foun d: 53.27% C,
5.87% H, 23.62% N.
(1R*,2R*,3S*,4S*,5S*,6R*)-5-[6-(Cyclopropylamino)-9H-purin-9-yl]-6-(hydroxymethyl)bicyclo-
[2.2.1]heptane-2,3-diol (19a): Ch rom atograph y on silica gel (50 g) in eth yl acetate–aceton e–
eth an ol–water (72:12:10:6). Yield 169 m g (85%) after crystallization from aceton e–m eth an ol
(10:1). M.p. 202–203.5 °C (decom p.). 1H NMR: 0.59 m , 2 H an d 0.71 m , 2 H (CH2 of
cyclopropyl); 1.71 dm , 1 H, Jgem = 10.7 (H-7a); 1.84 dm , 1 H, Jgem = 10.6 (H-7b); 2.21 m , 1 H
(H-4); 2.25 m , 1 H (H-1); 2.43 m , 1 H (H-6); 2.99 bs, 1 H (CH of cyclopropyl); 3.49 ddd, 1 H,
Jgem = 10.9, J(CH2,6) = 7.9, J(CH2,OH) = 5.1 (CH2Oa); 3.59 ddd, 1 H, Jgem = 10.9, J(CH2,6) =
7.0, J(CH2,OH) = 4.6 (CH2Ob); 3.75 td, 1 H, J(3,2) = J(3,OH) = 5.7, J(3,7a) = 1.6 (H-3);
3.94 bt, 1 H, J(2,3) = J(2,OH) = 5.6 (H-2); 3.97 dd, 1 H, J(5,6) = 5.3, J(5,7b) = 1.0 (H-5);
4.75 d, 1 H, J(OH,2) = 5.1 (2-OH); 4.76 d, 1 H, J(OH,3) = 5.2; 4.77 t, 1 H, J(OH,CH2) = 5.1
(CH2OH); 7.89 bs, 1 H (NH); 8.23 bs, 1 H (H-2′); 8.29 s, 1 H (H-8′). 13C NMR: 6.63 (CH2 of
cyclopropyl); 31.23 (C-7); 45.36 (C-1); 48.62 (C-6); 50.77 (C-4); 57.18 (C-5); 60.23 (CH2O);
67.72 (C-2); 71.89 (C-3); 119.67 (C-5′); 139.06 (C-8′); 149.02 (C-4′); 152.30 (C-2′); 155.82
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Novel Racemic Carbocyclic Nucleosides
19
(C-6′). FAB MS, m/z (rel.%): 332 (100) [M + H], 176 (80). For C16H21N5O3 (331.4) calculated:
57.99% C, 6.39% H, 21.13% N; foun d: 57.97% C, 6.40% H, 21.00% N.
(1R*,2R*,3S*,4S*,5R*,6S*)-5-[6-(Cyclopropylamino)-9H-purin-9-yl]-6-(hydroxymethyl)bicyclo-
[2.2.1]heptane-2,3-diol (19b): Ch rom atograph y on silica gel (50 g) in eth yl acetate–aceton e–
eth an ol–water (100:15:6:4). Yield 155 m g (78%) as a foam . 1H NMR: 0.60 m , 2 H an d
0.72 m , 2 H (CH2 of cyclopropyl); 1.46 dm , 1 H, Jgem = 10.7 (H-7a); 1.76 dm , 1 H, Jgem
=
10.6 (H-7b); 2.04 m , 1 H (H-1); 2.31 m , 1 H (H-6); 2.49 m , 1 H (H-4); 3.00 bs, 1 H (CH of
cyclopropyl); 3.31–3.50 m , 3 H (CH2O, H-3); 3.94 bt, 1 H, J(2,3) = J(2,OH) = 5.2 (H-2);
4.29 dd, 1 H, J(5,6) = 5.8, J(5,4) = 4.1 (H-5); 4.65 d, 1 H, J(OH,2) = 4.8 (2-OH); 4.66 d, 1 H,
J(OH,3) = 5.5 (3-OH); 4.80 t, 1 H, J(OH,CH2) = 5.1 (CH2OH); 7.91 bs, 1 H (NH); 8.24 bs, 1 H
(H-2′); 8.25 s, 1 H (H-8′). 13C NMR: 6.64 (CH2 of cyclopropyl); 29.36 (C-7); 42.41 (C-6);
45.91 (C-1); 48.34 (C-4); 57.65 (C-5); 63.31 (CH2O); 68.12 (C-3); 72.86 (C-2); 119.95 (C-5′);
140.00 (C-8′); 149.72 (C-4′); 152.41 (C-2′); 155.79 (C-6′). FAB MS, m/z (rel.%): 332 (100) [M +
H], 176 (40). For C16H21N5O3·1/3H2O (337.4) calculated: 56.96% C, 6.47% H, 20.76% N;
foun d: 56.88% C, 6.59% H, 20.55% N.
The authors are indebted to Ms J. Sklenářová for excellent technical assistance and to the staff of
the Analytical Laboratory of the Institute for elemental analyses. This work is a part of the research
project Z4 055 0506. It was supported by the Centre for New Antivirals and Antineoplastics, Ministry
of Education, Youth and Sports of the Czech Republic (1M0508), by the Programme of Targeted
Projects of Academy of Sciences of the Czech Republic (1QS400550501), and by Gilead Sciences, Inc.
(Foster City, CA, U.S.A.).
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