New and efficient synthesis of racemic cyclopent-3-en-1-yl nucleoside analogues and their derivatives

Article abstract of DOI:10.1135/cccc20061011

A new, efficient synthesis of racemic cyclopent-3-en-1-yl nucleoside analogues has been developed starting from cyclopentadiene. The key step is the regioselective hydroboration of an intermediately formed mixture of two alkylated cyclopentadienes to give

Full text of DOI:10.1135/cccc20061011

Racemic Cyclopent-3-en-1-yl Nucleoside Analogues
1011
NEW AND EFFICIENT SYNTHESIS OF RACEMIC
CYCLOPENT-3-EN-1-YL NUCLEOSIDE ANALOGUES
AND THEIR DERIVATIVES
1
2
3,
Bastian REICHARDT , Olaf R. LUDEK and Chris MEIER *
Department of Chemistry, Institute of Organic Chemistry,
Faculty of Mathematics, Informatics and Natural Sciences, University Hamburg,
1
Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany; e-mail: breichardt@web.de,
2
3
oludek@gmx.de, chris.meier@chemie.uni-hamburg.de
Received March 31, 2006
Accepted May 5, 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.
A n ew, efficien t syn th esis of racem ic cyclopen t-3-en -1-yl n ucleoside an alogues h as been de-
veloped startin g from cyclopen tadien e. Th e key step is th e regioselective h ydroboration of
an in term ediately form ed m ixture of two alkylated cyclopen tadien es to give one cyclo-
pen ten ol. Th e rem ain in g double bon d was furth er fun ction alized by h ydroboration , epoxid-
ation , cis-h ydroxylation an d cyclopropan ation .
Keyw ord s: Nucleosides; Carbocyclic n ucleosides; Cyclopen tan es; Cyclopropan ation ;
Hydroboration ; Pyrim idin es; An tivirals.
Nucleoside an alogues h ave attracted con siderable in terest due to th eir im -
portan t biological activity1. Various structural m odification s were in tro-
duced in both th e h eterocyclic base an d th e sugar m oiety2. In carbocyclic
n ucleosides th e furan ose oxygen is replaced by a m eth ylen e un it. Such
com poun ds are stable to h ydrolysis by ph osph orylases th at cleave th e
glycosidic bon d in con ven tion al n ucleosides. Con sequen tly, carbocyclic
n ucleosides display en h an ced biostability3. Th e rem oval of th e rin g oxygen
elim in ates th e an om eric an d gauch e effects, respon sible for forcin g th e fu-
ran system in to two distin ct con form ation s4. Sin ce th e con form ation of th e
five-m em bered rin g is believed to play a critical role in m odulatin g biologi-
cal activity, th e beh aviour of n ucleosides with a cyclopen tan e m oiety som e-
tim es differs sign ifican tly from th at of th eir n atural coun terparts5. Recen tly,
6
carbocyclic purin e an alogues such as carbovir 1 an d th e structurally re-
7
lated abacavir 2 (Ziagen ) were foun d to be poten t in h ibitors of HIV reverse
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 7, pp. 1011–1028
© 2006 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20061011

1012
Reichardt, Ludek, Meier:
8
tran scriptase. Moreover, en tecavir 3 (Baraclude) was approved by FDA in
2005 for th e treatm en t of ch ron ic HBV in fection s. Exam ples of bioactive
pyrim idin e an alogues are carba-BVdU 4 th at sh owed sign ifican t an ti-HSV-1
activity9 an d carba-dT 5 wh ich proved active again st HIV-1 an d HIV-2
(Ch art 1)10,11
.
CHART 1
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Racemic Cyclopent-3-en-1-yl Nucleoside Analogues
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A n um ber of syn th eses grouped in to two gen eral categories h ave been de-
sign ed for th e preparation of carbocyclic n ucleosides: th e lin ear an d th e
con vergen t approach . Th e form er approach in volves th e syn th esis of a
fun ction alized cyclopen tylam in e an d th en a stepwise form ation of th e
h eterocyclic base wh ile in th e latter case th e in tact h eterocycle is coupled to
a fun ction alized carbocyclic m oiety leadin g to a variety of carbocyclic n u-
cleosides startin g from on e com m on cyclopen tan e precursor.
Recen tly we publish ed a n ew procedure for th e preparation of carbocyclic
th ym idin e an alogues startin g from an alkylated cyclopen tadien e 6 13. In
two h ydroboration reaction s, on e en an tioselective reaction leadin g to
(1S,2R)-2-[(ben zyloxy)m eth yl]cyclopen t-3-en -1-ol (7)12 an d on e stereo-
specific step leadin g to cyclopen tan ol 8, th e required stereogen ic cen ters
were in troduced10,13–17. Con den sation of com poun d 8 with N3-protected
pyrim idin e n ucleobases usin g a m odified Mitsun obu protocol resulted in
carbocyclic n ucleosides like carba-dT 5. In addition we h ave sh own th at
3′-m odified carba-n ucleosides like carba-AZT are accessible (Sch em e 1)10.
SCHEME 1
Here, we report on a route th at offers even m ore syn th etic possibilities as
before.
RESULTS AND DISCUSSION
In our previous m eth od, cyclopen tadien e was deproton ated an d alkylated
with (ben zyloxy)m eth yl ch loride to give cyclopen tadien e 6 wh ich was th en
stereoselectively h ydroborated with (–)-diisopin ocam ph eylboran e. Alth ough
th is reaction created two n ew stereogen ic cen ters in on e step with excellen t
en an tiom eric excess (>97% ee) th e ch em ical yield was on ly about 55% 12
.
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Reichardt, Ludek, Meier:
Th e reason was th at th e in term ediately form ed dien e 6 un dergoes isom er-
ization in to two th erm odyn am ically m ore stable cyclopen tadien es 9 an d 10
(Sch em e 2). However, a closer look on th ese two isom erization products
brough t us to th e idea th at h ydroboration of th e m ixture sh ould lead even -
tually to on ly one product because th e h ydroboration proceeds always at
th e term in i of a dien e system due to in h om ogen eous electron den sity dis-
tribution (orbital-con trolled reaction )18. Two position s in 9, 10 are equiva-
len t (m arked with an asterisk in Sch em e 3) an d th e oth ers are sterically less
accessible. In a first attem pt, th e dien e m ixture was treated with 9-BBN as a
sterically dem an din g h ydroboration reagen t. In terestin gly, th e ch aracteriza-
tion of th e reaction product con firm s our in itial idea th at on ly com poun d
11 is form ed in 42% yield. Next, th e dien e m ixture was treated with
0.3 equiv. of BH3 in THF. Surprisin gly, after alkalin e work-up, again cyclo-
pen ten ol 11 was isolated as th e sole product in 59% overall yield (four steps
startin g from cyclopen tadien e).
To prove th e suitability of cyclopen ten ol 11 to be a startin g m aterial for
th e syn th esis of carbocyclic n ucleosides, pyrim idin e h eterocycles were in -
troduced usin g th e m odified Mitsun obu reaction con dition s as reported
previously13,14,16. Th us, 3-ben zoylth ym in e an d 3-ben zoyluracil were con -
den sed successfully with cyclopen ten ol 11. Alkalin e treatm en t of th e crude
reaction product led to O-ben zylcyclopen ten yl n ucleosides 12a an d 12b, re-
spectively. In parallel, cyclopen ten ol 11 was reacted with 3-[(ben zyloxy)-
m eth yl]th ym in e15 un der Mitsun obu con dition s leadin g to in term ediate 12c
in 90% yield. In th e case of 3-ben zoyl- an d 3-[(ben zyloxy)m eth yl]th ym in e
th e N1/O2-regioselectivity was foun d to be 75:15 an d 85:15 wh ile a 9:1
regioselectivity was foun d for 3-ben zoyluracil. Th e products were iden tified
by HMBC-NMR spectroscopy. Th ese values are iden tical to th ose reported
before for th e couplin gs to cyclopen tan ol 8. Th is clearly poin ts to an in trin -
sic property of th e pyrim idin e rin gs. Deben zylation of n ucleosides 12 pro-
ceeded in ca. 70% yield usin g BCl3 at –78 °C to give cyclopen ten yl
n ucleoside an alogues 13 19, respectively. Cyclopen ten yl n ucleosides such as
13 are an alogues of th e bioactive Neplan ocin A, D an d F (Ch art 1).
Th en , 5′-O-ben zylated N3-BOM-n ucleoside (BOM = (ben zyloxy)m eth yl)
(12c) was h ydroborated usin g 9-BBN with an ti-Markown ikow orien tation
wh ich led to th e form ation of protected carbocyclic th ym idin e 14 an d
deprotection led to (±)-carba-dT 5 sh owin g iden tical spectroscopic data as
before10. Th e reaction proceeded with an ti selectivity with respect to th e
h eterocycle. Con sequen tly, th e sterically dem an din g h ydroboration reagen t
attacks th e C=C double bon d from th e α-face (Sch em e 2). On th e wh ole,
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Reichardt, Ludek, Meier:
th e route startin g from a m ixture of cyclopen tadien es 9 an d 10 is even
sh orter com pared to our previously reported syn th esis13.
Moreover, th is strategy offers th e possibility of syn th esizin g n ew carbo-
cyclic n ucleosides because before or after in troduction of th e pyrim idin e
rin g th e double bon d can be fun ction alized. To dem on strate th at, cyclo-
pen ten yl n ucleoside 13a was treated with 3-ch loroperben zoic acid
(m-CPBA) to form an epoxide 15 (Sch em e 2). Such epoxide-con tain in g
carbocyclic n ucleosides are an alogues of th e n aturally occurrin g
Neplan ocin B an d C. Surprisin gly, we isolated both diastereom eric bicyclic
n ucleoside an alogues 15 as a 1:1 m ixture in 59% yield. Th us, in con trast to
th e h ydroboration reaction , th e un protected h eterocycle attach ed to th e
cyclopen ten yl rin g in 13a was n ot able to h in der th e attack from th e β-face
of th e alken e sufficien tly. It sh ould be m en tion ed th at both epoxides de-
com pose slowly durin g storage at room tem perature.
Cyclopen ten yl uracil n ucleoside (±)-12b was reacted with N-m eth yl-
m orph olin e-N-oxide (NMO) an d K2OsO4·2H2O in DMF for cis-dih ydroxyl-
ation . As expected, cis-diol 16 was isolated in 41% yield after deprotection
by h ydrogen olysis in th e presen ce of Pd/C. Takin g th e results of th e
epoxidation in to accoun t, th e cis-h ydroxylation surprisin gly took place ex-
clusively trans to th e h eterocycle. Th e relative stereoch em istry was proven
by NOE-experim en ts (Sch em e 2).
Bicyclic n ucleosides attracted recen tly con siderable in terest because th ey
are con form ation ally rigid or at least h igh ly con strain ed an alogues4,20
.
Th us, cyclopropan ation of th e cyclopen ten e rin g was in vestigated. In previ-
ous reports cyclopen t-3-en -1-ol (17) was treated with diiodom eth an e an d
dieth ylzin c (Furukawa’s reagen t)21 for cyclopropan ation (Sch em e 3a). Due
to com plexation of th e organ o-zin c reagen t by th e h ydroxy group (18), th e
cyclopropan ation proceeded in depen den tly to th e preferred con form ation
with cis-orien tation of th e two fun ction al groups (cis-19)22. However, treat-
in g BOM-cyclopen ten ol 11 with CH2I2 an d Zn Et2 th e bicyclic system
trans-20 was isolated in 81% yield.
Th is orien tation was un am biguously proven by NOE spectroscopy (stron g
NOE between proton A an d proton B; Sch em e 3b). Furth er eviden ce of th e
trans-con figuration was obtain ed after a con version of th e h ydroxy group
in com poun d trans-20 usin g PPh 3, ben zoic acid an d diisopropyl azodicarb-
oxylate (DIAD) to cis-20 (87% yield). As expected, no NOE was n ow ob-
served between proton A an d B. Con sequen tly, th e Zn -reagen t does n ot
com plex to th e h ydroxy group. Th e startin g m aterial 11 exists in two
en ergy-low en velope-con form ers. In on e con form ation (con form er B in
Sch em e 4) th e h ydroxy group m ay even form a h ydrogen bridge to th e oxy-
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Racemic Cyclopent-3-en-1-yl Nucleoside Analogues
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SCHEME 3
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Reichardt, Ludek, Meier:
gen atom of th e BOM group. In th is con form ation th e lower face of th e
m olecule is sh ielded by th e two substituen ts wh ile th e upper face is less
h in dered. Th us, th e Zn -reagen t approach es preferably from th at face lead-
in g to th e an ti orien tation of th e cyclopropan e an d th e h ydroxy group.
Neverth eless, th e reaction led to stereospecific cyclopropan ation of th e
cyclopen ten e rin g wh ich is un preceden ted. Attem pts to use sam arium
carben oid (ISm CH2I) form ed from a m ixture of sam arium , HgI2 an d CH2I2
(ref.23) for th e cyclopropan ation failed.
SCHEME 4
Bicyclo[3.1.0]h exan ol trans-20 was con verted in to th e pyrim idin e n ucleo-
side 21a (th ym in e) an d 21b (uracil) in about 50% yield. In th e products,
th e h eterocycle an d cyclopropan e are n ow in cis-orien tation . However, if
th e trans-orien tation is n eeded, bicyclo[3.1.0]h exan ol cis-20 would be th e
appropriate startin g m aterial leadin g to n ucleoside 23. Th e ben zyl protect-
in g group in n ucleoside an alogues 21, 22 was cleaved usin g Pd/C an d for-
m ic acid to give bicyclic n ucleoside an alogues 23a, 23b an d 24 in about
60% yield.
Cyclopen ten ol 11 an d bicyclo[3.1.0]h exan ol (±)-trans-20 were used for
th e first syn th eses of 6-ch loropurin e an alogues (Sch em e 5). Mitsun obu cou-
SCHEME 5
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Racemic Cyclopent-3-en-1-yl Nucleoside Analogues
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plin g of precursors (±)-11 or trans-20 with 6-ch loropurin e led to th e form a-
tion of th e protected purin e n ucleosides 25 an d 26 in 54 an d 95% yields,
respectively. Th e cis-orien tation in bicyclo[3.1.0]h exan ylpurin e 26 was con -
firm ed by a stron g NOE sign al between H8 of th e purin e an d HB of th e
th ree-m em bered rin g. Th e couplin g of th e bicyclic system an d th e purin e
rin g resulted in a 9:1 m ixture of N9/N7-regioisom ers wh ich were separated
by colum n ch rom atograph y. Th e regioisom ers were distin guish ed by th eir
HMBC-NMR spectra. Both com poun ds will serve in th e future as startin g
m aterials for th e preparation of, e.g., aden in e n ucleoside an alogues usin g
kn own procedures6,7,20
.
In sum m ary, we h ave elaborated an in terestin g n ew path way towards th e
syn th esis of fun ction alized carbocyclic pyrim idin e an d purin e n ucleoside
an alogues. Most in terestin gly, th e route open s an access to th e im portan t
class of bicyclic n ucleoside an alogues. Th e m eth od starts from ch eap
cyclopen tadien e an d is a powerful addition to our previously reported
m eth odology. Curren tly we are workin g on stereoselective h ydroboration
of a m ixture of alkylated cyclopen tadien es 9 an d 10. Th e biological evalua-
tion of th e com poun ds is un der in vestigation .
EXPERIMENTAL
All experim en ts in volvin g water-sen sitive com poun ds were con ducted un der scrupulously
dry con dition s (n itrogen atm osph ere) usin g stan dard syrin ge, can n ula, an d septa apparatus.
Solven ts: Et2O an d THF were distilled from sodium or potassium ben zoph en on e an d stored
over m olecular sieves. CH2Cl2 an d CH3CN were distilled from CaH2 an d stored over m olecu-
lar sieves. EtOAc, CH2Cl2, petroleum eth er an d CH3OH em ployed in ch rom atograph y were
distilled before use. Ch rom atograph y: Ch rom atotron (Harrison Research 7924), silica gel 60Pf
(Merck, with gypsum ), UV detection at 254 n m . TLC: an alytical th in layer ch rom atograph y
was perform ed on Merck precoated alum in ium plates 60 F254 with an 0.2 m m layer of silica
gel con tain in g a fluorescen ce in dicator; sugar-con tain in g com poun ds were visualized with
th e sugar spray reagen t (4-m eth oxyben zaldeh yde (0.5 m l), EtOH (9 m l), con cen trated H2SO4
(0.5 m l), an d HOAc (0.1 m l)) by h eatin g with a fan . For colum n ch rom atograph y, Merck
silica gel 60, 230–400 m esh was used. NMR spectra were recorded usin g (1H NMR) Bruker
AMX 400 at 400 MHz or Bruker DMX 500 at 500 MHz, (13C NMR) Bruker AMX 400 at 101
MHz or Bruker DMX 500 at 123 MHz. All 1H an d 13C NMR ch em ical sh ifts (δ-scale) are
quoted in ppm an d calibrated with solven t sign als; couplin g con stan ts (J) are given in Hz.
Th e spectra were recorded at room tem perature. ESI m ass spectra were m easured on
a
Fin n igan Th erm oQuest MAT 95 XL spectrom eter an d FAB h igh resolution (HR) m ass spectra
on a VG An alytical 70–250 F spectrom eter (m atrix was 3-n itroben zyl alcoh ol).
Gen eral Procedure 1. Couplin g of Pyrim idin es
To a suspen sion of PPh 3 (3 equiv.) in an h ydrous CH3CN, DIAD (3 equiv.) was added slowly
an d th e solution was stirred at 0 °C for 30 m in . Th is preform ed com plex was slowly added
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Reichardt, Ludek, Meier:
to a suspen sion of a protected n ucleobase (2 equiv.) an d th e alcoh ols (±)-11, (±)-cis-20 or
(±)-trans-20 (1 equiv.) in an h ydrous CH3CN at –40 °C un der n itrogen . Th e reaction was
slowly warm ed to room tem perature an d stirred overn igh t. Th e solven t was rem oved from
th e reaction m ixture an d th e N3-ben zoyl n ucleoside was ch rom atograph ed on silica gel
colum n (petroleum eth er–EtOAc, 1:2). Th is m aterial was dissolved in a m eth an olic NaOH
solution (1%) an d stirred at room tem perature overn igh t. Th e solution was n eutralized by
addition of 1 M HCl an d th en con cen trated. Th e crude m aterial was purified on silica gel
colum n (petroleum eth er–EtOAc, 2:1) to yield th e N1-alkylated com poun ds 12a, 12b, 21a,
21b an d 22 as ligh t yellow syrups.
Gen eral Procedure 2. Deben zylation of Cyclopen t-3-en -1-yl Nucleosides
BCl3 (1 M in CH2Cl2, 6 equiv.) was added slowly to a stirred solution of th e ben zylated
carba-n ucleosides (1 equiv.) in an h ydrous CH2Cl2 at –78 °C. Th e reaction m ixture was
warm ed to –25 °C an d CH3OH was added dropwise. Th e m ixture was allowed to warm to
room tem perature an d stirred overn igh t. Th e solven t was rem oved an d th e residue with
CH3OH was con cen trated th ree tim es. Th e crude product was purified by ch rom atograph y
on a Ch rom atotron (CH2Cl2–CH3OH gradien t 0→20%) to yield th e carba-n ucleosides as
wh ite solids. After lyoph ilization (CH3CN–water), th e deben zylated n ucleoside an alogues
were obtain ed as colorless solids.
Gen eral Procedure 3. Deben zylation of Bicyclic Nucleoside An alogues
Form ic acid was added to a stirred suspen sion of ben zylated carba-n ucleoside (1 equiv.) an d
palladium on ch arcoal in CH3OH. Th e reaction m ixture was warm ed to 50 °C for 12 h . Th e
solven t was rem oved an d th e crude product was purified by ch rom atograph y on
a
Ch rom atotron (CH2Cl2–MeOH gradien t 0→5%) to yield th e carba-n ucleoside as a wh ite
solid. After lyoph ilization (CH3CN–water), th e deben zylated n ucleoside an alogues were ob-
tain ed as colorless solids.
(±)-3-[(Ben zyl)oxym eth yl]cyclopen t-3-en -1-ol (11)
To a suspen sion of NaH (288 m g, 12.0 m m ol) in an h ydrous THF (10 m l) at 0 °C, was added
fresh ly distilled cyclopen tadien e (1.00 m l, 15 m m ol) un der n itrogen . Th e sligh tly pin k solu-
tion was stirred at 0 °C for 1 h an d th en added dropwise to a solution of (ben zyloxy)m eth yl
ch loride (1.7 m l, 12 m m ol) in an h ydrous THF (15 m l) at –50 °C. Th e reaction m ixture was
stirred at –40 °C for 2 h an d slowly warm ed to room tem perature overn igh t. Th e solven t was
evaporated un der reduced pressure. Th e residue was cooled to 0 °C an d a 1 M solution of
BH3·THF in THF (4.0 m l, 4.0 m m ol) was added dropwise. Th e solution was stirred at 0 °C for
1 h , slowly warm ed to room tem perature an d stirred at th is tem perature for an oth er 16 h .
Th e reaction m ixture was quen ch ed with 3 M NaOH (8.0 m l) solution an d H2O2 (30%;
8.0 m l) at 0 °C an d th e m ixture was stirred overn igh t. Th e form ed solid was rem oved by fil-
tration an d wash ed with Et2O. After ph ase separation th e aqueous layer was wash ed with
Et2O (3 × 15 m l), th e com bin ed organ ic fraction s were dried (an h ydrous Na2SO4) an d th e
solven t was rem oved un der reduced pressure. Th e residue was purified by silica gel ch rom a-
tograph y (petroleum eth er–EtOAc, 2:1) yieldin g 11 (1.30 g, 59%) as a ligh t yellow oil.
1H NMR (500 MHz, CDCl3): 7.38–7.27 (m , 5 H, CH-arom .); 5.66–5.63 (m , 1 H, H-4);
4.58–4.58 (m , 1 H, H-1); 4.51 (s, 2 H, CH2-ben zyl); 4.08 (s, 2 H, O-CH2); 2.75–2.67 (m , 2 H,
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Racemic Cyclopent-3-en-1-yl Nucleoside Analogues
1021
H-2a, H-5a); 2.38–2.30 (m , 2 H, H-2b, H-5b). 13C NMR (101 MHz, CDCl3): 139.9 (C-3); 138.8
(Cq-arom .); 128.5 (C-arom .); 127.9 (C-arom .); 127.8 (C-arom .); 125.1 (C-4); 72.3 (O-CH2);
72.2 (C-1); 68.9 (CH2-ben zyl); 43.3 (C-2); 42.8 (C-5). IR (film ), cm –1: 698, 946, 1168, 1198,
1453, 1496, 2849, 2920, 3030, 3396. HRMS-FAB, m/z: calculated for C13H16O2 (M + H)
205.1229, foun d 205.1224.
(±)-1-{4-[(Ben zyloxy)m eth yl]cyclopen t-3-en -1-yl}th ym in e (12a)
See Gen eral procedure 1. PPh 3 (1.89 g, 7.21 m m ol), DIAD (1.42 m l, 7.21 m m ol) in CH3CN
(20 m l), cyclopen ten ol (±)-11 (482 m g, 2.40 m m ol), 3-ben zoylth ym in e (980 m g, 4.83 m m ol)
in CH3CN (20 m l). Yield 370 m g (50%). 1H NMR (400 MHz, C6D6): 9.84 (bs, 1 H, NH);
7.28–7.03 (m , 5 H, CH-arom .); 6.44 (d, 1 H, 4J = 1.3, H-6); 5.28–5.25 (m , 1 H, H-3′);
5.12–5.11 (m , 1 H, H-1′); 4.26 (s, 2 H, CH2-ben zyl); 3.73–3.63 (m , 2 H, H-5′); 2.41–2.30 (m ,
2 H, H-6′a, H-2′a); 1.96–1.92 (m , 1 H, H-2′b); 1.91–1.88 (m , 1 H, H-6′b); 1.65 (d, 3 H, 4J =
1.0, CH3-th ym in e). 13C NMR (101 MHz, C6D6): 162.3 (C-4); 151.5 (C-2); 138.5 (Cq-arom .);
136.3 (C-6); 128.9 (C-arom .); 128.7 (C-arom .); 125.3 (C-3′); 124.8 (C-4′); 111.5 (C-5); 72.8
(C-5′); 68.6 (O-CH2); 53.6 (C-1′); 39.4 (C-2′); 39.3 (C-6′); 12.9 (CH3-th ym in e). IR (film ), cm –1
:
700, 1046, 1073, 1118, 1270, 1473, 1694, 2678, 2858, 2930, 3062, 3448. HRMS-FAB, m/z:
calculated for C18H20N2O3 (M + H) 313.1552, foun d 313.1541.
(±)-1-{4-[(Ben zyloxy)m eth yl]cyclopen t-3-en -1-yl}uracil (12b)
See Gen eral procedure 1. PPh 3 (2.20 g, 8.4 m m ol), DIAD (1.65 m l, 8.38 m m ol) in CH3CN
(20 m l), cyclopen ten ol (±)-11 (573 m g, 2.81 m m ol), 3-ben zoyluracil (1.21 g, 5.60 m m ol) in
CH3CN (20 m l). Yield 486 m g (58%). 1H NMR (500 MHz, CDCl3): 8.54 (bs, 1 H, NH);
7.30–7.18 (m , 5 H, CH-arom .); 7.09 (d, 1 H, 3J = 8.2, H-5); 5.65–5.63 (m , 1 H, H-3′); 5.59 (d,
1 H, 2J = 7.9, H-6); 5.29–5.24 (m , 1 H, H-1′); 4.44 (s, 2 H, CH2-ben zyl); 4.06–3.95 (m , 2 H,
H-5′); 2.91–2.81 (m , 2 H, H-2′a, H-6′a); 2.34–2.28 (m , 2 H, H-2′b, H-6′b). 13C NMR
(101 MHz, CDCl3): 163.1 (C-4); 150.8 (C-2); 140.9 (C-5); 140.6 (C-4′); 138.1 (Cq-arom .);
128.6 (C-arom .); 128.0 (C-arom .); 127.8 (C-arom .); 125.4 (C-3′); 103.2 (C-6); 72.9 (CH2-
ben zyl); 68.4 (C-5′); 53.4 (C-1′); 40.0 (C-2′); 39.8 (C-6′). IR (film ), cm –1: 699, 1028, 1093,
1203, 1383, 1459, 1666, 2081, 3450, 3854. MS-FAB, m/z: calculated for C17H18N2O3 (M + H)
299.1, foun d 299.2.
(±)-1-{4-[(Ben zyloxy)m eth yl]cyclopen t-3-en -1-yl}-3-[(ben zyloxy)m eth yl]th ym in e (12c)
See Gen eral procedure 1. PPh 3 (780 g, 2.98 m m ol), DIAD (0.56 m l, 2.8 m m ol) in CH3CN
(8 m l), cyclopen ten ol (±)-11 (204 m g, 1.00 m m ol), 3-[(ben zyloxy)m eth yl]th ym in e (517 m g,
2.10 m m ol) in CH3CN (8 m l). Yield 389 m g (90%). 1H NMR (400 MHz, CDCl3): 7.40–7.30
(m , 10 H, CH-arom .); 6.95 (d, 1 H, 4J = 1.0, H-6); 5.76–5.72 (m , 1 H, H-3′); 5.52 (s, 2 H,
O-CH2-N); 5.46–5.39 (m , 1 H, H-1′); 4.72 (s, 2 H, CH2-ben zyl-A); 4.55 (s, 2 H, CH2-ben zyl-B);
4.11–4.06 (m , 2 H, 5′-CH2); 2.96–2.85 (m , 2 H, H-2′a, H-6′a); 2.44–2.39 (m , 1 H, H-2′b);
2.39–2.34 (m , 1 H, H-6′b); 1.88 (d, 3 H, 4J = 1.0, CH3-th ym in e). 13C NMR (101 MHz, CDCl3):
163.3 (C-4); 150.2 (C-2); 145.3 (C4′); 140.8, 138.7 (Cq-arom .); 135.8 (C-6); 128.9, 128.8,
128.7, 128.3, 128.1, 128.0 (CH-arom .); 127.9 (C-3′); 111.2 (C-5); 73.1, 72.7 (CH2-ben zyl);
71.3 (O-CH2-N); 68.9 (C-5′); 54.0 (C-1′); 40.2 (C-2′); 39.9 (C-6′); 13.7 (CH3-th ym in e). IR
(film ), cm –1: 698, 738, 772, 810, 1028, 1092, 1150, 1211, 1269, 1360, 1453, 1496, 1548,
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 7, pp. 1011–1028

1022
Reichardt, Ludek, Meier:
1663, 1705, 2855, 2924, 3030. HRMS-FAB, m/z: calculated for C26H28N2O4 (M + H)
433.2127, foun d 433.2143.
(±)-1-[4-(Hydroxym eth yl)cyclopen t-3-en -1-yl]th ym in e (13a)
See Gen eral procedure 2. 12a (370 m g, 1.20 m m ol), BCl3 (1 M in CH2Cl2, 7.2 m l, 7.2 m m ol)
in an h ydrous CH2Cl2 (20 m l). Yield 172 m g (66%), m .p. 193–195 °C. 1H NMR (400 MHz,
DMSO-d6): 11.23 (bs, 1 H, NH); 7.29 (d, 1 H,4J = 1.3, H-6); 5.86–5.83 (m , 1 H, H-3′);
5.18–5.09 (m , 1 H, H-1′); 4.37–4.31 (m , 2 H, H-5′); 2.83–2.75 (m , 2 H, H-2′a, H-6′a);
2.50–2.43 (m , 2 H, H-2′b, H-6′b); 1.75 (d, 3 H, 4J = 1.0, CH3-th ym in e). 13C NMR (101 MHz,
DMSO-d6): 163.9 (C-4); 150.8 (C-2); 141.4 (C-4′); 137.6 (C-6); 128.7 (C-3′); 109.6 (C-5); 53.3
(C-1′); 43.1 (C-5′); 38.3 (C-6′); 38.3 (C-2′); 12.3 (CH3-th ym in e). IR (KBr), cm –1: 627, 762, 824,
1008, 1027, 1054, 1676, 2126, 2252, 3438. HRMS-FAB, m/z: calculated for C11H14N2O3
(M + H) 223.1083, foun d 223.1100.
(±)-1-[4-(Hydroxym eth yl)cyclopen t-3-en -1-yl]uracil (13b)
See Gen eral procedure 2. 13a (112 m g, 0.342 m m ol), BCl3 (1 M in CH2Cl2, 2.0 m l, 2.00
m m ol) in an h ydrous CH2Cl2 (10 m l). Yield 60.0 m g (76%), m .p. 144–147 °C. 1H NMR
(400 MHz, DMSO-d6): 11.25 (s, 1 H, NH); 7.41 (d, 1 H, 3J = 8.0, H-6); 5.85–5.83 (m , 1 H,
H-3′); 5.58 (d, 1 H, 3J = 8.0, H-5); 5.16–5.08 (m , 1 H, H-1′); 4.34 (s, 2 H, H-5′); 2.87–2.76 (m ,
2 H, H-2′a, H-6′a); 2.46–2.42 (m , 2 H, H-2′b, H-6′b). 13C NMR (101 MHz, DMSO-d6): 163.3
(C-4); 150.8 (C-2); 145.7 (C-4′); 142.0 (C-6); 128.7 (C-3′); 109.3 (C-5); 53.6 (C-1′); 43.0 (C-5′);
38.4 (C-6′) 38.4 (C-2′). IR (KBr), cm –1: 760, 1008, 1055, 1272, 1379, 1460, 1686, 2819, 3006,
3433. HRMS-FAB, m/z: calculated for C10H12N2O3 (M + H) 209.0926, foun d 209.0925.
(±)-1-{4-[(Ben zyloxy)m eth yl]cyclopen t-3-ol-1-yl}-3-[(ben zyloxy)m eth yl]th ym in e (14)
To a solution of protected n ucleoside 12c (100 m g, 0.231 m m ol) in an h ydrous THF (5 m l) at
0 °C, was added dropwise to a solution of 9-BBN (0.5 M in THF, 920 µl, 0.460 m m ol). Th e re-
action m ixture slowly warm ed to room tem perature overn igh t. Th e reaction m ixture was
quen ch ed with 3 M NaOH (170 µl) solution an d H2O2 (30%; 170 µl) at 0 °C, an d th e m ixture
was stirred overn igh t. Th e form ed solid was rem oved by filtration an d wash ed with Et2O. Af-
ter ph ase separation th e aqueous layer was wash ed with Et2O (3 × 5 m l), th e com bin ed or-
gan ic fraction s were dried (an h ydrous Na2SO4) an d th e solven t was rem oved un der reduced
pressure. Th e crude m aterial was purified by ch rom atograph y on a Ch rom atotron (CH2Cl2–
CH3OH gradien t 0→10%) yieldin g 14 (79 m g, 76%) as a colorless oil. 1H NMR (400 MHz,
CDCl3): 7.40–7.27 (m , 10 H, CH-arom .); 6.98 (d, 1 H, 4J = 1.0, H-6); 5.49 (s, 2 H, O-CH2-N);
5.19–5.10 (m , 1 H, H-1′); 4.70 (s, 2 H, CH2-ben zyl-A); 4.56 (d, 1 H, J = 12.0, CH2-ben zyl-B);
4.52 (d, 1 H, J = 12.0, CH2-ben zyl-B); 4.32–4.27 (m , 1 H, H-3′); 3.69 (dd, 1 H, 2J = 9.0, 3J =
4.1, H-5′a); 3.51 (d, 1 H, 2J = 9.0, 3J = 7.0, H-5′b); 2.28–2.17 (m , 2 H, H-4′, H-6′a); 2.09–2.03
(m , 2 H, H-2′); 1.81 (d, 3 H, 4J = 1.0, CH3-th ym in e); 1.54–1.47 (m , 1 H, H-6′b). 13C NMR
(101 MHz, CDCl3): 163.8 (C-4); 151.9 (C-2); 138.5, 138.3 (Cq-arom .); 136.4 (C-6); 128.7,
128.4, 128.2, 128.1, 128.1, 128.0 (CH-arom .); 110.8 (C-5); 75.8 (C-3′); 74.0 (CH2-ben zyl-A);
72.9 (C-5′); 72.4 (CH2-ben zyl-B); 71.2 (O-CH2-N); 55.3 (C-1′); 47.1 (C-4′); 39.6 (C-2′); 32.8
(C-6′); 13.6 (CH3-th ym in e). IR (film ), cm –1: 468, 611, 698, 736, 774, 1027, 1091, 1151, 1267,
1360, 1454, 1496, 1548, 1661, 2928, 3031, 3062, 3457. HRMS-FAB, m/z: calculated for
C
26H30N2O5 (M + H) 451.2233, foun d 451.2256.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 7, pp. 1011–1028

Racemic Cyclopent-3-en-1-yl Nucleoside Analogues
1023
(±)-cis/trans-1-[3,4-Epoxy-3-h ydroxym eth yl)cyclopen tyl]th ym in e (15)
To a solution of m-ch loroperben zoic acid (138 m g, 0.82 m ol) in an h ydrous CH2Cl2 (10 m l)
un der n itrogen , (±)-1-[4-(h ydroxym eth yl)cyclopen t-3-en -1-yl]th ym in e (13a ; 140 m g,
0.55 m m ol) was slowly added at 0 °C. Th e reaction m ixture was stirred an d allowed to warm
to room tem perature overn igh t. Th e reaction m ixture was diluted with a saturated solution
of sodium sulfite (5 m l) an d stirred at room tem perature After 1 h th e layers were separated,
th e aqueous ph ase was extracted with CH2Cl2 (3 × 10 m l), th e com bin ed organ ic ph ases
were dried (an h ydrous Na2SO4) an d th e solven t was rem oved un der reduced pressure. Th e
crude m aterial was purified by ch rom atograph y on a Ch rom atotron (CH2Cl2–CH3OH gradi-
en t 0→5%) to yield th e carba-n ucleosides as wh ite solids. After lyoph ilization (CH3CN–
water), th e n ucleoside an alogues were obtain ed (trans-15 (42.0 m g, 31%) an d cis-15 (39.0 m g,
28%)) as colorless solids (diastereom eric ratio: 1:1.2 (trans:cis)).
trans-15: m .p. 186 °C (decom p.). 1H NMR (500 MHz, DMSO-d6): 11.17 (bs, 1 H, NH); 7.52
(d, 1 H, 4J = 0.9, 1 H, H-6); 5.18–5.12 (m , 1 H, H-1′); 4.11 (d, 1 H, 2J = 12.0, H-5′a); 3.79 (d,
1 H, 2J = 12.3, H-5′b); 3.73–3.69 (m , 1 H, H-3′); 2.55–2.42 (m , 2 H, H-2′a, H-6′a); 2.09–2.01
(m , 2 H, H-2′b, H-6′b); 1.77 (d, 3 H, 4J = 0.9, CH3-th ym in e). 13C NMR (101 MHz, DMSO-d6):
164.0 (C-4); 151.5 (C-2); 138.4 (C-6); 108.8 (C-5); 68.1 (C-4′); 64.4 (C-3′); 53.0 (C-1′); 45.7
(C-5′); 35.6 (C-6′); 34.4 (C-2′); 12.8 (CH3-th ym in e). MS-ESI, m/z: calculated for C11H14N2O4
(M + Na) 261.1, foun d 261.1.
cis-15: m .p. 172 °C (decom p.). 1H NMR (500 MHz, DMSO-d6): 11.22 (bs, 1 H, NH); 7.62
(d, 1 H, 4J = 0.9, H-6); 4.57–4.49 (m , 1 H, H-1′); 4.14 (d, 1 H, 2J = 12.0, H-5′a); 3.77 (d, 1 H,
2J = 12.3, H-5′b); 3.72–3.65 (m , 1 H, H-3′); 2.32–2.22 (m , 2 H, H-2′a, H-6′a); 2.14–2.04 (m ,
2 H, H-2′b, H-6′b); 1.76 (d, 3 H, 4J = 0.9, CH3-th ym in e). 13C NMR (101 MHz, DMSO-d6):
163.8 (C-4); 150.8 (C-2); 138.8 (C-6); 109.4 (C-5); 64.8 (C-4′); 61.4 (C-3′); 51.5 (C-1′); 46.1
(C-5′); 32.0 (C-6′); 31.6 (C-2′); 12.1 (CH3-th ym in e). MS-ESI, m/z: calculated for C11H14N2O4
(M + Na) 261.1, foun d 261.2.
(±)-1-[3,4-Dih ydroxy-4-(h ydroxym eth yl)cyclopen tyl]uracil (16)
To a solution of th e ben zylated carbocyclic n ucleoside (±)-12b (106 m g, 0.360 m m ol) in an -
h ydrous DMF, N-m eth ylm orph olin eoxide (NMO; 77 µl, 0.75 m m ol) an d K2OsO4·2H2O
(5.00 m g, 0.02 m ol) were added. After stirrin g at room tem perature for 24 h , th e reaction
m ixture was quen ch ed with a solution of sodium h ydrogen sulfite (ten drops) an d th e sol-
ven t was rem oved un der reduced pressure. Th e residue was dissolved in EtOAc (10 m l) an d
wash ed with a solution of saturated sodium ch loride (3 × 10 m l). Th e organ ic layer was
dried (an h ydrous Na2SO4) an d th e solven t was rem oved un der reduced pressure. Th e crude
m aterial was purified by ch rom atograph y on a Ch rom atotron (CH2Cl2–CH3OH gradien t
0→5%) to yield th e carba-n ucleoside as wh ite solids. 1H NMR (400 MHz, DMSO-d6): 11.18
(bs, 1 H, NH); 7.63 (d, 1 H, 3J = 7.9, H-6); 7.56–7.45 (m , 5 H, CH-arom .); 5.50 (d, 1 H, 3J =
8.0, H-5); 5.21–5.12 (m , 1 H, H-1′); 4.79 (d, 1 H, 3J = 6.1, 3′-OH); 4.61 (s, 2 H, CH2-ben zyl);
4.53 (bs, 1 H, 4′-OH); 4.16 (dd, 1 H, 3J = 14.1, 3J = 7.8, H-3′); 3.62–3.54 (m , 2 H, H-5′);
1.98–1.86 (m , 4 H, H-2′, H-6′). 13C NMR (101 MHz, DMSO-d6): 163.2 (C-4); 150.9 (C-2);
143.0 (C-6); 138.5 (Cq-arom .); 128.3 (C-arom .); 127.5 (C-arom .); 127.4 (C-arom .); 101.4
(C-5); 78.8 (C-4′); 73.1 (C-5′); 72.6 (CH2-ben zyl); 71.6 (C-3′); 52.7 (C-1′); 38.8 (C-6′); 36.7
(C-2′). IR (film ), cm –1: 721, 1118, 1276, 1382, 1466, 1682, 2469, 2978, 3411. MS-FAB, m/z:
calculated for C17H20N2O5 (M + H) 333.1, foun d 333.2. A suspen sion of th e ben zylated diol
an d palladium on ch arcoal (10%; 50 m g) in EtOH (5 m l) was stirred un der H2 atm osph ere at
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 7, pp. 1011–1028

1024
Reichardt, Ludek, Meier:
room tem perature for 24 h . Th e m ixture was filtered, an d th e filtrate was evaporated. Th e
residue was purified by ch rom atograph y on a Ch rom atotron (CH2Cl2–CH3OH gradien t
0→5%) to yield th e carba-n ucleoside. After lyoph ilization (CH3CN–water), th e n ucleoside
an alogue was obtain ed in th e yield 29.0 m g (41%) as colorless solid, m .p. 205 °C. 1H NMR
(400 MHz, DMSO-d6): 11.17 (bs, 1 H, NH); 7.64 (d, 1 H, 3J = 8.1, H-6); 5.56 (d, 1 H, 3J = 8.1,
H-5); 5.04–4.95 (m , 1 H, H-1′); 4.76 (dd, 1 H, 3J = 5.5, 3J = 5.5, 5′-OH); 4.71 (d, 1 H, 3J = 6.3,
1 H, 3′-OH); 4.24 (s, 1 H, 4′-OH); 4.12 (dd, 1 H, 3J = 13.7, 3J = 6.3, H-3′); 3.36 (dd, 1 H, 2J =
11.0, 3J = 5.5, H-5′a); 3.28 (dd, 1 H, 2J = 11.0, 3J = 5.5, H-5′b); 1.99–1.88 (m , 2 H, H-2′);
1.87–1.79 (m , 2 H, H-6′). 13C NMR (101 MHz, DMSO-d6): 163.2 (C-4); 150.9 (C-2); 142.8
(C-6); 101.5 (C-5); 79.7 (C-4′); 70.9 (C-3′); 64.3 (C-5′); 52.4 (C-1′); 38.5 (C-2′); 37.0 (C-6′). IR
(film ), cm –1: 668, 1002, 1048, 1289, 1677, 2256, 2342, 2360, 3439. MS-FAB, m/z: calculated
for C10H14N2O5 (M + H) 243.1, foun d 243.1.
(±)-trans-1-[(Ben zyloxy)m eth yl]bicyclo[3.1.0]h exan -3-ol (20)
A solution of Et2Zn (1 M in h exan e, 4.0 m l, 4.0 m m ol) was added dropwise to cyclopen ten ol
11 (722 m g, 3.60 m m ol) in an h ydrous CH2Cl2 (20 m l) at –10 °C an d stirred for 15 m in . To
th is m ixture a solution of diiodom eth an e (322 µl, 4.05 m m ol) in an h ydrous CH2Cl2 (5 m l)
was added rapidly. After 15 m in , an Et2Zn solution (1 M in h exan e, 4.0 m l, 4.0 m m ol) was
added dropwise. A solution of diiodom eth an e (322 µl, 4.0 m m ol) in an h ydrous CH2Cl2
(5 m l) was added rapidly an d th e reaction m ixture was stirred at 0 °C overn igh t. After
quen ch in g with saturated NH4Cl solution (25 m l), th e m ixture was stirred at room tem pera-
ture overn igh t. Th e aqueous layer was wash ed with EtOAc (3 × 20 m l), th e organ ic ph ase
was wash ed with saturated NH4Cl solution , dried (an h ydrous Na2SO4) an d con cen trated.
Purification of th e residue was accom plish ed by ch rom atograph y on silica gel colum n
(petroleum eth er–EtOAc gradien t 0→50%) to yield 20 (636 m g, 83%) as a colorless oil.
1H NMR (400 MHz, C6D6): 7.31–7.07 (m , 5 H, CH-arom .); 4.32 (s, 2 H, CH2-ben zyl); 3.80
(m , 1 H, H-1); 3.33 (d, 1 H, 2J = 9.8, O-CHH); 3.13 (d, 1 H, 2J = 9.8, O-CHH); 1.99 (dd, 1 H,
2J = 12.5, 3J = 6.5, H-2a); 1.84 (dd, 2 H, 2J = 12.3, 3J = 6.6, H-2b, H-5a); 1.75–1.69 (m , 1 H,
H-5b); 1.05–1.00 (m , 1 H, H-4); 0.36 (dd, 1 H, 2J = 8.3, 3J = 5.0, CHH-cyclopropyl); 0.05 (dd,
1 H, 2J = 4.4, 3J = 4.4, CHH-cyclopropyl). 13C NMR (101 MHz, C6D6): 139.4 (Cq-arom .);
128.6 (C-arom .); 127.7 (C-arom .); 75.2 (O-CH2); 72.8 (CH2-ben zyl); 72.7 (C-1); 40.0 (C-2);
38.0 (C-5); 28.0 (C-3); 20.8 (C-4); 16.3 (CH2-cyclopropyl). IR (film ), cm –1: 698, 1028, 1272,
1398, 1496, 2491, 2858, 2935, 3062, 3397. MS-FAB, m/z: calculated for C14H18O2 (M + H)
219.1, foun d 219.2.
(±)-cis-1-[(Ben zyloxy)m eth yl]bicyclo[3.1.0]h exan -3-ol (20)
To a suspen sion of PPh 3 (630 m g, 2.40 m m ol) in dry Et2O (15 m l) at 0 °C un der n itrogen
was slowly added DIAD (473 µl, 2.40 m m ol) an d th e suspen sion was stirred for 30 m in . Th is
preform ed com plex was slowly added to a suspen sion of ben zoic acid (293 m g, 2.40 m m ol)
an d alcoh ol (±)-11 (175 m g, 0.81 m m ol) in an h ydrous Et2O (15 m l) at 0 °C un der n itrogen .
Th e reaction was slowly warm ed to room tem perature an d stirred for 16 h . Th e solid was re-
m oved by filtration an d wash ed with Et2O. Th e solven t was rem oved an d a m eth an olic
NaOH solution (1%; 20 m l) was added. Stirrin g was con tin ued at room tem perature over-
n igh t. Th e solution was n eutralized by addition of 1 M HCl an d th en con cen trated. Th e
crude m aterial was purified on silica gel colum n (petroleum eth er–EtOAc, 2:1) to yield th e
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 7, pp. 1011–1028

Racemic Cyclopent-3-en-1-yl Nucleoside Analogues
1025
alcoh ol (153 m g, 87%) as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.38–7.27 (m , 5 H,
CH-arom .); 4.53 (s, 2 H, CH2-ben zyl); 4.46–4.41 (m , 1 H, H-1); 3.51 (d, 1 H, 2J = 10.2,
O-CHH); 3.43 (d, 1 H, 2J = 10.4, O-CHH); 2.27–2.22 (m , 1 H, H-2a); 2.22–2.16 (m , 1 H,
H-5a); 1.84 (d, 1 H, 2J = 14.0, H-2b); 1.73 (d, 1 H, 2J = 14.2, H-5b); 1.23–1.16 (m , 1 H, H-4);
0.94 (dd, 1 H, 2J = 4.3, 3J = 4.3, CHH-cyclopropyl); 0.60–0.56 (m , 1 H, CHH-cyclopropyl).
13C NMR (101 MHz, CDCl3): 139.4 (Cq-arom .); 128.5 (C-arom .); 127.7 (C-arom .); 127.6
(C-arom .); 75.3 (O-CH2); 74.0 (C-1); 72.6 (C-ben zyl); 40.7 (C-2); 38.5 (C-5); 30.2 (C-3); 22.5
(C-4); 16.7 (CH2-cyclopropyl). IR (film ), cm –1: 738, 964, 1028, 1096, 1201, 1258, 1357, 1496,
2853, 2927, 3028, 3422. MS-FAB, m/z: calculated for C14H18O2 (M + H) 219.1, foun d 219.2.
cis-(±)-1-{4-[(Ben zyloxy)m eth yl]bicyclo[3.1.0]h exan -3-yl}th ym in e (21a)
See Gen eral procedure 1. PPh 3 (1.10 g, 4.00 m m ol), DIAD (788 µl, 4.00 m m ol) in CH3CN
(10 m l), (±)-trans-1-[(ben zyloxy)m eth yl]bicyclo[3.1.0]h exan -3-ol (20; 290 m g, 1.33 m m ol),
3-ben zoylth ym in e (653 m g, 3.21 m m ol) in CH3CN (10 m l). Yield 201 m g (46%). 1H NMR
(400 MHz, CDCl3): 8.35 (bs, 1 H, NH); 7.37–7.27 (m , 5 H, CH-arom .); 6.95 (d, 1 H, 4J = 0.9,
H-6); 5.19–5.10 (m , 1 H, H-1′); 4.53 (s, 2 H, CH2-ben zyl); 3.41 (d, 1 H, 2J = 10.1, H-5′a); 3.37
(d, 1 H, 2J = 10.1, H-5′b); 2.52–2.45 (m , 2 H, H-2′a, H-6′a); 1.91 (d, 3 H, 4J = 1.0, CH3-
th ym in e); 1.74 (dd, 1 H, 2J = 13.4, 3J = 9.0, H-6′b); 1.57 (dd, 1 H, 3J = 9.0, 4J = 2.0, H-2′b);
1.28–1.23 (m , 1 H, H-3′); 1.02 (dd, 1 H, 2J = 5.4, 3J = 8.2, CHH-cyclopropyl); 0.62 (dd, 1 H,
2J = 4.7, 3J = 4.7, CHH-cyclopropyl). 13C NMR (101 MHz, CDCl3): 165.1 (C-4); 150.8 (C-2);
138.5 (Cq-arom .); 137.1 (C-6); 128.6 (C-arom .); 127.7 (C-arom .); 110.7 (C-5); 75.2 (C-5′);
73.0 (CH2-ben zyl); 60.5 (C-1′); 36.9 (C-6′); 35.0 (C-2′); 29.6 (C-4′); 24.3 (CH2-cyclopropyl);
22.1 (C-3′); 12.7 (CH3-th ym in e). IR (film ), cm –1: 699, 740, 909, 1298, 1365, 1685, 2342,
2360, 3188. MS-FAB, m/z: calculated for C19H22N2O3 (M + H) 327.2, foun d 327.3.
cis-(±)-1-{4-[(Ben zyloxy)m eth yl]bicyclo[3.1.0]h exan -3-yl}uracil (21b)
See Gen eral procedure 1. PPh 3 (393 m g, 1.50 m m ol), DIAD (0.29 m l, 1.50 m m ol) in CH3CN
(5 m l), (±)-trans-1-[(ben zyloxy)m eth yl]bicyclo[3.1.0]h exan -3-ol (20; 113 m g, 0.52 m m ol),
3-ben zoyluracil (216 m g, 1.00 m m ol) in CH3CN (5 m l). Yield 84 m g (54%). 1H NMR
(400 MHz, CDCl3): 9.22 (bs, 1 H, NH); 7.37–7.26 (m , 5 H, CH-arom .); 7.15 (d, 1 H, 3J = 8.2,
H-6); 5.69 (d, 1 H, 3J = 8.0, H-5); 5.18–5.10 (m , 1 H, H-1′); 4.52 (s, 2 H, CH2-ben zyl); 3.41 (d,
1 H, 2J = 10.1, H-5′a); 3.37 (d, 1 H, 2J = 10.1, H-5′b); 2.54–2.47 (m , 2 H, H-6′a, H-2′a); 1.75
(dd, 1 H, 2J = 13.6, 3J = 8.5, H-6′b); 1.58 (ddd, 1 H, 2J = 13.9, 3J = 8.7, 3J = 1.7, H-2′b);
1.29–1.23 (m , 1 H, H-3′); 1.02–0.98 (m , 1 H, CHH-cyclopropyl); 0.59 (dd, 2J = 4.7, 3J = 4.7,
1 H, CHH-cyclopropyl). 13C NMR (101 MHz, CDCl3): 163.2 (C-4); 150.9 (C-2); 141.2 (C-6);
138.5 (Cq-arom .); 128.6 (C-arom .); 127.9 (C-arom .); 127.8 (C-arom .); 127.7 (C-arom .); 102.2
(C-5); 75.1 (C-5′); 73.0 (CH2-ben zyl); 60.7 (C-1′); 36.9 (C-6′); 35.0 (C-2′); 29.3 (C-4′); 23.9
(CH2-cyclopropyl); 21.4 (C-3′). IR (film ), cm –1: 699, 1028, 1379, 1420, 1686, 2863, 3059,
3449. HRMS-FAB, m/z: calculated for C18H20N2O3 (M + H) 313.1552, foun d 313.1578.
trans-(±)-1-{4-[(Ben zyloxy)m eth yl]bicyclo[3.1.0]h exan -3-yl}th ym in e (22)
See Gen eral procedure 1. PPh 3 (262 m g, 1.00 m m ol), DIAD (0.197 m l, 1.02 m m ol) in CH3CN
(5 m l), (±)-cis-1-[(ben zyloxy)m eth yl]bicyclo[3.1.0]h exan -3-ol (20; 75 m g, 0.34 m m ol),
3-ben zoylth ym in e (172 m g, 0.66 m m ol) in CH3CN (5 m l). Yield 82 m g (73%). 1H NMR
(400 MHz, CDCl3): 8.90 (bs, 1 H, NH); 7.38–7.27 (m , 5 H, CH-arom .); 7.08 (d, 4J = 1.0, 1 H,
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H-6); 4.83–4.73 (m , 1 H, H-1′); 4.56–4.54 (m , 2 H, CH2-ben zyl); 3.62 (d, 2J = 10.4, 1 H,
H-5′a); 3.39 (d, 2J = 10.4, 1 H, H-5′b); 2.23–2.11 (m , 2 H, H-2′a, H-6′a); 2.04–1.94 (m , 2 H,
H-2′b, H-6′b); 1.91 (d, 4J = 1.0, 3 H, CH3-th ym in e); 1.35–1.29 (m , 1 H, H-3′); 0.64 (dd, 2J =
5.1, 3J = 4.8, 1 H, CHH-cyclopropyl); 0.54 (dd, 2J = 5.8, 3J = 8.1, 1 H, CHH-cyclopropyl).
13C NMR (101 MHz, CDCl3): 163.7 (C-4); 151.1 (C-2); 138.5 (Cq-arom .); 136.9 (C-6); 128.6
(C-arom .); 127.8 (C-arom .); 127.7 (C-arom .); 111.5 (C-5); 75.2 (CH2-ben zyl); 74.6 (C-5′); 52.5
(C-1′); 34.4 (C-6′); 32.9 (C-2′); 27.3 (C-4′); 20.3 (C-3′); 13.5 (CH2-cyclopropyl); 12.7
(CH3-th ym in e). IR (film ), cm –1: 700, 739, 1072, 1266, 1299, 1373, 1454, 1578, 1686, 2865,
2933, 3032, 3199. MS-FAB, m/z: calculated for C19H22N2O3 (M + H) 327.2, foun d 327.2.
cis-(±)-1-[1-(Hydroxym eth yl)bicyclo[3.1.0]h exan -3-yl]th ym in e (23a)
See Gen eral procedure 3. 21a (181 m g, 0.55 m m ol), form ic acid (0.60 m l, 16.0 m m ol) in
CH3OH (5 m l). Yield 75 m g (57%), m .p. 195–197 °C. 1H NMR (400 MHz, DMSO-d6): 11.16
(bs, 1 H, NH); 7.51 (d, 1 H, 4J = 1.0, H-6); 5.06–4.96 (m , 1 H, H-1′); 4.59 (bs, 1 H, 5′-OH);
3.43 (d, 1 H, 2J = 11.4, H-5′a); 3.17 (d, 1 H, 2J = 11.2, H-5′b); 2.27–2.18 (m , 2 H, H-2′a,
H-6′a); 1.76 (d, 3 H, 4J = 1.0, CH3-th ym in e); 1.61 (dd, 1 H, 2J = 12.7, 3J = 10.2, H-6′b);
1.51–1.45 (m , 1 H, H-2′b); 1.13–1.08 (m , 1 H, H-3′); 0.86–0.83 (m , 1 H, CHH-cyclopropyl);
0.72 (dd, 1 H, 2J = 4.2, 3J = 4.2, CHH-cyclopropyl). 13C NMR (101 MHz, DMSO-d6): 163.8
(C-4); 150.8 (C-2); 138.0 (C-6); 108.9 (C-5); 65.7 (C-5′); 59.7 (C-1′); 35.4 (C-6′); 34.1 (C-2′);
31.0 (C-4′); 23.3 (CH2-cyclopropyl); 20.2 (C-3′); 12.0 (CH3-th ym in e). IR (KBr), cm –1: 1004,
1260, 1363, 1401, 1684, 1749, 2835, 3424. HRMS-FAB, m/z: calculated for C12H16N2O3 (M + H)
237.1239, foun d 237.1268.
cis-(±)-1-[1-(Hydroxym eth yl)bicyclo[3.1.0]h exan -3-yl]uracil (23b)
See Gen eral procedure 3. 21b (29 m g, 0.09 m m ol), form ic acid (0.20 m l, 5.30 m m ol) in
CH3OH (5 m l). Yield 13 m g (61%), m .p. 168–170 °C. 1H NMR (400 MHz, DMSO-d6): 11.23
(s, 1 H, NH); 7.41 (d, 1 H, 3J = 8.0, H-6); 5.58 (d, 1 H, 3J = 8.0, H-5); 5.06–4.96 (m , 1 H,
H-1′); 4.59 (bs, 1 H, 5′-OH); 3.43 (d, 1 H, 2J = 11.4, H-5′a); 3.17 (d, 1 H, 2J = 11.2, H-5′b);
2.27–2.18 (m , 2 H, H-2′a, H-6′a); 1.61 (dd, 1 H, 2J = 12.7, 3J = 10.2, H-6′b); 1.51–1.45 (m ,
1 H, H-2′b); 1.13–1.08 (m , 1 H, H-3′); 0.86–0.83 (m , 1 H, CHH-cyclopropyl); 0.72 (dd, 1 H,
2J = 4.2, 3J = 4.2, CHH-cyclopropyl). 13C NMR (101 MHz, DMSO-d6): 163.3 (C-4); 150.8
(C-2); 141.6 (C-6); 109.3 (C-5); 65.7 (C-5′); 59.7 (C-1′); 35.4 (C-6′); 34.1 (C-2′); 31.0 (C-4′);
23.3 (CH2-cyclopropyl); 20.2 (C-3′). HRMS-FAB, m/z: calculated for C11H14N2O3 (M + H)
223.1083, foun d 223.1097.
trans-(±)-1-[1-(Hydroxym eth yl)bicyclo[3.1.0]h exan -3-yl]th ym in e (24)
See Gen eral procedure 3. 22 (49.0 m g, 0.15 m m ol) in CH3OH (5 m l). Yield 23 m g (64%),
m .p. 182–186 °C. 1H NMR (400 MHz, DMSO-d6): 11.21 (bs, 1 H, NH); 7.59 (d, 1 H, 4J = 1.0,
H-6); 4.62–4.51 (m , 1 H, H-1′); 3.97 (d, 1 H, 2J = 10.9, H-5′a); 3.68 (d, 1 H, 2J = 10.9, H-5′b);
2.81–2.66 (m , 2 H, H-2′a, H-6′a); 2.60–2.54 (m , 2 H, H-2′b, H-6′b); 1.74 (d, 3 H, 4J = 1.0,
CH3-th ym in e); 1.46–1.40 (m , 1 H, H-3′); 0.74 (dd, 1 H, 2J = 4.8, 3J = 4.8, CHH-cyclopropyl);
0.66 (dd, 1 H, 2J = 8.3, 3J = 8.3, CHH-cyclopropyl). 13C NMR (101 MHz, DMSO-d6): 163.7
(C-4); 150.7 (C-2); 139.0 (C-6); 100.2 (C-5); 64.5 (C-5′); 52.7 (C-1′); 35.0 (C-6′); 33.8 (C-2′);
31.6 (C-4′); 23.8 (CH2-cyclopropyl); 22.9 (C-3′); 12.0 (CH3-th ym in e). IR (film ), cm –1: 482,
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Racemic Cyclopent-3-en-1-yl Nucleoside Analogues
1027
737, 1026, 1269, 1301, 1393, 1474, 1682, 2939, 3435. HRMS-ESI, m/z: calculated for
C
12H16N2O3 (M + Na) 259.1059, foun d 259.1071.
(±)-9-{4-[(Ben zyloxy)m eth yl]cyclopen t-3-en -1-yl}-6-ch loro-9H-purin e (25)
To a suspen sion of PPh 3 (783 g, 2.98 m m ol) in an h ydrous THF (20 m l), DIAD (0.59 m l,
3.0 m m ol) was added slowly an d th e solution was stirred at 0 °C for 30 m in . Th e preform ed
com plex was slowly added to a suspen sion of 6-ch loropurin e (464 m g, 2.93 m m ol) an d
(±)-4-[(ben zyloxy)m eth yl]cyclopen t-3-en -1-ol (11; 300 m g, 1.47 m m ol) in an h ydrous THF
(20 m l) at –40 °C un der n itrogen . Th e reaction was slowly warm ed to room tem perature an d
stirred overn igh t. Th e solven t was rem oved from th e reaction m ixture an d th e purin e
n ucleoside was purified on silica gel colum n (petroleum eth er–EtOAc, 1:2) to yield th e title
com poun d 25 (272 m g, 54%) as sligh t yellow syrup. 1H NMR: (400 MHz, CDCl3): 8.75 (s,
1 H, H-2); 8.18 (s, 1 H, H-8); 7.38–7.29 (m , 5 H, CH-arom .); 5.86–5.83 (m , 1 H, H-3′);
5.47–5.40 (m , 1 H, H-1′); 4.57 (s, 2 H, CH2-ben zyl); 4.16–4.13 (m , 2 H, H-5′); 3.18–3.06 (m ,
2 H, H-2′a, H-6′a); 2.80–2.69 (m , 2 H, H-2′b, H-6′b). 13C NMR (101 MHz, CDCl3): 152.1
(C-2); 151.9 (C-4); 145.7 (C-4′); 143.5 (C-8); 138.6 (Cq-arom .); 134.6 (C-6); 132.2 (C-5);
128.6 (CH-arom .); 128.0 (CH-arom .); 127.8 (CH-arom .); 125.1 (C-3′); 72.9 (CH2-ben zyl); 68.3
(C-5′); 54.2 (C-1′); 40.6 (C-6′); 40.3 (C-2′). IR (film ), cm –1: 699, 812, 917, 1028, 1453, 1732,
2854, 2924, 3064. HRMS-FAB, m/z: calculated for C18H17ClN4O (M + H) 341.1169, foun d
341.1181.
(±)-9-{1-[(Ben zyloxy)m eth yl]bicyclo[3.1.0]h exan -3-yl}-6-ch loro-9H-purin e (26)
For preparation see 25. PPh 3 (865 m g, 3.30 m m ol), DIAD (650 µl, 3.30 m m ol) in an h ydrous
THF (20 m l), trans-20 (235 m g, 1.08 m m ol), 6-ch loropurin e (340 m g, 2.22 m m ol), an h y-
drous THF (20 m l). Yield 353 m g (95%). 1H NMR: (400 MHz, CDCl3): 8.73 (bs, 1 H, H-2);
8.13 (s, 1 H, H-8); 7.38–7.27 (m , 5 H, CH-arom .); 5.26–5.18 (m , 1 H, H-1′); 4.55 (s, 2 H,
CH2-ben zyl); 3.54 (d, 1 H, 2J = 10.2, H-5a′); 3.40 (d, 1 H, 2J = 10.2, H-5b′); 2.79–2.72 (m ,
2 H, H-2a′, H-6a′); 2.27 (dd, 1 H, 2J = 14.0, 3J = 6.9, H-6b′); 2.14 (ddd, 1 H, 2J = 14.1, 3J = 6.6,
4J = 1.7, H-2b′); 1.44–1.38 (m , 1 H, H-3′); 0.99–0.96 (m , 1 H, CHH-cyclopropyl); 0.75 (dd,
1 H, 2J = 4.8, 3J = 4.8, CHH-cyclopropyl). 13C NMR (101 MHz, CDCl3): 151.8 (C-2); 151.2
(C-4); 143.5 (C-8); 138.5 (Cq-arom .); 134.5 (C-6); 132.3 (C-5); 128.6 (C-arom .); 127.8
(C-arom .); 127.7 (C-arom .); 74.8 (C-5′); 73.0 (CH2-ben zyl); 59.2 (C-1′); 37.6 (C-6′); 35.7
(C-2′); 30.0 (C-4′); 22.2 (C-3′); 22.1 (CH2-cyclopropyl). IR (film ), cm –1: 739, 941, 1092, 1195,
1396, 1437, 1653, 1717, 3447. HRMS-FAB, m/z: calculated for C19H19ClN4O (M + H)
355.1326, foun d 355.1338.
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