Synthesis of carbocyclic 4′-C-hydroxymethyl analogues of azidodeoxythymidine, deoxythymidine, deoxydidehydrothymidine and thymidine carba analogue with fused oxetane ring

Article abstract of DOI:10.1135/cccc20000395

Tosylation of (±)-1-[trans-4-hydroxy-3,3-bis(hydroxymethyl)cyclopentyl]-5- methylpyrimidine-2(1H),4(3H)-dione (1) and (±)-1-[cis-4-hydroxy-3,3-bis(hydroxymethyl)cyclopentyl]-5- methylpyrimidine-2(1H),4(3H)-dione (2) and treatment of the obtained 1-[(1R(black star),3R(black star),4S(black star))-4-hydroxy-3-(hydroxymethyl)-3-[(tosyloxy) methyl]cyclopentyl]-5-met hylpyrimidine2(1H),4(3H)-dione (6) and 2-[(1R(black star),3S(black star),4R(black star))-4-hydroxy-3-(hydroxymethyl)-3-](tosyloxy)- methyl[cyclopentyl]-5-methylpyrimidine-2(1H),4(3H)-dione (9) with methanolic sodium methoxide gave 1-[(1R(black star),4S(black star),6S(black star))-4-hydroxymethyl-2-oxabicyclo[3.2.0]hept-6-yl] -5-methylpyrimidinf-2(1H),4(3H)-dione (7) and 1-[(1R(black star),4S(black star),6R(black star))-4-hydroxymethyl-2-oxabicyclo-[3.2.0]hept-6- yl]-5-methylpyrimidine-2(1H),4(3H)-dione (10), respectively. Treatment of (±)-1-[cis.v-4-mesyloxy-3,3-bis[(trityloxy)methyl]cyclopentyl]-5- methylpyrimidine-2(1H), 4(3H)-dione (11), which was prepared from 2 by tritylation and mesylation, with 1,8-diazabicyclo[5.4.0]undec-7-ene in dimethylformamide afforded after deprotection (±)-1-[4,4-bis-(hydroxymethyl)cyclopent-2-en-1-yl]-5-methylpyrimidine- 2(1H),4(3H)-dione (14). Hydrogenation of 14 led to (±)-1-[3,3-bis(hydroxymethyl)cyclopentyl]-5-methylpyrimidine-2(1H),4(3H)- dione (15). (±)-1-[trans-4-Mesyloxy-3,3-bis[(trityloxy)methyl]cyclopentyl]-5- methylpyrimidine-2(1H),4(3H)-dione (17), which was prepared from 1, was converted to (1R(black star),9R(black star)(black star))-6-methyl-5-oxo-11,11-bis(trityloxymethyl)-2-oxa-4,8- diazatricyclo[7.2.1.0^3,8]dodec-3,6-diene (18). The compound 18 was deprotected and heated with lithium azide in dimethylformamide to give (±)-1-[trans-4-azido-3,3-bis(hydroxymethyl)cyclopentyl|-5- methylpyrimidine-2(1H),4(3H)-dione (21).

Full text of DOI:10.1135/cccc20000395

Carbocyclic 4′-C-Hydroxymethyl Analogues
395
SYNTHESIS OF CARBOCYCLIC 4′-C-HYDROXYMETHYL ANALOGUES
OF AZIDODEOXYTHYMIDINE, DEOXYTHYMIDINE,
DEOXYDIDEHYDROTHYMIDINE AND THYMIDINE
CARBA ANALOGUE WITH FUSED OXETANE RING
1,
2
Hubert HŘEBABECKÝ * and Antonín HOLÝ
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
2
166 10Prague 6, Czech Republic; e-mail: hubert@uochb.cas.cz, uochb@uochb.cas.cz
Received Jan uary 18, 2000
Accepted March 10, 2000
Tosylation of (±)-1-[trans-4-h ydroxy-3,3-bis(h ydroxym eth yl)cyclopen tyl]-5-m eth ylpyrim i-
din e-2(1H),4(3H)-dion e (1) an d (±)-1-[cis-4-h ydroxy-3,3-bis(h ydroxym eth yl)cyclopen tyl]-
5-m eth ylpyrim idin e-2(1H),4(3H)-dion e (2) an d treatm en t of th e obtain ed 1-{(1R*,3R*,4S*)-
4-h yd ro xy-3-(h yd ro xym et h yl)-3-[(t o sylo xy)m et h yl]cyclo p en t yl}-5-m et h ylp yrim id in e-
2(1H),4(3H)-dion e (6) an d 1-{(1R*,3S*,4R*)-4-h ydroxy-3-(h ydroxym eth yl)-3-[(tosyloxy)-
m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-2(1H),4(3H)-dion e (9) with m eth an olic sodium
m eth oxide gave 1-[(1R*,4S*,6S*)-4-h ydroxym eth yl-2-oxabicyclo[3.2.0]h ept-6-yl]-5-m eth yl-
pyrim idin e-2(1H),4(3H)-dion e (7) an d 1-[(1R*,4S*,6R*)-4-h ydroxym eth yl-2-oxabicyclo-
[3.2.0]h ept-6-yl]-5-m eth ylpyrim idin e-2(1H),4(3H)-dion e (10), respectively. Treatm en t of
(±)-1-{cis-4-m esyloxy-3,3-bis[(trityloxy)m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-2(1H),4(3H)-
dion e (11), wh ich was prepared from 2 by tritylation an d m esylation , with 1,8-diaza-
bicyclo[5.4.0]un dec-7-en e in dim eth ylform am ide afforded after deprotection (±)-1-[4,4-bis-
(h ydroxym eth yl)cyclopen t-2-en -1-yl]-5-m eth ylpyrim idin e-2(1H),4(3H)-dion e (14). Hydrogen -
ation of 14 led to (±)-1-[3,3-bis(h ydroxym eth yl)cyclopen tyl]-5-m eth ylpyrim idin e-2(1H),4(3H)-
dion e (15). (±)-1-{trans-4-Mesyloxy-3,3-bis[(trityloxy)m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (17), wh ich was prepared from 1, was con verted to (1R*,9R*)-6-m eth yl-
5-oxo-11,11-bis(trityloxym eth yl)-2-oxa-4,8-diazatricyclo[7.2.1.03,8]dodec-3,6-dien e (18). Th e
com poun d 18 was deprotected an d h eated with lith ium azide in dim eth ylform am ide to give
(±)-1-[trans-4-azido-3,3-bis(h ydroxym eth yl)cyclopen tyl]-5-m eth ylpyrim idin e-2(1H),4(3H)-
dion e (21).
Key w ord s: Carban ucleosides; Carbocyclic n ucleosides; 4′-C-Bran ch ed n ucleosides;
Cyclopen tan es; Nucleosides; Pyrim idin es.
Replacem en t of th e oxygen in th e sugar portion of th e n ucleoside with a
m eth ylen e un it results in carbocyclic n ucleoside an alogues wh ich sh ow en -
h an ced biostability. Th e discovery of th e an tibiotic an d an titum or activity
of th e n atural carbocyclic n ucleosides aristerom ycin an d n eplan ocin A
stim ulated th e search for oth er carbocyclic n ucleoside an alogues with bio-
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

396
Hřebabecký, Holý:
logical activity. Later on , addition al syn th etic carbocyclic n ucleosides with
im portan t th erapeutic properties were discovered. Developm en t in th e area
of syn th etic approach es to carbocyclic n ucleosides is th e subject of several
reviews1.
Th is com m un ication is a con tin uation of our program aim ed at th e syn -
th esis of 2′-deoxy-4′-C-substituted n ucleosides an d at structure–an tiviral ac-
tivity relation sh ip studies2 an d deals with th e syn th esis of racem ic carba
an alogues of 2′-deoxy-4′-C-(h ydroxym eth yl)n ucleosides. Th e presen t paper
con cern s th e syn th esis of racem ic carbocyclic 4′-C-h ydroxym eth yl an a-
logues of 3′-azido-3′-deoxy-, 3′-deoxy-, an d 3′-deoxy-2′,3′-dideh ydroth ym i-
din e an d an an alogue with fused oxetan e rin g in th e position 3′,4′. Th e
sam e oxetan e derivative of th ym idin e in h ibits HIV replication in A301
(Alex) cells with rem arkably low bon e m arrow toxicity3. Most recen tly a
racem ic carbocyclic an alogue of 2′,3′-dideh ydro-2′,3′-dideoxy-4′-C-(h ydroxy-
m eth yl)guan osin e was syn th esized4 by a m ultistep procedure from 2-aza-
bicyclo[2.2.1]h ept-5-en -3-on e.
Sin ce th e separation of th e startin g stereoisom eric carbocyclic n ucleosides
1 an d 2 is difficult (cf. ref.2h ), a m ixture of th e isom ers was tritylated
(Sch em e 1). Th e obtain ed m ixture of trityl derivatives was easily separated
HOCH2
HOCH2
TrOCH2
TrOCH2
B
B
B
(ii)
(i)
TrOCH2
HO
TrOCH2
HO
+
+
HO
3
4
1 + 2
(iv)
(ii)
HOCH2
HOCH2
TsOCH2
HOCH2
B
B
B
B
B
4
5
B
(iii)
6
HOCH2
HO
TsOCH2
HO
3
TsOCH2
HO
1
7
O
2
1
7
5
6
HOCH2
TsOCH2
TsOCH2
TsOCH2
B
B
(iii)
O
HOCH2
HO
HOCH2
HOCH2
HO
+
HO
10
2
9
8
(iv)
B = thymin-1-yl
(i) TrCl/pyridine, 38% of 3, 34% of 4; (ii) 80% aqueous CF3COOH, 92% of 1 and 94% of 2;
(iii) TsCl/pyridine, 20% of 5, 68% of 6, 17% of 8 and 69% of 9; (iv) 0.25 M MeONa/MeOH,
53% of 7 (19% of recovered 6), 33% of 10 (25% of recovered 9)
SCHEME 1
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Carbocyclic 4′-C-Hydroxymethyl Analogues
397
on silica gel to give pure (±)-trans isom er 3 (38% yield) an d (±)-cis isom er 4
(34% yield). Treatm en t of th e trityl derivatives with 80% aqueous trifluoro-
acetic acid afforded free n ucleoside an alogues 1 an d 2 (cf. ref.2h ). Tosylation
of th e (±)-trans isom er 1 led to a m ixture of th e ditosyl derivative 5 (20%
yield) an d th e m on otosyl derivative 6 (68% yield) with h ydroxy an d
(tosyloxy)m eth yl groups in cis position . Th e ditosyl derivative 8 (17% yield)
an d th e m on otosyl derivative 9 (69% yield) were obtain ed in th e sam e
m an n er from cis isom er 2. Th e greater reactivity of th e 4′-(h ydroxym eth yl)
group was also observed in 4′-h ydroxym eth ylth ym idin e3. Mon otosylates 6
an d 7 were treated with m eth an olic sodium m eth oxide givin g com poun ds
with fused oxetan e rin gs 7 (53% yield) an d 10 (33% yield), respectively.
Th e startin g m on otosyl derivatives were also recovered from th e reaction
m ixture: 19% of 6 an d 25% of 9. Th is reaction is accom pan ied by th e cleav-
age of th e C–N bon d. Th e position s of absorption ban ds in UV spectra of
th e oxetan es 7 an d 10 rem ain ed virtually un ch an ged in depen den tly of pH
wh ereas in alkalin e m edium , th e absorption decreased: such pattern is ch ar-
acteristic of N1-substituted uracil derivatives5. Usin g th e sam e procedure,
th e an alogue of 2′-deoxyuridin e with fused oxetan e rin g in th e position
3′,4′ was prepared (cf. ref.2e). In th is case, cleavage of th e C–N bon d was n ot
observed.
Mesylation of th e ditrityl derivative 4 an d treatm en t of th e obtain ed
m esylate 11 with 1,8-diazabicyclo[5.4.0]un dec-7-en e in dim eth ylform am ide
at 125 °C (Sch em e 2) led to th e cyclopen ten e derivative 13 (89% yield).
ROCH2
ROCH2
ROCH2
HOCH2
HOCH2
B
B
B
(i)
(ii)
(iv)
4
ROCH2
MsO
15
11, R = trityl
12, R = H
13, R = trityl
14, R = H
(v)
(iii)
(vi)
(vi)
HOCH2
B
B = thymin-1-yl
7
14
+
16
(i) MsCl/pyridine, 95%; (ii) DBU/DMF, 125 oC, 89%; (iii) 80% aqueous CH3COOH, 84%;
(iv) Pd/C, H2, 81%; (v) 80% aqueous CF3COOH, 92%; (vi) NaH/DMF, 47% of 13, 24% of 14
SCHEME 2
Deprotection of 13 with 80% aqueous acetic acid afforded the free analogue 14.
Hydrogen ation of 14 over palladium on activated carbon gave th e carbo-
cyclic dideoxyn ucleoside 15 (81% yield).
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Hřebabecký, Holý:
Th e ditrityl derivative 11 was deprotected with 80% aqueous trifluoro-
acetic acid an d th e obtain ed com poun d 12 was treated with sodium h y-
dride in dim eth ylform am ide givin g un saturated an alogue 14 (24% yield)
an d th e un saturated h ydroxym eth yl derivative 16 (47% yield) in stead of
th e expected oxetan e 7. Th e oxetan e 7 was n ot in volved as an in term ediate
in th is reaction , because it rem ain ed un ch an ged un der th e reaction con di-
tion s.
Mesylation of com poun d 3 an d treatm en t of th e obtain ed m esyl deriva-
tive 17 with 1,8-diazabicyclo[5.4.0]un dec-7-en e in aceton itrile at 60 °C
(Sch em e 3) afforded th e an h ydro derivative 18 (74% yield). Th e open in g of
2,3′-bon d with lith ium azide in dim eth ylform am ide at 150 °C resultin g in a
relatively h igh yield of 1-(3-azido-2,3-dideoxy-5-O-trityl-β-D-ribofuran osyl)-
5-eth yluridin e is described in th e literature (see, e.g., ref.6). However, th e re-
action of th e an h ydro derivative 19 with lith ium azide un der described
O
O
O
HN
N
N
N
HN
N
O
CH3
(ii)
O
CH3
(iv)
O
CH3
TrOCH2
ROCH2
ROCH2
ROCH2
(i)
3
TrOCH2
MsO
ROCH2
14
+
N3
17
20, R = Ac
21, R = H
18, R = trityl
19, R = H
(v)
(iii)
(i) MsCl/pyridine, 85%; (ii) DBU/acetonitrile, 60 oC, 74%; (iii) 80% aqueous CF3COOH, 83%;
(iv) 1. LiN3/DMF, 150 oC, 2. Ac2O/DMAP/MeCN, 17.5% of 14 and 49% of 20; (v) MeONa/MeOH, 99%
SCHEME 3
con dition s led to a com plex un separable m ixture of products. Th e com -
poun d 19, wh ich was obtain ed by deprotection of 18 with 80% aqueous
trifluoroacetic acid, was treated with lith ium azide in dim eth ylform am ide
at 150 °C. Ch rom atograph y of products of th e reaction afforded 17.5% of
th e un saturated derivative 14 an d th e crude azido an alogue 21. Th is prod-
uct was acetylated an d th e obtain ed acetate 20 was easily purified by ch ro-
m atograph y on silica gel. Th e free azido n ucleoside an alogue 21 was
obtain ed by m eth an olysis of 20. Th e an h ydro rin g open in g was n ot accom -
pan ied by N-1 to N-3 m igration , wh ich h as been described for cleavage of
som e 2,2′-an h ydron ucleosides with h ydrogen ch loride an d of 2,3′-an h ydro-
n ucleosides with azide (see ref.7 an d referen ces th erein ), because in frared
spectrum of th e acetate 20 exh ibits NH ban d at 3 391 cm –1, in agreem en t
with th e literature data8 for N-1 isom er. UV spectrum of th e free azido de-
rivative 21 was also ch aracteristic of N1-substituted uracil derivatives5.
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Carbocyclic 4′-C-Hydroxymethyl Analogues
399
In con clusion , n ew racem ic carbocyclic 4′-C-h ydroxym eth yl an alogues of
azidodeoxyth ym idin e, deoxydideh ydroth ym idin e, deoxyth ym idin e, an d
1-[(1R*,4S*,6S*)-4-h ydroxym eth yl-2-oxabicyclo[3.2.0]h eptan -6-yl]-5-m eth yl-
pyrim idin e-2(1H),4(3H)-dion e (7) (th e carba an alogue of th e an ti-HIV com -
poun d, th ym idin e derivative with 3′,4′-fused oxetan e rin g) were prepared.
Th e syn th esized com poun ds will be tested for an tiviral activity.
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Kofler block an d are un corrected. IR spectra were re-
corded on a Zeiss UR 20 spectroph otom eter (waven um bers in cm –1) an d UV spectra on a
Un icam SP 8000 spectrom eter. 1H NMR spectra (δ, ppm ; J, Hz) were m easured on a Varian
XL-200 (200 MHz) in strum en t in h exadeuteriodim eth yl sulfoxide with tetram eth ylsilan e as
in tern al stan dard. Colum n ch rom atograph y was perform ed on 30–60 µm silica gel (Service
Laboratories of th e In stitute) an d th in -layer ch rom atograph y (TLC) on Silufol UV 254 foils
(Kavalier, Votice). Solven ts were evaporated at 2 kPa an d bath tem perature 30–60 °C; th e
com poun ds prepared were dried at 13 Pa an d 50 °C.
(±)-1-{trans-4-Hydroxy-3,3-bis[(trityloxy)m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (3) an d (±)-1-{cis-4-h ydroxy-3,3-bis[(trityloxy)m eth yl]cyclopen tyl}-
5-m eth ylpyrim idin e-2(1H),4(3H)-dion e (4)
A solution of a m ixture of 1 an d 2 (1.89 g, 7 m m ol; cf. ref.2h ) an d triph en ylm eth yl ch loride
(4.74 g, 17 m m ol) in pyridin e (40 m l) was h eated at 100 °C for 1 h . Th e solven t was evapo-
rated an d th e residue was partition ed between eth yl acetate (200 m l) an d water (100 m l).
Th e organ ic layer was separated, wash ed with water (3 × 100 m l), dried over sodium sulfate
an d th e solven t was evaporated. Ch rom atograph y of th e residue on silica gel (600 g) in
toluen e–eth yl acetate (2 : 1) afforded 1.79 g (34% yield) of cis isom er 4 an d 2.01 g (38%
yield) of trans isom er 3 (both after crystallization from eth an ol).
Isomer 3. M.p. 228–229 °C. For C50H46N2O5 (754.9) calculated: 79.55% C, 6.14% H,
3.71% N; foun d: 79.26% C, 6.22% H, 3.49% N. 1H NMR: 1.44 dd, 1 H, J(2a′,1′) = 9.5,
J(2a′,2b′) = 13.1 (H-2a′); 1.54–1.63 m , 1 H (H-5a′); 1.68–1.82 m , 1 H (H-5b′); 1.73 s, 3 H
(CH3); 2.02 dd, 1 H, J(2b′,4′) = 9.2 (H-2b′); 3.00 d, 1 H an d 3.41 d, 1 H, Jgem = 8.9 (CH2O);
3.08 d, 1 H an d 3.42 d, 1 H, Jgem = 9.2 (CH2O); 4.14–4 20 m , 1 H (H-4′); 4.65–4.83 m , 1 H
(H-1′); 4.71 d, 1 H, J(4′,OH) = 4.6 (4′-OH); 7.12 s, 1 H (H-6); 7.29 m , 30 H (H-arom .); 11.16 s,
1 H (NH).
Isomer 4. M.p. 265–266 °C. For C50H46N2O5 (754.9) calculated: 79.55% C, 6.14% H,
3.71% N; foun d: 79.32% C, 6.27% H, 3.60% N. 1H NMR: 1.35–1.49 m , 2 H (H-2a′, H-5a′);
1.68 s, 3 H (CH3); 1.75 ddd, 1 H, J(5b′,4′) = 4.9, J(5b′,5a′) = 14.2, J(5b′,1′) = 9.1 (H-5b′); 1.99 dd,
1 H, J(2b′,1′) = 8.5, J(2b′,2a′) = 13.1 (H-2b′); 2.90 d, 1 H an d 3.29 d, 1 H , Jgem = 9.2 (CH2O);
3.27 d, 1 H an d 3.49 d, 1 H, Jgem = 8.0 (CH2O); 3.91 m , 1 H (H-4′); 4.60–4.76 m , 1 H (H-1′);
5.11 d, 1 H, J(OH,4′) = 4.3 (4′-OH); 7.22–7.41 m , 31 H (H-6, H-arom .); 11.16 s, 1 H (NH).
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Hřebabecký, Holý:
(±)-1-[trans-4-Hydroxy-3,3-bis(h ydroxym eth yl)cyclopen tyl]-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (1)
A solution of trityl derivative 3 (1.51 g, 2 m m ol) in 80% aqueous trifluoroacetic acid (25 m l)
was set aside at room tem perature for 15 m in . Th e solven t was evaporated an d th e residue
was partition ed between eth er (20 m l) an d water (30 m l). Th e aqueous layer was separated,
wash ed with eth er (2 × 10 m l) an d n eutralized with Dowex 1 (HCO−3 form ). Th e ion
exch an ger was filtered off, wash ed with water an d th e com bin ed filtrates were taken down
givin g 497 m g (92%) of 1. For C12H18N2O5 (270.3) calculated: 53.32% C, 6.71% H, 10.36% N;
foun d: 53.10% C, 6.83% H, 10.21% N. Th e 1H NMR spectra of 1 an d com poun d prepared
before2h were iden tical.
(±)-1-[cis-4-Hydroxy-3,3-bis(h ydroxym eth yl)cyclopen tyl]-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (2)
Usin g th e sam e procedure as in th e preparation of 1, trityl derivative 4 (1.51 g, 2 m m ol) was
deprotected givin g 510 m g (94%) of 2. For C12H18N2O5 (270.3) calculated: 53.32% C,
6.71% H, 10.36% N; foun d: 53.15% C, 6.64% H, 10.30% N.
Th e 1H NMR spectra of 2 an d com poun d prepared before2h were iden tical.
(±)-1-{trans-4-Hydroxy-3,3-bis[(tosyloxy)m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (5) an d 1-{(1R*,3R*,4S*)-4-Hydroxy-3-(h ydroxym eth yl)-
3-[(tosyloxy)m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-2(1H),4(3H)-dion e (6)
A solution of 1 (270 m g, 1 m m ol) an d tosyl ch loride (210 m g, 1.1 m m ol) in pyridin e
(3.5 m l) was allowed to stan d at room tem perature for 5 h an d th en water (50 µl) was
added. After stan din g at room tem perature for 10 m in , th e solven t was evaporated. Ch rom a-
tograph y of th e residue on a silica gel colum n afforded 110 m g (20%) of ditosyl derivative
5 as a solid foam an d 290 m g (68%) of m on otosyl derivative 6 (after crystallization from
eth an ol).
Racemate 5. For C26H30N2O7S2 (546.7) calculated: 57.13% C, 5.53% H, 5.12% N, 11.73% S;
foun d: 56.80% C, 5.44% H, 4.88% N, 11.46 % S. 1H NMR: 1.37 dd, 1 H, J(2a′,1′) = 9.9,
J(2a′,2b′) = 13.9 (H-2a′); 1.70–1.86 m , 2 H (H-2b′, H-5a′); 1.75 s, 3 H (CH3); 2.11 m , 1 H,
J(5b′,4′) = 6.8, J(5b′,4′) = 7.7, J(5b′,5a′) = 14.7 (H-5b′); 2.43 s, 6 H (2 × CH3, tosyl); 3.88 d, 1 H
an d 4.05 d, 1 H, Jgem = 10.1 (CH2O); 3.93 s, 2 H (CH2O); 3.98 m , 1 H (H-4′); 4.85 m , 1 H, ΣJ =
35.4 (H-1′); 5.23 d, 1 H, J(OH,4′) = 4.3 (4′-OH); 7.47 d, 2 H an d 7.73 d, 2 H, J = 8.2 (H-tosyl);
7.49 d, 2 H an d 7.75 d, 2 H, J = 8.2 (H-tosyl); 7.50 s, 1 H (H-6); 11.21 s, 1 H (NH).
Racemate 6. M.p. 167–170 °C. For C19H24N2O7S (424.5) calculated: 53.76% C, 5.70% H,
6.60% N, 7.55% S; foun d: 53.63% C, 5.81% H, 6.71% N, 7.39% S. 1H NMR: 1.31 dd, 1 H,
J(2a′,1′) = 10.2, J(2a′,2b′) = 13.7 (H-2a′); 1.70–2.15 m , 3 H (2 × H-5′, H-2b′); 1.77 d, 3 H, J =
0.9 (CH3); 2.42 s, 3 H (CH3, tosyl); 3.33–3.46 m , 2 H (CH2O); 3.93–4.07 m , 2 H (H-4′,
CH2OH); 4.02 s, 2 H (CH2OTs); 4.84–5.02 m , 2 H (4′-OH, H-1′); 7.49 d, 2 H, J = 8.2 an d 7.79
dd, 2 H, J = 8.2, 3.5 (H-tosyl); 7.50 s, 1 H (H-6); 11.20 s, 1 H (NH).
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1-[(1R*,4S*,6S*)-4-Hydroxym eth yl-2-oxabicyclo[3.2.0]h ept-6-yl]-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (7)
A solution of 6 (212 m g, 0.5 m m ol) in 0.25 M m eth an olic sodium m eth oxide (6 m l) was set
aside at room tem perature for 20 h an d th en Dowex 50 (H+) was added (to pH ≈ 2). Th e ion
exch an ger was filtered off, wash ed with m eth an ol an d th e com bin ed filtrates were n eutral-
ized with Dowex 1 (HClO–3 form ). Th e resin was filtered off, wash ed with m eth an ol an d th e
com bin ed filtrates were evaporated. Ch rom atograph y of th e residue on silica gel (20 g) in
eth yl acetate–aceton e–eth an ol–water (19 : 3 : 2 : 1) gave 40 m g (19%) of startin g 6, 10 m g
(16%) of th ym in e, an d 67 m g (53%) of 7 (after crystallization from eth an ol), m .p. 184–186 °C.
For C12H16N2O4 (252.3) calculated: 57.13% C, 6.39% H, 11.10% N; foun d: 57.09% C, 6.59%
H, 11.02% N. UV (water): λm ax 274 n m (ε 10 500); (0.1 M NaOH): λm ax 272 n m (ε 7 700).
1H NMR: 1.63–2.03 m , 4 H (2 × H-5′, 2 × H-7′); 1.78 s, 3 H (CH3); 3.45–3.60 m , 2 H (CH2O);
4.11 d, 1 H an d 4.54 d, 1 H, Jgem = 5.8 (2 × H-3′); 4.90 d, 1 H, J(1′,7a′) = 3.1 (H-1′); 4.94 t,
1 H, J(OH,CH2) = 5.5 (CH2OH); 5.46 m , 1 H, ΣJ = 34.8 (H-6′); 7.65 d, 1 H, J = 0.8 (H-6);
11.28 s, 1 H (NH).
(±)-1-{cis-4-Hydroxy-3,3-bis[(tosyloxy)m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (8) an d 1-{(1R*,3R*,4S*)-4-Hydroxy-3-(h ydroxym eth yl)-
3-[(tosyloxy)m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-2(1H),4(3H)-dion e (9)
Usin g th e sam e procedure as described in th e preparation of tosylates 5 an d 6, th e tri-
h ydroxy com poun d 2 (270 m g, 1 m m ol) was con verted in to ditosylate 8 (92 m g; 17%) an d
m on otosylate 9 (295 m g; 69%).
Racemate 8. For C26H30N2O7S2 (546.7) calculated: 57.13% C, 5.53% H, 5.12% N, 11.73% S;
foun d: 56.80% C, 5.44% H, 4.88% N, 11.46 % S. 1H NMR: 1.51 dd, 1 H, J(2a′,1′) = 9.6,
J(2a′,2b′) = 13.9 (H-2a′); 1.68–1.82 m , 2 H (H-5a′, H-2b′); 1.76 s, 3 H (CH3); 2.18 ddd, 1 H,
J(5b′,4′) = 5.5, J(5b′,5a′) = 14.0, J(5b′,1′) = 7.9 (H-5b′); 2.41 s, 3 H (CH3, tosyl); 2.43 s, 3 H
(CH3, tosyl); 3.77–3.91 m , 1 H (H-4′); 3.83 s, 2 H (CH2O); 4.05 s, 2 H (CH2O); 4.70–4.87 m ,
1 H (H-1′); 5.45 d, 1 H, J(OH,4′) = 4.6 (4′-OH); 7.46 d, 2 H an d 7.72 d, 2 H, J = 8.2 (H-tosyl);
7.50 d, 2 H an d 7.78 d, 2 H, J = 8.2 (H-tosyl); 7.55 s, 1 H (H-6); 11.21 s, 1 H (NH).
Racemate 9. M.p. 188–189 °C. For C19H24N2O7S (424.5) calculated: 53.76% C, 5.70% H,
6.60% N, 7.55% S; foun d: 53.79% C, 5.82% H, 6.50% N, 7.63% S. 1H NMR: 1.40 dd, 1 H,
J(2a′,1′) = 9.5, J(2a′,2b′) = 13.1 (H-2a′); 1.68 ddd, 1 H, J(5a′,4′) = 5.3, J(5a′,5b′) = 14.1, J(5a′,1′) =
7.9 (H-5a′); 1.77 s, 3 H (CH3); 1.83 dd, 1 H, J(2b′,1) = 8.6 (H-2b′); 2.29 ddd, 1 H, J(5b′,4′) =
5.5, J(5b′,1′) = 8.7 (H-5b′); 2.40 s, 3 H (CH3, tosyl); 3.20 d, 2 H, J(CH2,OH) = 4.9 (CH2O);
3.94 ddd, 1 H (H-4′); 4.09 s, 2 H (CH2OTs); 4.79–4.96 m , 1 H (H-1′); 4.87 t, 1 H (CH2OH);
5.22 d, 1 H, J(OH,4′) = 4.3 (4′-OH); 7.47d, 2 H an d 7.78 d, 2 H, J = 8.2 (H-tosyl); 7.60 s, 1 H
(H-6); 11.20 s, 1 H (NH).
1-[(1R*,4S*,6R*)-4-Hydroxym eth yl-2-oxabicyclo[3.2.0]h ept-6-yl]-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (10)
Usin g th e sam e procedure as in th e preparation of th e oxetan e 7, tosylate 9 (212 m g, 0.5
m m ol) produced oxetan e 10 (42 m g; 33%). Startin g 9 (53 m g; 25%) was recovered an d th y-
m in e (22 m g; 35%) was form ed.
Racemate 10. M.p. 157–158 °C. For C12H16N2O4 (252.3) calculated: 57.13% C, 6.39% H,
11.10% N; foun d: 57.01% C, 6.48% H, 11.03% N. UV (water): λm ax 275 n m (ε 10 750); (0.1 M
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Hřebabecký, Holý:
NaOH): λm ax 273 n m (ε 8 200). 1H NMR: 1.78 d, 3 H, J = 1.2 (CH3); 1.99–2.26 m , 4 H (2 × H-5′,
2 × H-7′); 3.36–3.52 m , 2 H (CH2O); 4.12 d, 1 H an d 4.47 d, Jgem = 6.1 (2 × H-3′); 4.90 m , 1 H,
ΣJ = 30.0 (H-6′); 4.94 t, 1 H, J(OH,CH2) = 5.4 (CH2OH); 4.94 dd, 1 H, J(1′,7a′) = 3.7, J(1′,7b′) =
4.3 (H-1′); 8.00 d, 1 H, J = 1.2 (H-6); 11.23 s, 1 H (NH).
(±)-1-{cis-4-Mesyloxy-3,3-bis[(trityloxy)m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (11)
Meth an esulfon yl ch loride (1.24 m l, 16 m m ol) was added to a stirred solution of trityl deriv-
ative 4 (3.02 g, 4 m m ol) in pyridin e (28 m l). After stan din g at room tem perature for 5 h ,
water (1 m l) was added an d, after stan din g for 10 m in , th e solven t was evaporated an d th e
residue was partition ed between eth yl acetate (100 m l) an d water (100 m l). Th e organ ic
layer was wash ed with water (3 × 100 m l), dried over an h ydrous sodium sulfate an d evapo-
rated. Ch rom atograph y of th e residue on a colum n of silica gel (250 g) in eth yl acetate–
toluen e (2 : 3) afforded 2.97 g (89%) of m esylate 11. For C51H48N2O7S (833.0) calculated:
73.53% C, 5.81% H, 3.36% N, 3.85% S; foun d: 73.25% C, 5.92% H, 3.17% N, 3.70% S.
1H NMR: 1.63 s, 3 H (CH3); 1.54–1.68 m , 1 H; 2.00–2.30 m , 3 H; 2.97 s, 3 H (CH3SO2); 2.99 d,
1 H an d 3.28 d, 1 H, Jgem ≈ 8 (CH2O); 3.26 s, 2 H (CH2O); 4.71–4.89 m , 1 H (H-1′); 4.82 t, 1 H,
J(4′,5a′) ≈ J(4′,5b′) ≈ 6.1 (H-4′); 7.29 m , 31 H (H-arom ., H-6); 11.26 s, 1 H (NH).
(±)-1-[cis-3,3-Bis(h ydroxym eth yl)-4-(m esyloxy)cyclopen tyl]-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (12)
A solution of trityl derivative 11 (833 m g, 1 m m ol) in 80% aqueous trifluoroacetic acid
(12 m l) was set aside at room tem perature for 10 m in . Th e solven t was evaporated an d th e
residue was partition ed between eth er (10 m l) an d water (20 m l). Th e aqueous layer was sep-
arated, wash ed with eth er (2 × 10 m l) an d n eutralized with Dowex 1 (HCO−3 form ). Th e ion
exch an ger was filtered off, wash ed with water an d th e com bin ed filtrates were taken down .
Crystallization of th e residu e from eth an ol gave 320 m g (92%) of m esylate 12, m .p .
131–133 °C. For C13H20N2O7S (348.4) calculated: 44.82% C, 5.79% H, 8.04% N, 9.20% S;
foun d: 44.80% C, 6.04% H, 7.80% N, 8.95% S. 1H NMR: 1.73 dd, 1 H, J(2a′,1′) = 10.3,
J(2a′,2b′) = 13.1 (H-2a′); 1.78 s, 3 H (CH3); 1.93 dd, 1 H, J(2b′,1′) = 8.6 (H-2b′); 2.17 ddd, 1 H,
J(5a′,4′) = 6.5, J(5a′,5b′) = 13.1, J(5a′,1′) = 9.5 (H-5a′); 2.41–2.55 m , 1 H (H-5b′); 3.19 s, 3 H
(CH3SO2); 3.36 s, 2 H (CH2O); 3.45 d, 1 H an d 3.54 d, 1 H, Jgem = 10.5 (CH2O); 4.23 brs (OH
groups); 4.88 t, 1 H, J(4′,5b′) = 6.4 (H-4′); 4.91 m , 1 H (H-4); 7.59 s, 1 H (H-6); 11.24 s, 1 H
(NH).
(±)-1-{4,4-Bis[(trityloxy)m eth yl]cyclopen t-2-en -1-yl}-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (13)
A solution of m esylate 11 (1.67 g, 2 m m ol) an d 1,8-diazabicyclo[5.4.0]un dec-7-en e (0.47 m l,
3 m m ol) in dim eth ylform am ide (17 m l) was h eated at 125 °C for 6 h . Th e residue was parti-
tion ed between eth yl acetate (100 m l) an d water (50 m l). Th e organ ic layer was separated,
wash ed with water (3 × 50 m l), dried over an h ydrous sodium sulfate an d con cen trated to a
sm all volum e. Th e crystallin e product was filtered off to give 1.31 g (89%) of 13, m .p.
119–121 °C. For C50H44N2O4 (736.9) calculated: 81.50% C, 6.02% H, 3.80% N; foun d:
81.21% C, 5.99% H, 3.64% N. 1H NMR: 1.25 dd, 1 H, J(5a′,1′) = 6.1, J(5a′,5b′) = 14.0 (H-5a′);
1.58 s, 3 H (CH3); 2.04 dd, 1 H, J(5b′,1′) = 8.5 (H-5b′); 3.01 d, 1 H an d 3.25 d, 1 H, Jgem = 8.5
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(CH2O); 3.08 s, 2 H (CH2O); 5.36 m , 1 H (H-1′); 5.88 dd, 1 H, J(3′,2′) = 5.5, J(3′,1′) = 1.9
(H-3′); 6.23 dd, 1 H, J(2′,1′) = 2.0 (H-2′); 6.85 d, 1 H, J = 0.9 (H-6); 7.30 s, 15 H an d 7.26 s,
15 H (trityl); 11.23 s, 1 H (NH).
(±)-1-[4,4-Bis(h ydroxym eth yl)cyclopen t-2-en -1-yl]-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (14)
A solution of th e trityl derivative 13 (1.11 g, 1.5 m m ol) in 80% aqueous acetic acid was
h eated at 60 °C for 2 h . Th e m ixture was con cen trated, th e residue was wash ed with toluen e
(2 × 5 m l) an d crystallized from m eth an ol to obtain 215 m g (57%) of th e racem ic diol 14,
m .p. 119–121 °C. Colum n chrom atography of m other liquors on silica gel (40 g) in ethyl acetate–
aceton e–eth an ol–water (19 : 3 : 2 : 1) afforded addition al 103 m g (27%) of 14. For
C
12H16N2O4 (252.3) calculated: 57.13% C, 6.39% H, 11.10% N; foun d: 56.99% C, 6.36% H,
11.02% N. 1H NMR: 1.47 dd, 1 H, J(5a,1) = 5.9, J(5a,5b) = 13.8 (H-5a); 1.74 s, 3 H (CH3);
2.18 dd, 1 H, J(5b,1) = 9.0 (H-5b); 3.30 d, 2 H, J(CH2,OH) = 5.5 (CH2O); 3.53 dd, 1 H, J(CH2,
OH) = 5.5 an d 3.49 dd, 1 H, J(CH2,OH) = 5.1, Jgem = 10.5 (CH2O); 4.65 t, 1 H, J(OH,CH2) =
5.5 (CH2OH); 4.71 t, 1 H, J(OH,CH2) = 5.3 (CH2OH); 5.53 m , 1 H (H-1); 5.65 dd, 1 H,
J(3,2) = 5.6, J(3,1) = 2.0 (H-3); 5.91 dd, 1 H, J(2,1) = 2.0 (H-2); 7.38 s, 1 H (H-6′); 11.21 s, 1 H
(NH).
(±)-1-[3,3-Bis(h ydroxym eth yl)cyclopen tyl]-5-m eth ylpyrim idin e-2(1H),4(3H)-dion e (15)
Pd/C (20 m g; 10%) was added to a solution of 14 (76 m g, 0.3 m m ol) in m eth an ol (2 m l)
an d th e m ixture was h ydrogen ated at 50 °C an d atm osph eric pressure for 5 h . Th e solids
were rem oved by filtration th rough Celite wash ed with a h ot m ixture of m eth an ol–eth yl
acetate (1 : 1; 5 × 2 m l) an d th e com bin ed filtrates were evaporated. Crystallization of th e
residue from m eth an ol afforded 62 m g (81%) of racem ic 15, m .p. 216–218 °C. For
C
12H18N2O4 (254.3) calculated: 56.68% C, 7.14% H, 11.02% N; foun d: 56.61% C, 7.12% H,
10.94% N. 1H NMR: 1.28–1.83 m , 6 H (2 × H-2′, 2 × H-5′, 2 × H-4′); 1.78 s, 1 H (CH3);
3.24 dd, 2 H, J(CH2,OH) = 5.0, J = 1.7 (CH2O); 3.33 d, 2 H, J(CH2,OH) = 5.0 (CH2O); 4.60 t,
1 H, J(OH,CH2) = 5.0 (CH2OH); 4.61 t, 1 H, J(OH,CH2) = 5.0 (CH2OH); 4.66–4.84 m , 1 H
(H-1′); 7.57 d, 1 H, J = 0.8 (H-6); 11.18 s, 1 H (NH).
(±)-1-[3-(Hydroxym eth yl)cyclopen t-3-en -1-yl]-5-m eth ylpyrim idin e-2(1H),4(3H)-dion e (16)
Sodium h ydride (160 m g, 4 m m ol; 60% dispersion ) was added to a stirred solution of
m esylate 12 (348 m g, 1 m m ol) in dim eth ylform am ide (5 m l). Th e m ixture was stirred at
room tem perature for 2 h , th en n eutralized with acetic acid an d evaporated. Ch rom atogra-
ph y of th e residue on a silica gel colum n (35 g) in eth yl acetate–aceton e–eth an ol–water
(100 : 15 : 6 : 4) afforded 98 m g (47%) of 16 an d 60 m g (24%) of 14 (both after crystalliza-
tion from eth an ol).
Racemate 16. M.p. 192–195 °C. For C11H14N2O3 (222.3) calculated: 59.45% C, 6.35% H,
12.60% N; foun d: 59.45% C, 6.45% H, 12.53% N. UV (water): λm ax 276 n m (ε 10 100); (0.1 M
NaOH): λm ax 274 n m (ε 8 000). 1H NMR: 1.75 d, 3 H, J = 1.0 (CH3); 2.29–2.45 m , 2 H (2 ×
H-5′); 2.61–2.80 m , 2 H (2 × H-2′); 3.99 d, 2 H, J(CH2,OH) = 5.5 (CH2O); 4.82 t, 1 H
(CH2OH); 5.13 m , 1 H, J(1′,5a′) ≈ J(1′,5b′) ≈ 4.5, J(1′,2a′) ≈ J(1′,2b′) ≈ 9.0 (H-1′); 5.55 t, 1 H,
J(4′,5a′) = J(4′,5b′) = 2.1 (H-4′); 7.28 d, 1 H, J = 1.0 (H-6); 11.22 s, 1 H (NH).
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Hřebabecký, Holý:
Treatm en t of Oxetan e Derivative 7 with Sodium Hydride
Sodium h ydride (32 m g, 0.8 m m ol; 60% dispersion ) was added to a stirred solution of 7
(50 m g, 0.2 m m ol) in dim eth ylform am ide (1 m l). Th e m ixture was stirred at room tem pera-
ture for 2 h , th en n eutralized with acetic acid an d evaporated. Ch rom atograph y of th e
residue on silica gel (5 g) in ethyl acetate–acetone–ethanol–water (100 : 15 : 6 : 4) afforded 48 m g
(96%) of th e startin g oxetan e 7.
(±)-1-{trans-4-Mesyloxy-3,3-bis[(trityloxy)m eth yl]cyclopen tyl}-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (17)
Meth an esulfon yl ch loride (1.24 m l, 16 m m ol) was added to a stirred solution of trityl
drivative 3 (3.02 g, 4 m m ol) in pyridin e (28 m l). After stan din g at room tem perature for 5 h ,
water (1 m l) was added. After stan din g for 10 m in , th e solven t was evaporated an d th e resi-
due was partition ed between eth yl acetate (100 m l) an d water (100 m l). Th e organ ic layer
was wash ed with water (3 × 100 m l), dried over an h ydrous sodium sulfate an d evaporated.
Crystallization of th e residue from eth an ol afforded 2.83 g (85%) of th e m esyl derivative 17,
m .p. 185–185.5 °C. For C51H48N2O7S (833.0) calculated: 73.53% C, 5.81% H, 3.36% N,
3.85% S; foun d: 73.42% C, 5.92% H, 3.28% N, 4.18% S. 1H NMR: 1.67 dd, 1 H, J(2a′,1′) =
10.0, J(2a′,2b′) = 13.1 (H-2a′); 1.75 s, 3 H (CH3); 1.98–2.17 m , 3 H (2 × H-5′, H-2b′); 2.94 s,
3 H (CH3SO2); 3.06 d, 1 H an d 3.09 d, 1 H, Jgem = 6.4 (CH2); 3.35 d, 1 H an d 3.40 d, 1 H,
Jgem = 9.5 (CH2); 4.71 m , 1 H, ΣJ = 38.8 (H-1′); 5.09 t, 1 H, J(4′,5a′) = J(4′,5b′) = 5.5 (H-4′);
7.25–7.36 m , 31 H (H-6, H-arom .); 11.22 s, 1 H (HN).
(1R*,9R*)-6-Meth yl-5-oxo-11,11-bis(trityloxym eth yl)-2-oxa-4,8-diazatricyclo-
[7.2.1.03,8]dodec-3,6-dien e (18)
To a solution of th e m esylate 17 (1.67g, 2 m m ol) in aceton itrile (25 m l) 1,8-diazabicyclo-
[5.4.0]un dec-7-en e (0.6 m l, 4 m m ol) was added. Th e m ixture was h eated to 60 °C for 6 h ,
th en cooled an d th e crystallin e com poun d was filtered off, wash ed with aceton itrile, th en
with eth er. It was obtain ed 1.09 g (74%) of 18, m .p. 300–302 °C. For C50H44N2O4 (736.9)
calculated: 81.50% C, 6.02% H, 3.80% N; foun d: 81.21% C, 5.87% H, 3.65% N. 1H NMR:
1.32–1.15 m , 2 H (2 × H-10); 1.75 brs, 4 H (CH3, H-12a); 2.05 brd, 1 H, J(12b,12a) = 12.8
(H-12b); 2.69 d, 1 H an d 3.79 d, 1 H, Jgem = 9.2 (CH2O); 2.84 d, 1 H an d 3.39 d, 1 H, Jgem
=
9.5 (CH2O); 4.15 brs, 1 H (H-1); 4.84 brs, 1 H (H-9); 7.14 d, 1 H, J ≈ 1 (H-7); 7.20 m , 15 H
an d 7.35 m , 15 H (2 × trityl).
(1R*,9R*)-11,11-Bis(h ydroxym eth yl)-6-m eth yl-5-oxo-2-oxa-4,8-diazatricyclo-
[7.2.1.03,8]dodec-3,6-dien e (19)
A solution of trityl derivative 18 (737 m g, 1 m m ol) in 80% aqueous trifluoroacetic acid
(10 m l) was set aside at room tem perature for 10 m in . Th e solven t was evaporated an d th e
residue was partition ed between eth er (10 m l) an d water (20 m l). Th e aqueous layer was sep-
arated, wash ed with eth er (2 × 10 m l) an d n eutralized with Dowex 1 (HCO−3 form ). Th e ion
exch an ger was filtered off, wash ed with water an d th e com bin ed filtrates were taken down .
Crystallization of th e residue from m eth an ol gave 210 m g (83%) of racem ic an h ydro
derivative 19, m .p. 244–247 °C. For C12H16N2O4 (252.3) calculated: 57.13% C, 6.39% H,
11.10% N; foun d: 56.96% C, 6.50% H, 10.92% N. 1H NMR: 1.61 dd, 1 H, J(12a,9) = 4.3,
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Carbocyclic 4′-C-Hydroxymethyl Analogues
405
J(12a,12b) = 14.0 (H-12a); 1.75 d, 3 H, J = 0.9 (CH3); 1.83 dd, 1 H, J(12b,9) = 2.4 (H-12b);
2.13 dt, 1 H, J(10a,1) ≈ J(10a,9) ≈ 1, J(10a,10b) = 13.1 (H-10a); 2.32 dt, 1 H, J(10b,1) =
J(10b,9) = 3.1 (H-10b); 3.22–3.50 m , 4 H (2 × CH2O); 4.39 m , 1 H (H-9); 4.72 m , 2 H (H-1,
OH); 4.91 brs, 1 H (OH); 7.43 d, 1 H, J = 1.2 (H-7).
(±)-1-[trans-4-Azido-3,3-bis(acetoxym eth yl)cyclopen tyl]-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (20)
A solution of th e an h ydro derivative 19 (252 m g, 1 m m ol) an d lith ium azide (490 m g, 10
m m ol) in dim eth ylform am ide (7 m l) was h eated at 150 °C for 8 h . Th e solven t was evapo-
rated an d th e residue was ch rom atograph ed on a silica gel colum n in eth yl acetate–aceton e–
eth an ol–water (200 : 30 : 12 : 8) givin g 198 m g of crude azido n ucleoside 21 an d 44 m g
(17.5%) of cyclopen tyl derivative 14. To a solution of crude 21 in aceton itrile (3 m l), acetic
an h ydride (0.4 m l) an d 4-(dim eth ylam in o)pyridin e (50 m g) were added an d th e solution
was allowed to stan d for 2 h at room tem perature. Meth an ol (0.5 m l) was added an d, after
10 m in , th e solven t was evaporated. Ch rom atograph y of th e residue on a silica gel colum n
in eth yl acetate–toluen e (4 : 1) afforded 186 m g (49%) of acetate 20. For C16H21N5O6 (379.4)
calculated: 50.66% C, 5.58% H, 18.46% N; foun d: 50.39% C, 5.70% H, 18.18% N. IR (c =
2%, CHCl3): 3 391 (NH); 2 111, 1 273 (N3); 1 741 (C=O, ester); 1 705, 1 689 (C=O, th y-
m in e); 1 238, 1 045 (C–O, ester). 1H NMR: 1.68 dd, 1 H, J(2a′,1′) = 9.8, J(2a′,2b′) = 13.7
(H-2a′); 1.78 s, 3 H (CH3); 1.98–2.18 m , 2 H (H-5a′, H-2b′); 2.05 s, 3 H an d 2.06 s, 3 H
(CH3CO); 2.33 dt, 1 H, J(5b′,2′) = J(5b′,4′) = 7.0, J(5b′,5a′) = 14.9 (H-5b′); 4.06 s, 2 H (CH2O);
4.10 s, 2 H (CH2O); 4.90 m , 1 H, ΣJ = 35.0 (H-1′); 7.58 d, 1 H, J = 0.8 (H-6); 11.25 s, 1 H
(NH).
(±)-1-[trans-4-Azido-3,3-bis(h ydroxym eth yl)cyclopen tyl]-5-m eth ylpyrim idin e-
2(1H),4(3H)-dion e (21)
A solution of diacetate 20 (112 m g, 0.3 m m ol) in 0.1 M m eth an olic sodium m eth oxide (2 m l)
was allowed to stan d for 2 h at room tem perature. Neutralization with Dowex 50 (H+) an d
evaporation afforded 88 m g (99%) of th e azido n ucleoside 21 as a solid foam . For
C
12H17N5O4 (295.3) calculated: 48.81% C, 5.80% H, 23.72% N; foun d: 48.52% C, 6.01% H,
23.41% N. UV (water): λm ax 275 n m (ε 10 400); (0.1 M NaOH): λm ax 273 n m (ε 7 800).
1H NMR: 1.51 dd, 1 H, J(2a′,1′) = 9.6, J(2a′,2b′) = 13.3 (H-2a′); 1.78 d, 3 H, J = 1.0 (CH3); 1.94 dd,
1 H, J(2b′,1′) = 7.7 (H-2b′); 1.90–2.28 m , 2 H (2 × H-5′); 3.40 d, 4 H, J = 4.9 (2 × CH2O); 4.23 dd,
1 H, J(4′,5a′) = 6.5, J(4′,5b′) = 7.8 (H-4′); 4.67 t, 1 H, J(OH,CH2) = 4.9 (CH2OH); 4.67 t, 1 H,
J(OH,CH2) = 5.4 (CH2OH); 4.93 pen tet, 1 H, J = 8.5 (H-1′); 7.54 d, 1 H, J = 1.0 (H-6); 11.20 s,
1 H (NH).
The authors are indebted to Ms J. Sklenářová and Ms A. Sterecová for excellent technical assistance,
to Ms M. Snopková for the 1H NMR measurements, and to the staff of the Analytical Laboratory of
this Institute (Dr Pechanec, Head) for the elemental analyses. This study was supported by the Grant
Agency of the Czech Republic (grant No. 203/97/0375).
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