Ring-expanded nucleoside analogues. 1,3-Dioxan-5-yl pyrimidines

Article abstract of DOI:10.1021/jo9715231

1,3-Dioxan-5-yl pyrimidine nucleoside analogues, higher homologues of antiviral and anticancer 1,3-dioxolanes, were prepared from bis-1,3- tritylglycerol and 3-benzoylated bases (uracil, 5-fluorouracil, thymine). Mitsunobu condensation, deprotection, and cycloacetalization gave cis/trans mixtures of 2,5-disubstituted-1,3-dioxanes in which the desired cis stereoisomers predominated. Cytosine derivatives could not be obtained in this manner; N⁴-benzoylcytosine afforded an O-2 alkylated Mitsunobu product that rearranged to an O²-(2,3-dihydroxypropyl)cytosine on detritylation with aqueous acetic acid. Cytosine and 5-fluorocytosine nucleosides were therefore prepared from the corresponding uracils via their 1,2-4-triazole derivatives. ¹H NMR data established the conformational preference for equatorial 2'- hydroxymethyl and axial 5'-base in the cis isomers; the trans compounds were diequatorial. Despite their conformations, the cis nucleosides showed no antiviral activity.

Full text of DOI:10.1021/jo9715231

4574
J . Org. Chem. 1998, 63, 4574-4580
Articles
Rin g-Exp a n d ed Nu cleosid e An a logu es. 1,3-Dioxa n -5-yl
P yr im id in es
Gina Cadet, Ching-See Chan, Rose Y. Daniel, Claudette P. Davis, Deodialsingh Guiadeen,
George Rodriguez, Tamara Thomas, Sean Walcott, and Peter Scheiner*
Department of Natural Science, York College, City University of New York, J amaica, New York 11451
Received August 13, 1997
1,3-Dioxan-5-yl pyrimidine nucleoside analogues, higher homologues of antiviral and anticancer
1,3-dioxolanes, were prepared from bis-1,3-tritylglycerol and 3-benzoylated bases (uracil, 5-fluo-
rouracil, thymine). Mitsunobu condensation, deprotection, and cycloacetalization gave cis/trans
mixtures of 2,5-disubstituted-1,3-dioxanes in which the desired cis stereoisomers predominated.
Cytosine derivatives could not be obtained in this manner; N4-benzoylcytosine afforded an O-2
alkylated Mitsunobu product that rearranged to an O2-(2,3-dihydroxypropyl)cytosine on detritylation
with aqueous acetic acid. Cytosine and 5-fluorocytosine nucleosides were therefore prepared from
the corresponding uracils via their 1,2,4-triazole derivatives. 1H NMR data established the
conformational preference for equatorial 2′-hydroxymethyl and axial 5′-base in the cis isomers;
the trans compounds were diequatorial. Despite their conformations, the cis nucleosides showed
no antiviral activity.
In tr od u ction
cleoside analogues. The present paper describes the
synthesis, conformational characteristics, and antiviral
properties of cis-1,3-dioxan-5-yl pyrimidine nucleosides
(3a ).
The antiviral and anticancer activity of the L-nucleo-
sides 11,2 and 23,4 prompted us to consider the properties
of their higher homologues 3. Formally derived from the
1,3-dioxolanes and 1,3-oxathiolanes by insertion of a
methylene group between C1′ and the furanosyl O, these
compounds and the corresponding 1,3-dithianes are of
interest for several reasons. As with other dideoxy
nucleosides (AZT, ddC, etc.) their lack of a secondary (3′)
hydroxyl suggests potential activity as viral DNA poly-
merase inhibitors and/or chain terminators.5 Compounds
3 also offer the opportunity to examine the effects of
additional annular heteroatom substitution on the con-
formation and configuration (3b) of ring-expanded nu-
NH2
R
N
O
N
B
OH
OH
B
OH
O
O
O
X
O
S
1a B = thymin-1-yl
b B = cytosin-1-yl
3a X = O
b X = S
2a R = H (Lamivudine, 3TC)
b R = F (FTC)
c B = 5-fluorocytosin-1-yl
(1) Norbeck, D.; Spanton, S.; Broder, S.; Mitsuya, H. Tetrahedron
Lett. 1989, 30, 6263. (b) Kim, H. O.; Ahn, S. K.; Alves, A. J .; Beach, J .
W.; J eong, L. S.; Choi, B. G.; Van Roey, P.; Schinazi, R. F.; Chu, C. K.
J . Med. Chem. 1992, 35, 1987. (c) Kim, H. O.; Schinazi, R. F.;
Shanmuganathan, K.; J eon, L. S.; Beach, J . W.; Nampalli, S.; Cannon,
D. L.; Chu, C. K. J . Med. Chem. 1993, 36, 519.
Although many six-membered ring nucleoside ana-
logues (pyranose,6 cyclohexanyl,7 cyclohexenyl8) have
been prepared, substantiated antiviral activity was not
reported until 1993.
(2) Grove, K. L.; Guo, X.; Liu, S.-H.; Gao, Z.; Chu, C. K.; Cheng,
Y.-C. Cancer Res. 1995, 55, 3008.
In that year Herdewijn and co-workers described a
series of 1,5-anhydrohexitol nucleosides (4) that showed
potent selective activity against several Herpes-type
(3) (a) Soudens, H.; Yao, X.-J .; Gao, Q.; Belleau, B.; Kraus, J .-L.;
Nguyen-Ba,.; Spira, B.; Wainberg, M. A. Antimicrob. Agents Chemother.
1991, 35, 1386. (b) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.;
Mathis, R.; Cannon, D.; J eong, L.-S.; Beach, J . W.; Choi, W.-B.; Yeola,
S.; Liotta, D. C. Antimicrob. Agents Chemother. 1992, 6, 672. (c) Beach,
J . W.; J eong, L. S.; Alves, A. J .; Pohl, D.; Kim, H. O.; Chang, C.-N.;
Doong, S.-L.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K. J . Org. Chem.
1992, 57, 2217. (d) J in, H.; Siddiqui, M. A.; Evans, C. A.; Tse, H. L. A.;
Mansour, T.; Goodyear, M. D.; Ravenscroft, P.; Beels, C. D. J . Org.
Chem. 1995, 60, 2621 and references therein.
(4) (a) Chang, C.-N.; Doong, S.-L.; Zhou, J . H.; Beach, J . W.; J eong,
L.-S.; Chu, C. K.; Tsai, C.-H.; Cheng, Y.-C. J . Biol. Chem. 1992, 267,
13938. (b) Schinazi, R. F.; McMillan, A.; Cannon, D.; Mathis, R.; Lloyd,
R. M.; Peck, A.; Sommadossi, J .-P.; St. Clair, M.; Wilson, J .; Furman,
P. A.; Painter, G.; Choi, W.-B.; Liotta, D. C. Antimicrob. Agents
Chemother. 992, 36, 2423.
(6) (a) Herdewijn, P.; Van Aershot, A. Bull. Soc. Chim. Belg. 1990,
99, 169. (b) Herdewijn, P.; Van Aershot,; Balzarini, J .; De Clercq, E.
Nucleosides Nucleotides 1991, 10, 119. (c) Pederson, H.; Pederson, E.
B.; Nielsen, C. M. Heterocycles 1992, 34, 265.
(7) (a) Ramesh, K.; Wolfe, M. S.; Lee, Y.; Vandervelde, D.; Borchardt,
R. T. J . Org. Chem. 1992, 57, 5861. (b) Maurinsh, Y.; Schraml, J .; De
Winter, H.; Blaton, N.; Peeters, O.; Lescrinier, E.; Rozenski, J .; Van
Aershot, A.; De Clercq, E.; Busson, R.; Herdewijn, P. J . Org. Chem.
1997, 62, 2861.
(8) (a) Arango, J . H.; Geer, A.; Rodriguez, J .; Young, P. E.; Scheiner,
P. Nucleosides Nucleotides 1993, 12, 773. (b) Reference 7b. (c) Perez-
Perez, M.-J .; Rozenski, J .; Busson, R.; Herdewijn, P. J . Org. Chem.
1995, 60, 1531. (d) Konkel, M. J .; Vince, R. Nucleosides Nucleotides
1995, 14, 2061.
(5) Herdewijn, P.; Van Aershot, A.; Balzarini, J .; De Clercq, E. In
New Methods in Drug Research, Vol. 3; Makriyannis, A., Ed.; Prous
Science Publishers: S.A. 1989; Chapter 7, p 1036.
S0022-3263(97)01523-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/13/1998

Ring-Expanded Nucleoside Analogues
J . Org. Chem., Vol. 63, No. 14, 1998 4575
Sch em e 1
NH3/MeOH
O
O
O
N
O
N
OH
R
R
R
R
NBz
NBz
O
NH
NH
1. NH3/MeOH
2. 80% HOAc
DEAD
Ph3P
+
+
N
O
OTr
OTr
N
H
O
O
6
7a R = H
b R = F
c R = Me
OTr
8a-c
OTr
OH
9a-c
OH
OAc OH
10b,c
O
N
BzOCH2CHO
TsOH
R
NH
O
O
N
HO
O
R
N
O
H
O
1. NH3/MeOH
cis-5a-c
O
2. chromatography
O
R
O
NH
O
N
OBz
O
11a-c
O
HO
trans-5a-c
viruses.9 A notable structural feature of these com-
pounds is the axial orientation of their bases. In previ-
ously described inactive six-membered nucleosides, bases
occupied equatorial or pseudoequatorial positions, unfa-
vorable for kinase mediated 5′-phosphorylation required
for the initial step in viral DNA polymerase inhibitory
activity.9 However, conformational analysis supported
by NMR data clearly established the preference for the
axial base conformation of 4, partially accounting for the
antiviral activity. Molecular modeling showed 4 (with
its axial base) to resemble closely natural nucleosides in
size and shape,7b,9a thus facilitating enzymatic recogni-
tion.
nucleosides cis-5 should exist (predominantly) with their
bases positioned axially (conformation A rather than B),
as required for biological activity in the 1,5-anhydrohexi-
tol (4) series. The diequatorial conformation C would of
course be expected for the trans-5 isomers.
HO
B
B
HO
O
O
H
O
H
B
O
O
O
HO
H
H
cis-5
A
B
H
B
O
B
O
B
O
HO
O
HO
O
HO
H
trans-5
C
OH
4
As well as conformation, incorporation of various
annular heteroatoms could also provide a measure of
dimensional control in the design of ring-expanded
nucleoside analogues. By virtue of their altered bond
lengths and angles, the geometry of such nucleosides
might be modified in predictable ways.12
The notable antiviral activity of several synthetic L
(“unnatural”) nucleosides, for example, 1 and 2, has
focused attention on chirality as an important parameter
In principle, appropriate incorportion of heteroatoms
in a cyclohexane ring could provide an alternative means
for obtaining axially oriented bases. Conformational
preferences of saturated six-membered heterocycles have
been extensively investigated. For the target cis-2-
hydroxymethyl-1,3-dioxan-5-yl nucleosides (cis-5), two
effects are most important.10 Substituents at the 2-posi-
tion of 1,3-dioxanes favor the equatorial position to a
greater extent than do the same substituents in cyclo-
hexane, an effect attributed to enhanced 1,3-diaxial
interactions resulting from the shorter C-O bond dis-
tance in the heterocycle.11 On the other hand, “steric”
requirements of annular O or S, including their axial lone
pairs, are considerably less than those of C with an axial
H. An axial substituent at the 5-position of a 1,3-dioxane
is therefore less subject to unfavorable 1,3-diaxial inter-
actions than it would be in cyclohexane. As a conse-
quence, the preferred conformation of a cis-2,5-disubsti-
tuted-1,3-dioxane is determined primarily by the equa-
torial 2-substituent, not the 5-substituent. Accordingly,
(9) (a) Verheggen, I.; Van Aershot, A.; Toppet, S.; Snoeck, R.;
J anssen, G.; Balzarini, J .; De Clercq, E.; Herdewijn, P. J . Med. Chem.
1993, 36, 2033. (b) Verheggen, I.; Van Aershot, A.; Van Meervelt, L.;
Rozenski, J .; Wiebe, L.; Snoeck, R.; Andrei, G. Balzarini, J .; Claes, P.;
De Clercq, E.; Herdewijn, P. J . Med. Chem. 1995, 38, 826. (c) Hossain,
N.; Rozenski, J .; De Clercq, E.; Herdewijn, P. J . Org. Chem. 1997, 62,
2242.
(10) (a) Eliel, E. L. Acc. Chem. Res. 1970, 3, 1. (b) Eliel, E. L. Angew.
Chem., Int. Ed. Engl. 1972, 11, 739. (c) Riddell, F. G. The Conforma-
tional Analysis of Heterocyclic Compounds; Academic Press: London,
1980.
(11) Eliel, E. L.; Knoeber, M. J . Am. Chem. Soc. 1968, 90, 3444.
(12) (a) Gelan, J .; Anteunis, M. Bull. Soc. Chim. Belg. 1968, 77, 423.
(b) de Kok, A. J .; Romers, C. Recl. Trav. Chim. Pays-Bas 1970, 89,
313.

4576 J . Org. Chem., Vol. 63, No. 14, 1998
Cadet et al.
for antiviral activity and selectivity.13-15 But unlike most
other cyclic nucleoside analogues, the 1,3-dioxanes 5 are
achiral, related to neither the D nor the L carbohydrate
families. In view of the propensity of L nucleosides to
select rapidly and completely for drug resistant virus
strains,16 the effect of the symmetry of 5 on biological
activity was also of interest. Synthesis of cis-5 was
undertaken to explore these effects.
Sch em e 2
NHR
NHBz
NHR
N
N
N
DEAD
Ph3P
80% HOAc
N
+ 6
O
N
O
O
N
H
CH2CHCH2OH
OTr
OTr
OH
13a R = Bz
b R = Ac
15
Resu lts a n d Discu ssion
NH3/MeOH
NH3/MeOH
Preparation of cis-5a -c was accomplished in satisfac-
tory overall yield (29-59%) as shown in Scheme 1.
Mitsunobu condensation of bis-1,3-trityloxy-2-propanol17
(6) with 3-benzoyluracil,18 3-benzoyl-5-fluorouracil,19 and
3-benzoylthymine18 (7a -c) gave products 8a -c, respec-
tively. Debenzoylation (ammonia in methanol, room
temperature) followed by detritylation (80% acetic acid,
75 °C) afforded the necessary 1-(1,3-dihydroxy-2-propyl)-
pyrimidines 9a -c.20 A minor side product (<6%) isolated
from the detritylation of the 5-fluorouracil and thymine
derivatives proved to be the half O-acetylated products
(10b,c). The site of Mitsunobu alkylation, N-1 rather
than O-2, was established by 1H and 13C NMR and
comparison with previously reported spectra.9,21 NMR
examination of the crude Mitsunobu reaction mixtures
revealed only trace amounts of isomeric products.
2-Substituted-1,3-dioxanes (also 1,3-dithianes, 1,3-
oxathianes) are conveniently prepared by cycloacetaliza-
tion of aldehydes with 1,3-diols (or 1,3-dithiols, 3-mer-
capto alcohols). Benzoyloxyacetaldehyde,22 a protected
R-hydroxyaldehyde, reacted well with the 1,3-dihydroxy-
2-propyl-substituted pyrimidines (9a -c) to afford cis/
trans mixtures of the 1,3-dioxanes 11a -c. Under the
conditions employed (no solvent, TsOH catalyst, 80 °C,
2-3 mmHg), the desired cis stereoisomers were the major
products, constituting 70-86% of the crude cyclization
mixtures. Although a kinetic preference for the forma-
tion of cis-2,5-dialkyl-1,3-dioxanes has been previously
noted,23 the cis isomers (cis-11) might also be thermody-
namically more stable than the trans due to intramo-
NH2
N
NH2
N
N
N
O
O
CH2CHCH2OH
OTr
OTr
14
OH
16
lecular H-bonding between the 2-hydroxy pyrimidine
tautomers and the dioxanyl oxygens. Similar stabiliza-
tion has been invoked to account for the greater ther-
modynamic stability of cis-(axial)-5-hydroxymethyl-2-
isopropyl-1,3-dioxane as compared with its trans (diequa-
torial) isomer,24 as well as for the axial preference of
5-hydroxy-1,3-dithianes.25
Acid-catalyzed equilibration of the thymine derivatives
(cis- and trans-5c) supported this supposition. Ap-
proached from both directions using pure cis-5c and a
25% cis-75% trans mixture (DMSO solvent, 60-65 °C,
BF3 etherate catalyst, degassed and sealed in NMR
tubes), the same equilibrium mixture was obtained: 75%
cis-25% trans, corresponding to an energy difference ∆G
) 0.78 ((0.08) kcal/mol.
Debenzoylation of 11 (NH3/MeOH) and silica gel chro-
matography gave the major product cis-5; pure samples
of the minor product trans-5, on the other hand, could
not be obtained by either column chromatography or
HPLC. Attempts to isolate the (minor) trans isomers
were therefore not pursued. NMR data described for
these compounds were obtained from later column frac-
tions, mixtures rich (>70%) in the trans isomers but in
all cases contaminated with the cis.
(13) Valeria, M.; Roberts, S. M.; Storer, R.; Bethell, R. J . Chem. Soc.,
Perkin Trans. 1 1994, 1477.
(14) Skalski, V.; Yang, C.-N.; Dutschman, G.; Cheng, Y.-C. J . Biol.
Chem. 1993, 268, 23234.
(15) (a) Boucher, C. A. B.; Gu, Z.; Gao, Q.; Cammack, N. Antimicrob.
Agents Chemother. 1993, 37, 2231. (b) Schinazi, R. F.; Lloyd, R. M.;
Nguyen, M. H.; et al. Antimicrob. Agents Chemother. 1993, 37, 875.
(c) Gu, Z.; Gao, Q.; Fang, H.; et al. Antimicrob. Agents Chemother. 1994,
38, 275.
(16) Van Draanen, N. A.; Tisdale, N.; Parry, N. R.; J ensen, R.;
Dornsife, R. A.; Tuttle, J . V.; Averett, D. R.; Koszalka, G. W.
Antimicrob. Agents Chemother. 1994, 38, 868.
(17) Mikhailov, S. N.; Smrt, J . Collect. Czech. Chem. Commun. 1975,
40, 3080.
(18) Cruickshank, K. A.; J iricny, J .; Reese, C. B. Tetrahedron Lett.
1984, 25, 681.
(19) Kametani, T.; Kigasawa, K.; Hiragi, M.; Wakisaka, K.; Haga,
S.; Nagamatsu, Y.; Sugi, H.; Fukawa, K.; Irino, O.; Yamamoto, T.;
Nishimura, N.; Taguchi, A.; Okada, T.; Nakayama, M. J . Med. Chem.
1980, 23, 1324.
(20) This method has also been used to prepare the corresponding
9-adeninyl (78% from unprotected adenine) and 9-guaninyl (33% from
2-amino-6-chloropurine) derivatives of 9.
(21) (a) Bronson, J . J .; Ghazzouli, I.; Hitchcock, M. J . M.; Webb, R.
R.; Martin, J . C. J . Med. Chem. 1989, 32, 1457. (b) Bonnal, C.; Chavis,
C.; Lucas, M. J . Chem. Soc., Perkin Trans. 1 1994, 1401. (c) Rodriguez,
J . B.; Marquez, V. E.; Nicklaus, M. C.; Mitsuya, H.; Barchi, J . J . J .
Med. Chem. 1994, 37, 3389. (d) Toyota, A.; Katagiri, N.; Kaneko, C.
Heterocycles 1993, 36, 1625.
Attempts to prepare the cis-cytosin-1-yl nucleoside (5d )
via the method of Scheme 1 failed. Mitsunobu condensa-
tion of N4-benzoylcytosine and 6 gave predominantly O-2
alkylated product 13a (Scheme 2). NMR analysis of the
crude product indicated a ratio of ca. 8:1 (O-2:N-1
alkylation), in general agreement with other Mitsunobu
alkylations reported for this base.8c,21b Predominant O-2
alkylation also occurred with N4-acetylcytosine and 6 to
give 13b. Verification of the O-2 assignment was ob-
tained by 13C and 1H NMR; the H-2′ (OCH) chemical
shifts of 13a ,b (δ 5.53, 5.46, respectively) were ap-
preciably downfield from those of the N-1 Mitsunobu
products 8a -c (δ 4.92-4.99). Debenzoylation of 13a
gave 14, a compound that permitted direct comparison
with 13C spectra reported for other O-2 alkylated
cytosines.8c,21a,b The values observed for C5, C6, and C2
(24) (a) Eliel, E. L.; Kaloustian, M. K. Chem. Commun. 1970, 290.
(b) Eliel, E. L.; Banks, H. D. J . Am. Chem. Soc. 1972, 94, 171.
(25) (a) Luttringhaus, A.; Kabuss, S.; Prinzbach, H.; Langenbucher,
F. Ann. 1962, 653, 195. (b) Abraham, R. J .; Thomas, W. A. J . Chem.
Soc. 1965, 335.
(22) Shiao, M.-J .; Yang, C.-Y.; Lee, S.-H.; Wu, T.-C. Synth. Commun.
1988, 18, 359.
(23) Riddell, F. G.; Robinson, M. J . T. Tetrahedron 1967, 23, 3417.

Ring-Expanded Nucleoside Analogues
J . Org. Chem., Vol. 63, No. 14, 1998 4577
Ta ble 1. Selected 1H Ch em ica l Sh ifts (in δ) for cis- a n d
Sch em e 3
tr a n s-5a
N
N
OH or NH2
O
N
N
N
4
R
R
R
N 3
5
NH
N
2
NH3
1. p-ClC6H4POCl2
2.
6
H
N 1
O
N
1,4-dioxane
MeOH
O
O
1′
N
6′
O
N
H
5′
H
4′
H
2′
O
3′
HO
O
O
O
O
H
H
cis-5
OBz
OBz
12
O
11a R = H
b R = F
2
5
H
1′
N 3
1
N
6
6′
O
5′
H
4′
2′
O
3′
NH2
OH or NH2
HO
4
R
H
H
H
N
R
trans-5
N
O
HO
O
O
H-6b
+ trans
compd
base
H-4′(6′)ax
H-4′(6′)eq
H-5′
cis-5a
U
5FU
T
C
5FC
U
5FU
T
C
4.14
4.13
4.08
4.05
4.08
4.21
4.21
4.22
4.18
4.19
4.29
4.31
4.30
4.32
4.30
4.51
4.50
4.53
4.60
4.55
8.16
8.39
8.08
8.12
8.27
7.71
8.16
7.53
7.65
8.01
cis-5d R = H
e R = F
b
c
d
e
(δ 99.1, 157.4, and 164.8, respectively) are consistent with
O-2 but not N-1 alkylation.
trans-5a
3.89-4.04 (m)
3.94 (t) 4.04 (dd)
3.88-4.10 (m)
3.85 (t) 3.99 (dd)
3.88-4.02 (m)
b
c
d
e
In contrast to the N-1 substituted pyrimidines 8a -c
(Scheme 1), 13a produced a rearranged product, N4-
benzoyl-O2-(2,3-dihydroxypropyl)cytosine (15), on treat-
ment with 80% acetic acid (Scheme 2). Deacylation of
the rearranged product gave the O-2 alkylated cytosine
16.
5FC
a
b
400 MHz, DMSO-d6 solvent, TMS reference. All doublets (J
) 7.2-7.8 Hz) except cis- and trans-5c, singlets.
Ta ble 2. H-4′(6′), H-5′ Cou p lin g Con sta n ts (in h er tz) for
The properties (NMR, mp) of 15 and 16 differed
markedly from those reported for the corresponding N-1
alkylated isomers.26 Although the migration of trityl
groups under acidic conditions has been reported,27 the
present rearrangement is plausibly explained by in-
tramolecular nucleophilic attack of 1° hydroxyl on C-2,
followed by ring opening of the dioxolane intermediate.
Alternatively, a pathway involving nucleophilic attack by
cytosine on a glycidyl intermediate, similar to that
recently proposed in a different context,28 might be
involved. Further investigation may clarify the nature
of the rearrangement.
Because of O-2 alkylation, the cytosine and 5-fluoro-
cytosine nucleosides (cis-5d ,e) were prepared from the
corresponding 2-benzoyloxymethyl-1,3-dioxanyluracil and
5-fluorouracil derivatives 11a ,b, respectively, by the
1,2,4-triazole method29 (Scheme 3). The major cis ste-
reoisomers were again isolated chromatographically.
Stereochemical and conformational assignments were
facilitated by the 1H NMR correlations developed by Eliel
and co-workers for 1,3-dioxanes and 1,3-dithianes.30 The
relative chemical shifts of the H-5′ (dioxanyl) protons and
the H-6 (pyrimidinyl) protons were particularly informa-
tive, as were the H-4′(6′)-H-5′ coupling constants. In
the cis isomers (cis-5a -e) signals for the equatorial H-5′
cis- a n d tr a n s-5c
compd
J 4′(6′)ax,4′(6′)eq
J 4′(6′)ax,5′
J 4′(6′)eq,5′
cis-5c
trans-5c
11.0
10.5
1.8
11.0
1.6
6.0
occurred at higher field (∆δ ) 0.19-0.28 ppm) than those
of the axial H-5′ of the corresponding trans isomers
(trans-5a -e), due to deshielding of the latter by the ring
oxygens. For the same reason, the pyrimidinyl H-6 of
the axially oriented bases in the cis compounds appeared
downfield (∆δ ) 0.23-0.55 ppm) from that of the corre-
sponding trans isomers. Relevant chemical shifts are
given in Table 1.
A distinctive, easily recognizable pattern for H-4′(6′)
and H-5′ was observed for the cis products (cis-5a -e).
The H-5′ signals appeared as somewhat broadened single
peaks reflecting the small but similar magnitudes of 3J 4a,5
3
and J 4e,5 (ca. 1.7 Hz). In agreement with earlier
observations,30c the equatorial H-4′(6′) signals of the cis
and trans compounds were downfield from the axial H-4′-
(6′) signals (∆δ ) 0.07-0.14 ppm). At 400 MHz, both
H-4′(6′)e and H-4′(6′)a in the cis isomers appeared as
characteristic distorted doublets. The partial experimen-
tal spectrum (H-4′(6′), H-5′) of cis-5c was accurately
reproduced by H NMR simulation31 using the δ-values
1
given in Table 1 and the coupling constants (3J ) tabulated
in Table 2. Similar simulations were effected for the
other cis isomers.
(26) Bronson, J . J .; Ferrara, L. M.; Howell, H. G.; Brodfueher, P.
R.; Martin, J . C. Nucleosides Nucleotides 1990, 9, 745.
(27) Bartlett, P. A.; Green, F. R. J . Am. Chem. Soc. 1978, 100, 4858.
(28) Liang, C.; Lee, D. W.; Newton, M. G.; Chu, C. K. J . Org. Chem.
1995, 60, 1546.
(29) Lin. T-S.; Luo, M.-Z.; Liu, M.-C.; Clarke-Katzenburg, R. H.;
Cheng, Y.-C.; Prusoff, W. H.; Mancini, W. R.; Birnbaum, G. I.; Gabe,
E. J .; Giziewicz, J . J . Med. Chem. 1991, 34, 2607.
(30) (a) Eliel, E. L.; Hutchins, R. O. J . Am. Chem. Soc. 1969, 91,
2703. (b) Eliel. E. L.; Kandasamy, D.; Sechrest, R. C. J . Org. Chem.
1977, 42, 1533. (c) Kaloustian, M. K.; Dennis, N.; Mager, S.; Evans, S.
A.; Alcudia, F.; Eliel, E. L. J . Am. Chem. Soc. 1976, 98, 956.
Spectra of the minor trans isomers (trans-5) were
entirely different; axial H-5′ appeared as well-defined
multiplets, while H-4′(6′)e in trans-5b,d appeared as a
doublet of doublets and H-4′(6′)a as a distorted triplet,
(31) Advanced Chemistry Development, Inc., HNMR 2.5, simultator
program.

4578 J . Org. Chem., Vol. 63, No. 14, 1998
Cadet et al.
as previously described for other 1,3-dioxanes.32 Over-
lapping signals made it difficult to discern this pattern
in trans-5a ,c,e. The partial spectrum of trans-5c, rep-
resentative of the trans isomers, was simulated with the
data in Tables 1 and 2. The observed coupling constants
agree well with those of other cis- and trans-2,5-disub-
stituted-1,3-dioxanes reported by Eliel and co-work-
ers.30,32 As anticipated, the bases are axially positioned
in cis-5a -e.
An tivir a l Testin g. Cis nucleosides 5a -e were evalu-
ated for activity against the following viruses, HSV-1,
HSV-2, HBV, EBV, and HIV-1, by previously described
procedures.33 None of the compounds showed significant
antiviral activity: HSV-1 and -2 and HIV-1, ED50 > 100
µM; EBV and ED50 > 50 µM; HBV, ED50 > 10 µM. No
cytotoxicity was observed.
was removed under reduced pressure. Products (8a -c) were
isolated by column chromatography, dissolved in methanol
(250 mL), cooled to 0 °C, saturated with gaseous ammonia and
stirred for 16-20 h. Solvent and ammonia were removed
under reduced pressure, and the residue was stirred with 80%
acetic acid (200 mL) at 70-75 °C until the original suspensions
became clear and TLC indicated completion of the reaction
(4-8 h). Following solvent removal and re-evaporation with
added toluene (2 × 50 mL) under reduced pressure, the
resulting white to beige mixtures were suspended in water (60
mL) and extracted with methylene chloride (3 × 50 mL).
Evaporation of the water layer gave 9a -c, purified further
by either column chromatography (elution with 3% methanol
in methylene chloride) or recrystallization from chloroform-
methanol mixtures.
1-(1,3-Dih yd r oxy-2-p r op yl)u r a cil (9a ): 68%. Mp: 153-
155 °C. UV: λmax 266 nm. 1H NMR: δ 3.60-3.63 (m, 4H),
4.42 (m, 1H), 4.92 (s, 2H), 5.52 (d, 1H, J ) 8 Hz), 7.58 (d, 1H,
J ) 8 Hz), 11.17 (s, 1H). 13C NMR: δ 59.1, 100.2, 143.7, 151.5,
163.3. Anal. Calcd for C7H10N2O4: C, 45.16; H, 5.41; N, 15.05.
Found: C, 45.26; H, 5.36; N, 15.12.
Con clu sion s
1-(1,3-Dih yd r oxy-2-p r op yl)-5-flu or ou r a cil (9b ): 41%.
Mp: 175-176 °C. UV: λmax 273 nm. 1H NMR: δ 3.58-3.65
(m, 4H), 4.44 (m, 1H), 4.95 (t, 2H, J ) 4.2 Hz), 7.98 (d, 1H, J
) 7.2 Hz), 11.68 (br s, 1H). 13C NMR: δ 59.2, 59.7, 128.5 (d,
2J ) 33.2 Hz), 139.8 (d, 1J ) 227.2 Hz), 150.6, 157.4 (d, 2H, 2J
) 26.7 Hz). Anal. Calcd for C7H9FN2O4: C, 41.18; H, 4.44;
N, 13.72. Found: C, 41.29; H, 4.41; N, 13.71.
1-(1-Acetyloxy-3-h ydr oxy-2-pr opyl)-5-flu or ou r acil (10b):
isolated (6%) during the column chromatography of 9b. 1H
NMR: δ 1.99 (s, 3H), 3.66 (m, 2H), 4.27 (d, 2H, J ) 5.6 Hz),
4.66 (m, 1H), 5.16 (t, 1H, J ) 8.4 Hz), 8.16 (d, 1H, J ) 5.6
Hz), 11.43 (s, 1H). Treatment with methanolic ammonia (room
temperature, 15 h) quantitatively converted 10b to 9b.
1-(1,3-Dih ydr oxy-2-pr opyl)th ym in e (9c): 78%. Mp: 227-
229 °C. UV: λmax 271 nm. 1H NMR: δ 1.77 (s, 3H), 3.58-
3.64 (m, 4H), 4.43 (m, 1H), 4.90 (t, 2H, J ) 7.7 Hz), 7.47 (s,
1H), 11.15 (s, 1H). 13C NMR: δ 12.1, 58.8, 59.0, 107.8, 139.2,
151.5, 163.9. Anal. Calcd for C8H12 N2O4: C, 48.00; H, 6.04;
N, 13.99. Found: C, 48.08; H, 6.02; N, 14.00.
An efficient synthesis of ring-expanded achiral 1,3-
dioxan-5-yl nucleosides containing pyrimidine bases has
been developed. Under the cyclization conditions em-
ployed, the cis stereoisomers, analogous to natural â-ano-
mers, were preferentially formed. As predicted from
conformational considerations, the cis products (5a -e)
possess equatorial 2′-hydroxymethyl substituents and
axial 5′-bases, confirming the potential of annular het-
eroatom substitution for conformational control in ring-
expanded nucleoside analogues. Despite their axial
bases, cis-5a -e did not show the antiviral activity of the
conformationally related 1,5-anhydrohexitols (4). Ad-
ditional factors, such as the 2° hydroxyl group of 4,34 may
be necessary for antiviral activity.
Exp er im en ta l Section
1-(1-Acetyloxy-3-h yd r oxy-2-p r op yl)th ym in e (10c): iso-
lated (4%) during column chromatography of 9c. 1H NMR: δ
1.77 (s, 3H), 1.98 (s, 3H), 3.65 (m, 2H), 4.28 (m, 2H), 4.63 (m,
1H), 5.10 (t, 1H, J ) 5.6 Hz), 7.58 (s, 1H), 11.23 (s, 1H). 13C
NMR: δ 12.0, 20.4, 55.8, 58.9, 61.5, 108.5, 138.6, 151.4, 163.7,
170.0. Treatment with methanolic ammonia (room tempera-
ture, 13 h) quantitatively converted 10c to 9c.
General methods were the same as previously described.35
UV spectra were recorded with a Perkin-Elmer Lambda 2 UV/
vis spectrophotometer; 1H NMR spectra were determined with
a Varian Inova 400 MHz spectrometer (13C at 100 MHz) or a
Brucker 200 MHz (13C at 50 MHz). Unless otherwise specified
UV spectra were obtained in methanol solutions and spectra
were recorded on DMSO-d6 solutions with TMS as internal
standard. Column and thin-layer chromatography utilized
silica gel; eluents were methylene chloride with increasing
amounts of methanol. Melting points are uncorrected. El-
emental analyses were performed by Atlantic Microlab, Nor-
cross, GA.
Gen er a l P r oced u r e for Mitsu n obu Con d en sa tion a n d
Dep r ot ect ion . 1-(1,3-Dih yd r oxy-2-p r op yl)p yr im id in es
(9a -c). Diethyl azodicarboxylate (DEAD) (4.40 g, 25.3 mmol)
dissolved in anhydrous tetrahydrofuran (40 mL) was added
dropwise at room temperature, under a nitrogen atmosphere,
to a stirred solution or suspension of triphenylphosphine (6.56
g, 25.0 mmol), bis-1,3-trityloxy-2-propanol (6)17 (5.77 g, 10.0
mmol), and the appropriate base18,19 (20.0 mmol) in anhydrous
1,4-dioxane (200 mL). After addition, the stoppered flask was
stirred at room temperature for 16-23 h, and then solvent
N4-Ben zoyl-O2-(bis-1,3-tr ityloxy-2-pr opyl)cytosin e (13a).
Mitsunobu condensation of 6 and N4-benzoylcytosine (as above)
gave, after column chromatography, 13a (36%) contaminated
with ca. 6% of isomeric material (presumably the N-1 alkylated
isomer). Pure product was obtained by rechromatography.
Mp: 107-110 °C. 1H NMR (CDCl3): δ 3.40-3.52 (m, 4H), 5.53
(quint., 1H, J ) 5.2 Hz), 7.2-7.4 (m, 30H), 7.49-7.66 (m, 3H),
7.85 (d, 1H, J ) 5.6 Hz), 8.02 (d, 2H, J ) 7.7 Hz), 8.49 (d, 1H,
J ) 5.6 Hz), 11.13 (s, 1H). 13C NMR (CDCl3): δ 61.9, 74.9,
86.6, 103.9, 127.3, 127.7, 128.7, 129.1, 132.9, 133.3, 143.9,
159.0, 160.7, 164.3, 165.9. Anal. Calcd for C52H43N3O4: C,
80.69; H, 5.60; N, 5.43. Found: C, 80.58; H, 5.67; N, 5.38.
N4-Acetyl-O2-(bis-1,3-tr ityloxy-2-p r op yl)cytosin e (13b):
prepared as for 13a , 29%. Mp: 231-232 °C. 1H NMR
(CDCl3): δ 2.20 (s, 3H), 3.42-3.55 (m, 4H), 5.46 (quint., 1H, J
) 5.2 Hz), 7.2-7.4 (m, ca. 30H), 7.72 (d, 1H, J ) 5.6 Hz), 7.84
(s, 1H), 8.33 (d, 1H, J ) 5.6 Hz). Anal. Calcd for C47H41N3O4:
C, 79.30; H, 5.81; N, 5.90. Found: C, 79.03; H, 5.87; N, 5.78.
O2-(Bis-1,3-tr ityloxy-2-p r op yl)cytosin e (14). A sample
of 13a (70 mg, 0.09 mmol) dissolved in methanol (20 mL),
cooled to 0 °C, saturated with ammonia, and allowed to stand
for 36 h at room temperature deposited fine white crystals (47
mg, 78%). Recrystallized from aqueous MeOH, mp 117-121
°C. 1H NMR (CDCl3): δ 3.42 (dd, 2H, J ) 9.6, 7.6 Hz), 3.53
(dd, 2H, J ) 9.6, 4.8 Hz), 4.89 (s, 2H), 5.45 (quint., 1H, J )
5.2 Hz), 6.00 (d, 1H, J ) 5.6 Hz), 7.2-7.4 (m, Tr H’s), 7.93 (d,
1H, J ) 5.6 Hz). 13C NMR (CDCl3): δ 62.0, 74.0, 86.4, 99.1,
126.8, 127.7, 128.8, 144.0, 157.4, 164.7, 164.8. Anal. Calcd
(32) Abraham, R. J .; Banks, H. D.; Eliel, E. L.; Hofer, O.; Kaloustian,
M. K. J . Am. Chem. Soc. 1972, 94, 1913.
(33) HSV: Bastow, K. F.; Dersem D. D.; Cheng, Y.-C. Antimicrob.
Agents Chemother. 1983, 23, 914. EBV: Yao, G.-Q.; Tsai, C.-H.; Cheng,
Y.-C. Virus Genes 1995, 9, 247. HIV-1: Mellors, J . W.; Dutschman, G.
E.; Im, G.-J .; Tramontano, E.; Winkler, S. R.; Cheng, Y.-C. Mol.
Pharmacol. 1992, 41, 446. HBV: Doong, S.-L.; Tsai, C.-H.; Schinazi,
R. F.; Liotta, D. C.; Cheng, Y.-C. Proc. Natl. Acad. Sci. U.S.A. 1991,
88, 8495.
(34) Perez-Perez, M.-J .; De Clercq, E.; Herdewijn, P. Bioorg. Med.
Chem. Lett. 1996, 6, 1457.
(35) Scheiner, P.; Geer, A.; Buckner, A.-M.; Imbach, J .-L.; Schinazi,
R. F. J . Med. Chem. 1989, 32, 73.

Ring-Expanded Nucleoside Analogues
J . Org. Chem., Vol. 63, No. 14, 1998 4579
for C45H39N3O3‚0.5H2O: C, 79.62; H, 5.94; N, 6.19. Found: C
79.50; H, 6.17; N, 6.20.
(m, 1H), 4.71 (s, 1H), 4.92 (t, 1H, J ) ca. 2 Hz, exchangeable),
5.58 (d, 1H, J ) 7.6 Hz), 7.71 (d, 1H, J ) 7.6 Hz), 11.34 (br s,
1H).
N4-Ben zoyl-O2-(2,3-d ih yd r oxyp r op yl)cytosin e (15). A
sample of 13a (1.31 g, 1.70 mmol) was dissolved in 80%
(aqueous) acetic acid (50 mL) and heated for 11 h at 60-65
°C. After removal of the solvent and re-evaporation with
added 1-butanol and then toluene, the residue was shaken
with a mixture of water and methylene chloride (50 mL each).
The aqueous layer was evaporated under reduced pressure to
give 15 (0.305 g, 62%), further purified by recrystallization
from ethyl acetate-methanol (5:1). Mp: 156-158 °C. 1H
NMR: δ 3.49 (t, 2H, J ) 5.6 Hz), 3.85 (m, 1H), 4.27 (dd, 1H,
J ) 10.8, 6.4 Hz), 4.37 (dd, 1H, J ) 6.4, 4.4 Hz), 4.70 (t, 1H,
J ) 5.6 Hz), 4.90 (d, 1H, J ) 5.2 Hz), 7.54 (t, 2H, J ) 7.6 Hz),
7.62 (t, 1H, J ) 7.2 Hz), 7.87 (d, 1H, J ) 5.4 Hz), 8.04 (d, 2H,
J ) 8.0 Hz), 8.52 (d, 1H, J ) 5.4 Hz), 11.14 (s, 1H). 13C NMR:
62.7, 68.5, 69.5, 104.3, 128.2, 128.3, 132.4, 133.3, 160.1, 160.2,
164.5, 167.0. Anal. Calcd for C14H15N3O4: C, 58.11; H, 5.23;
N, 14.53. Found: C, 57.88; H, 5.30; N, 14.37.
cis-5-F lu or o-1-(2-h yd r oxym et h yl-1,3-d ioxa n -5-yl)u r -
a cil (cis-5b): 71%. Mp: 207-208 °C. UV: λmax 266 nm. 1H
NMR: δ 3.43 (m, 2H), 4.13 (apparent d, 2H), 4.21 (apparent
d, 2H), 4.31 (s, 1H), 4.71 (t, 1H, J ) 4.0 Hz), 4.98 (t, 1H, J )
6.0 Hz), 8.39 (d, 1H, J ) 7.6 Hz), 11.94 (s, 1H). 13C NMR: δ
47.5, 62.5, 67.7, 101.0, 128.3 (d, 2J ) 34 Hz), 139.3 (d, 1J )
2
227 Hz), 149.6, 156.9 (d, J ) 26 Hz). Anal. Calcd for C9H11
-
FN2O5: C, 43.91; H, 4.50; N, 11.38. Found: C, 43.99; H, 4.51;
N, 11.36.
tr a n s-5-F lu or o-1-(2-h yd r oxym et h yl-1,3-d ioxa n -5-yl)-
u r a cil (tr a n s-5b) (estimated, 15%). 1H NMR: δ 3.94 (t, 2H,
J ) 11.0 Hz), 4.04 (dd, 2H, J ) 10.8, 4.8 Hz), 4.50 (m, 1H),
4.58 (t, 1H, J ) 4.4 Hz, exchangeable), 4.95 (t, 1H, J ) 6.4
Hz), 8.16 (d, 1H, J ) 7.2 Hz), 11.85 (s, 1H).
cis-1-(2-Hyd r oxym eth yl-1,3-d ioxa n -5-yl)th ym in e (cis-
5c): 76%. Mp: 230-231 °C. UV: λmax 271 nm. 1H NMR: δ
1.79 (s, 3H), 3.43 (m, 2H), 4.08 (apparent d, 2H), 4.22 (apparent
d, 2H), 4.30 (s, 1H), 4.71 (t, 1H, J ) 4.0 Hz), 4.97 (t, 1H, J )
6.4 Hz), 8.08 (s, 1H), 11.33 (s, 1H). 13C NMR: δ 12.3, 47.1,
62.5, 67.8, 101.0, 107.9, 139.4, 151.0, 163.7. Anal. Calcd for
O2-(2,3-Dih yd r oxyp r op yl)cytosin e (16). Compound 15
(0.134 g, 0.464 mmol) treated with methanolic ammonia as
for 14 gave a quantitative yield of 16, mp ) 129-131 °C from
ethyl acetate-MeOH (4:1). 1H NMR: δ 7.84 (d, 1H, J ) 7.2
Hz), 6.81 (br s, 2H), 6.06 (d, 1H, J ) 7.2 Hz), 4.89 (d, 1H, J )
4.8 Hz), 4.61 (t, 1H, J ) 6.0 Hz) 4.16 (dd, 1H, J ) 10.8, 4.4
Hz), 4.05 (dd, 2H, J ) 10.4, 6.0 Hz), 3.73 (m, 1H), 3.40 (t, 2H,
J ) 6.0 Hz). 13C NMR: δ 62.7, 67.6, 69.6, 99.1, 156.0, 164.8,
165.1. Anal. Calcd for C7H11N3O3: C, 45.40; H, 5.99; N, 22.69.
Found: C, 45.47; H, 5.99; N, 22.74.
C
10H14N2O5: C, 49.58; H, 5.83; N, 11.56. Found: C, 49.47; H,
5.77; N, 11.49.
tr a n s-1-(2-H yd r oxym et h yl-1,3-d ioxa n -5-yl)t h ym in e
(tr a n s-5c) (estimated, 18%). 1H NMR: δ 1.74 (s, 3H), 3.40
(m, 2H), 3.88-4.10 (m, 4H), 4.53 (m, 1H), 4.59 (t, 1H, J ) 4.6
Hz), ∼5 (v br s), 7.53 (s, 1H). 13C NMR: δ 12.2, 47.0, 62.4,
66.5, 100.9, 109.0, 137.6, 151.7, 164.9.
Gen er a l P r oced u r e for Cycloa ceta liza tion a n d Dep r o-
tection . cis-1-(2-Hyd r oxym eth yl-1,3-d ioxa n -5-yl)p yr im -
id in es (cis-5a -c). In a one-necked 10 mL flask with a
vacuum takeoff adapter, a stirred mixture of a 1-(1,3-dihy-
droxy-2-propyl)pyrimidine (9, 5.00 mmol), freshly distilled
benzoyloxyacetaldehyde22 (2.46 g, 15.0 mmol), and ca. 25 mg
of p-toluenesulfonic acid was heated (oil bath) at 75-80 °C
and 1-2 mmHg. The suspension became clear after about 1
h. When TLC of the mixture (chloroform-methanol, 9.5:0.5)
showed no pyrimidine starting material and a new product
spot (2-3 h), heating was discontinued, and the cooled mixture
was taken up in methylene chloride (50 mL), extracted with
saturated NaHCO3 solution (25 mL) and water (25 mL), and
dried over MgSO4. Removal of the solvent gave ca. 3.9 g of
crude material (product + aldehyde) that was chromato-
graphed over silica gel (75 g), affording 11 (3.1-4.6:1, cis:trans,
by NMR) on elution with 2% methanol in methylene chloride.
Product 11, a cis/trans mixture, was dissolved in methanol (200
mL), cooled to 0 °C, saturated with ammonia, and stirred at
room temperature for 15-22 h. Evaporation of the solvent
gave a mixure of 5 and benzamide, separated easily by passage
through a silica gel column (60 g) and elution with 2%
methanol in methylene chloride. Pure cis-5 eluted first,
followed by mixtures of cis- and trans-5. The cis products were
recrystallized from chloroform-methanol mixtures. A small
sample (∼2 mg) of trans-5c was obtained by thick layer
chromatography (silica gel, eluent chloroform-methanol 9:1,
100 mL + 2 mL benzene and 1 drop of acetic acid); similar
attempts to isolate pure samples of the other trans-5 com-
pounds were unsuccessful. Isolated yields of cis-5 are given
below; yields of trans-5 are estimated from the NMR spectra
of the crude cis/trans mixtures, using the integrated values of
the pyrimidinyl C-5 signals of the cis and trans compounds
and the isolated yields of the cis. NMR data for the trans
compounds were obtained from binary mixtures rich in trans-
5, by subtraction of the pure cis isomer.
Gen er a l P r oced u r e for th e P r ep a r a tion of Cytosin -1-
yl Der iva tives (cis-5d ,e). A solution of 11a or 11b (7.10
mmol) and 1,2,4-triazole (6.83 g, 98.9 mmol) in anhydrous
pyridine (45 mL) was cooled to 0 °C. Under an atmosphere of
dry nitrogen, 4-chlorophenyl dichlorophosphate (5.0 g, 20.4
mmol) was added dropwise over 5 min to the cold, stirred
solution. After 4 h at 0 °C the ice bath was removed and the
orange solution was stirred at room temperature for 20 h.
Removal of solvent under reduced pressure gave tarry dark
material that was re-evaporated three times with added
toluene, dissolved in methylene chloride (100 mL), and ex-
tracted with four portions of water (50 mL each). The aqueous
layers were re-extracted twice with methylene chloride (50 mL
each), and the combined organic layers were dried (MgSO4)
and evaporated to give a brownish solid. Chromatography
(silica gel, 50 g) gave the triazole derivative cis/trans-12 which
was used without additional purification. Product 12 was
stirred at room temperature with concentrated ammonium
hydroxide (15 mL) and 1,4-dioxane (30 mL) for 20 h; solvent
was removed and the residue treated with saturated metha-
nolic ammonia (50 mL) for 24 h and then evaporated to give
cis/trans-5. Pure samples of cis-5d ,e were obtained by chro-
matography and elution with 2% methanol in methylene
chloride, along with cis/trans mixtures. Small amounts of the
uracil derivatives cis-5a and cis-5b were also isolated.
cis-1-(2-Hyd r oxym eth yl-1,3-d ioxa n -5-yl)cytosin e (cis-
5d ): 38%. Mp: 245-247 °C. UV: λmax 275 nm. 1H NMR: δ
3.37 (m, 2H), 4.05 (apparent d, 2H), 4.18 (apparent d, 2H),
4.32 (s, 1H), 4.69 (t, 1H, J ) 10.2 Hz), 4.94 (t, 1H, J ) 6.4 Hz),
5.73 (d, 1H, J ) 7.2 Hz), 6.99, 7.16 (br s’s, 2H, exchangeable),
8.12 (d, 1H, J ) 7.2 Hz). 13C NMR: δ 47.8, 62.7, 67.9, 93.0,
101.2, 144.0, 155.4, 165.4. Anal. Calcd for C9H13N3O4: C,
47.57; H, 5.77; N, 18.49. Found: C, 47.63; H, 5.74; N, 18.46.
tr a n s-1-(2-H yd r oxym et h yl-1,3-d ioxa n -5-yl)cyt osin e
(tr a n s-5d ) (estimated, 7%). 1H NMR: δ ∼3.4 (ca. 2H, partially
covered), 3.85 (t, 2H, J ) 10.4 Hz), 3.93 (dd, 2H, J ) 10.4, 7.2
Hz), 4.59 (t, 1H, J ) 4.8 Hz), 4.60 (m, 1H), 4.93 (t, 1H, J ) 4.8
Hz), 5.71 (d, 1H, J ) 7.4 Hz), 7.13, 7.26 (br s’s, 2H, exchange-
able), 7.65 (d, 1H, J ) 7.4 Hz).
cis-1-(2-Hyd r oxym eth yl-1,3-d ioxa n -5-yl)u r a cil (cis-5a ):
62%. Mp: 191-192 °C. UV: λmax 266 nm. 1H NMR: δ 3.39
(m, 2H), 4.14 (apparent d, 2H), 4.21 (apparent d, 2H), 4.29 (br
s, 1H), 4.70 (t, 1H, J ) 3.7 Hz), 4.92 (t, 1H, J ) ca. 2 Hz,
exchangeable), 5.60 (d, 1H, J ) 7.9 Hz), 8.16 (d, 1H, J ) 7.9
Hz), 11.32 (s, 1H). 13C NMR: δ 47.5, 62.4, 67.7, 100.6, 101.1,
143.7, 150.9, 163.2. Anal. Calcd for C9H12N2O5: C, 47.35; H,
5.30; N, 12.28. Found: C, 47.47; H, 5.30; N, 12.18.
cis-5-F lu or o-1-(2-h yd r oxym et h yl-1,3-d ioxa n -5-yl)cy-
tosin e (cis-5e): 39%. Mp: 253-255 °C. UV: λmax 283 nm.
1H NMR: δ 3.42 (dd, 2H, J ) 4.0, 6.0 Hz), 4.08 (apparent d,
2H), 4.19 (apparent d, 2H), 4.30 (s, 1H), 4.70 (t, 1H, J ) 4.0
Hz), 4.94 (t, 1H, J ) 6.2 Hz), 7.50, 7.65 (br s’s, 2H), 8.27 (d,
1H, J ) 7.6 Hz). 13C NMR: δ 48.2, 62.5, 67.8, 101.1, 128.8 (d,
tr a n s-1-(2-Hydr oxym eth yl-1,3-dioxan -5-yl)u r acil (tr an s-
5a ) (estimated, 11%). 1H NMR: δ 3.89-4.05 (m, 4H), 4.51

4580 J . Org. Chem., Vol. 63, No. 14, 1998
Cadet et al.
2J ) 32 Hz), 138.4 (d, 1J ) 239 Hz), 153.7, 156.9(d, 2J ) 13
Hz). Anal. Calcd for C9H12FN3O4: C, 44.08; H, 4.93; N, 17.14.
Found: C, 44.15; H, 4.92; N, 17.18.
tr a n s-5-F lu or o-1-(2-h yd r oxym eth yl-1,3-d ioxa n -5-yl)cy-
tosin e (tr a n s-5e): (estimated, 9%). 1H NMR: δ 3.38 (m, 2H),
3.88-4.02 (m, 4H), 4.55 (m, 1H), 4.57 (t, 1H, J ) 2.8 Hz,
exchangeable), 4.91 (t, 1H, J ) 6.0 Hz), 7.65, 7.75 (br s’s, 2H),
8.01 (d, 1H, J ) 7.2 Hz).
trans, a ratio that did not change further with time. No
additional products were detected.
Ack n ow led gm en t. The authors gratefully acknowl-
edge Professor Y.-C. Cheng, Department of Pharmacol-
ogy, Yale University School of Medicine, for the antiviral
testing results. The study was made possible by the
financial support of the National Institutes of Health,
Minorities Biomedical Research Support, Grant
GM08153.
Acid -Ca t a lyzed E q u ilib r a t ion of cis- a n d tr a n s-1-(2-
Hyd r oxym eth yl-1,3-d ioxa n -5-yl)th ym in es. A solution of
cis-5c in hexadeuteriodimethyl sulfoxide (0.1 mmol in 0.75 mL)
was placed in an NMR tube with TMS and boron trifluoride
etherate (ca. 50 µL each). The tube and its contents were
degassed by two freeze-thaw cycles, sealed, and maintained
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds cis-5a -e, 8a -c, 9a ,b,c, 10b,c, 12a ,b, 13-16; 13
C
NMR of cis-5a -e, 9a ,b,c, 10c, 12a , 13-16 (36 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
in
a water bath at 60-65 °C (tube A). An NMR tube
containing a mixture of 75% trans-5c and 25% cis-5c was
similarly prepared (tube B). Periodically, the C-6 proton
signals (singlets: δ 8.08 (cis), δ 7.53 (trans)) were integrated.
After 29 days, tube A, 83% cis, 17% trans; tube B, 70% cis,
30% trans. After 47 days both tubes contained 75% cis, 25%
J O9715231