Preparation of 4'-substituted thymidines by substitution of the thymidine 5'-esters.

Article abstract of DOI:10.1021/jo001223a

tert-Butyl thymidylate 3 was prepared from thymidine 1 in six steps and 67% overall yield. When the lithium trianion of 3 (prepared by treatment of 3 with excess LDA and then excess tert-butyllithum) is reacted with electrophiles, trapping occurs stereoselectively from either the alpha- or beta-face depending on the electrophile (Scheme 1). Deuterioacetic acid in deuteriomethanol affords mainly the alpha-deuterated product (4a/4b = 2.4:1) while all other electrophiles, e.g., phenylselenenyl chloride, allyl bromide, and N-fluorobenzenesulfonimide (NFSI), give predominately (or completely) the products of attack from the beta-face (5bcd/4bcd = 3.7:1 to 100:0). The structures of the products were determined by coupling constant analysis of both the initial compounds and the diols 6bcd prepared by ester reduction and by formation of the acetonides 7bc. The methyl ester of the 3'-epimer of thymidylic acid 9 was also prepared from thymidine 1 in nine steps and 74% overall yield. When the lithium trianion of 9 (prepared by treatment of 9 with excess LDA and then excess tert-butyllithum) is reacted with electrophiles, trapping also occurs stereoselectively with attack on either the alpha- or beta-face depending on the electrophile (Scheme 2). Again, deuterioacetic acid in deuteriomethanol affords mainly the beta-deuterated product (11a/10a = 1.6:1) while all other electrophiles, e.g., phenylselenenyl chloride, methyl iodide, allyl bromide, and NFSI, gave predominately (or completely) the product of attack from the alpha-face (8.7:1 to 100: 0). Again, the structures of the products were determined by coupling constant analysis of both the initial compounds, and the diols 12b-e were prepared by reduction of the ester and by formation of the acetonides 13bcd. A rationale has been developed using molecular mechanics calculations to explain the diastereoselectivity that involves staggered axial attack on the sp(2) carbon opposite to the pseudoaxial alkoxy group in the most stable half-chair conformation of the enolates, as shown in Schemes 3-5.

Full text of DOI:10.1021/jo001223a

2624
J . Org. Chem. 2001, 66, 2624-2635
P r ep a r a tion of 4′-Su bstitu ted Th ym id in es by Su bstitu tion of th e
Th ym id in e 5′-Ester s
Michael E. J ung* and Akemi Toyota
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569
jung@chem.ucla.edu
Received August 10, 2000
tert-Butyl thymidylate 3 was prepared from thymidine 1 in six steps and 67% overall yield. When
the lithium trianion of 3 (prepared by treatment of 3 with excess LDA and then excess
tert-butyllithum) is reacted with electrophiles, trapping occurs stereoselectively from either the R-
or â-face depending on the electrophile (Scheme 1). Deuterioacetic acid in deuteriomethanol affords
mainly the R-deuterated product (4a /4b ) 2.4:1) while all other electrophiles, e.g., phenylselenenyl
chloride, allyl bromide, and N-fluorobenzenesulfonimide (NFSI), give predominately (or completely)
the products of attack from the â-face (5bcd /4bcd ) 3.7:1 to 100:0). The structures of the products
were determined by coupling constant analysis of both the initial compounds and the diols 6bcd
prepared by ester reduction and by formation of the acetonides 7bc. The methyl ester of the 3′-
epimer of thymidylic acid 9 was also prepared from thymidine 1 in nine steps and 74% overall
yield. When the lithium trianion of 9 (prepared by treatment of 9 with excess LDA and then excess
tert-butyllithum) is reacted with electrophiles, trapping also occurs stereoselectively with attack
on either the R- or â-face depending on the electrophile (Scheme 2). Again, deuterioacetic acid in
deuteriomethanol affords mainly the â-deuterated product (11a /10a ) 1.6:1) while all other
electrophiles, e.g., phenylselenenyl chloride, methyl iodide, allyl bromide, and NFSI, gave
predominately (or completely) the product of attack from the R-face (8.7:1 to 100: 0). Again, the
structures of the products were determined by coupling constant analysis of both the initial
compounds, and the diols 12b-e were prepared by reduction of the ester and by formation of the
acetonides 13bcd . A rationale has been developed using molecular mechanics calculations to explain
the diastereoselectivity that involves staggered axial attack on the sp2 carbon opposite to the
pseudoaxial alkoxy group in the most stable half-chair conformation of the enolates, as shown in
Schemes 3-5.
In tr od u ction a n d Ba ck gr ou n d
cently, in connection with biological studies of the mech-
anism of synthetic nucleases, we published a synthesis
of 4′-deuteriothymidine,6 which proceeded via deuteration
of the anion of the corresponding 5′-ester. We now report
the use of such anions of the 5′-esters of 2′-deoxy
nucleosides and their analogues.
Most syntheses of 4′-carbon-branched nucleosides
usually involve reactions of various 5′-oxo nucleoside
derivatives, e.g., 4′-formyl and 4′-acyl nucleosides. Thus,
4′-carbon-substituted nucleosides were prepared years
ago by the Syntex group via an aldol condensation-
Cannizzaro reaction process to give the 4′,4′-bis-hydroxy-
methyl derivatives.7 These diols could then be converted
into other compounds since the R-hydroxymethyl group
is generally more reactive than the â-hydroxymethyl
group,5a,8 an approach that has since been successfully
applied often to the synthesis of more complex deriva-
tives.9 Another very interesting route employs dimethyl
Modified nucleosides have become useful agents for the
treatment of cancer and viral diseases due to their good
antitumor and antiviral activity.1 In particular, several
nucleosides with substituents at the 4′-position are good
candidates as antiviral agents.2 For example, 4′-azido-
thymidine demonstrated very potent anti-HIV activity,
but its high toxicity rendered it ineffectual as an antiviral
drug.3 Other 4′-substitutions, such as fluoro,4 cyano,5 and
even an unusual oxetane,5 have also afforded nucleosides
with strong activity, including anti-HIV activity. Re-
(1) (a) DeClercq, E. Nucleosides Nucleotides 1994, 13, 1271. (b)
Perigaud, C.; Gosselin, G.; Imbach, J . L. Nucleosides Nucleotides 1992,
11, 903. (c) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
(2) For a good review, see: Prisbe, E. J .; Maag, H.; Verheyden, J .
P. H.; Rydzewski, R. M. in Nucleosides and Nucleotides as Antitumor
and Antiviral Agents; Chu, C. K., Baker, D. C., Eds.; Pergamon: New
York, 1993; pp 101-113.
(3) Maag, H.; Rydzewski, R. M.; McRoberts, M. J .; Crawford-Ruth,
D.; Verheyden, J . P. H.; Prisbe, E. J . J . Med. Chem. 1992, 35, 1440.
(4) 4′-Fluoroadenosine and its 5′-sulfamoyl derivative, nucleocidin:
(a) Maguire, A. R.; Meng, W.-d.; Roberts, S. M.; Willetts, A. J . J . Chem.
Soc., Perkin Trans. 1 1993, 1795. (b) J enkins, I. D.; Verheyden, J . P.
H.; Moffatt, J . G. J . Am. Chem. Soc. 1976, 98, 3346. (c) Owens, G. R.;
Verheyden, J . P. H.; Moffatt, J . G. J . Am. Chem. Soc. 1976, 98, 3346.
(d) Guillerm, D.; Muzard, M.; Allart, B.; Guillerm, G. Bioorg. Med.
Chem. Lett. 1995, 5, 1455.
(5) (a) O-Yang, C.; Wu, H. Y.; Fraser-Smith, E.; Walker, K. A. M.
Tetrahedron Lett. 1992, 33, 37. (b) O-Yang, C.; Kurz, W.; Eugui, E.
M.; McRoberts, M. J .; Verheyden, J . P. H.; Kurz, L. J .; Walker, K. A.
M. Tetrahedron Lett. 1992, 33, 41.
(6) J ung, M. E.; Xu, Y. Heterocycles 1998, 47, 349.
(7) (a) Youssefyeh, R. D.; Verheyden, J . P. H.; Moffatt, J . G. J . Org.
Chem. 1979, 44, 1301. (b) J ones, G. H.; Taniguchi, M.; Tegg, D.; Moffatt,
J . G. J . Org. Chem. 1979, 44, 1309.
(8) Maag, H.; Schmidt, B.; Rose, S. J . Tetrahedron Lett. 1994, 35,
6449.
(9) (a) Marx, A.; Erdmann, P.; Senn, M.; Korner, S.; J ungo, T.;
Petretta, M.; Imwinkelried, P.; Dussy, A.; Kulicke, K. J .; Macko, L.;
Zehnder, M.; Giese, B. Helv. Chim. Acta 1996, 79, 1980. (b) Thrane,
H.; Fesnholt, J .; Regner, M.; Wengel, J . Tetrahedron 1995, 51, 10389.
(c) Nomura, M.; Shuto, S.; Tanaka, M.; Sasaki, T.; Mori, S.; Shigeta,
S.; Matsuda, A. J . Med. Chem. 1999, 42, 2901.
10.1021/jo001223a CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/24/2001

Preparation of 4′-Substituted Thymidines
J . Org. Chem., Vol. 66, No. 8, 2001 2625
Sch em e 1
L-tartrate and builds up the 4′-substituted nucleoside in
a multistep sequence.10 Although considerably longer,
this sequence allows for the introduction of both purine
and pyrimidine bases as well as modified bases. We
decided to expand our earlier investigation on the use of
the trianions of thymidine nucleosides6 to determine if
other electrophiles could also be added. Herein we report
the results of our study of the stereochemistry of the
addition of electrophiles to the anions of the 5′-esters of
thymidine.
to remove the diisopropylamine from the complex with
the trianion in order to produce the more reactive
unchelated lithium salt. Thus, we routinely added a full
equivalent of n- or tert-butyllithium to reform the LDA
and thereby remove it from the trianion complex, a
procedure first discovered by Seebach and co-workers and
since often used.13 Thus, deprotonation of the ester 3
using excess LDA (normally about 5-5.6 equiv) followed
by reformation of the LDA with tert-butyllithium and
deuteration gave mainly the R-deuterio thymidylate 4a
(43%), along with a smaller amount of the â-isomer 5a
(18%). This is in agreement with our earlier reported
results, although we were unable at the time to isolate
any of the minor â-isomer 5a . Thus, as we reported,
deuteration occurs primarily, but not exclusively, from
the R-face.
However, when the lithium trianion of 3 was trapped
with other electrophiles, the product of the reaction from
the â face was the major isomer isolated. For example,
phenylselenenyl chloride gave mainly 5b (57%) along
with a small amount of the R-isomer 4b (5%) and allyl
bromide gave mostly the â-isomer 5c (34%) with 9% of
the R-isomer 4c being produced.14 Using the strong,
commercially available fluorinating agent N-fluoro-
benzenesulfonimide (NFSI) as the electrophile afforded
mainly the â-fluoro 3′-sulfonate 5d in 48% yield (under
different conditions, one can isolate the free alcohol 5e
Resu lts a n d Discu ssion
Although several methods exist for the preparation of
thymidylic acid and its derivatives directly from thymi-
dine,11 we opted for a longer approach to guarantee the
purity of the starting materials. Thus we prepared the
tert-butyl ester of thymidylic acid 3 from thymidine 1 by
a multistep route which gave very pure product. We
protected first the 5′-hydroxyl group as the mono-
methoxytrityl (MMTr) ether and then the 3′-hydroxyl as
the tert-butyldiphenylsilyl (TPS) ether. After hydrolysis
of the MMTr ether, we carried out an oxidation with
TEMPO and iodobenzene diacetate (BAIB)12 to give the
acid 2 in nearly quantitative yield over the four steps
(Scheme 1). Formation of the tert-butyl ester with EDCI
and tert-butyl alcohol and desilylation with TBAF af-
forded the desired substrate 3 in 71% yield.
In our earlier study of the triple deprotonation of the
(13) (a) Laube, T.; Dunitz, J . D.; Seebach, D. Helv. Chim. Acta 1985,
68, 1371. (b) Aebi, J . D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1507.
(c) For a review, see: J uaristi, E.; Beck, A. K.; Hansen, J .; Matt, T.
Mukhopadhyay, T.; Simson, M.; Seebach, D. Synthesis 1993, 1271.
(14) It is known that phenylselenenylation of 3′-protected (acetate
or silyl ether) 4′-formyl nucleoside derivatives using PhSeCl and
triethylamine affords mostly the 4′â-selenophenyl aldehydes, although
small amount of the R-isomer are obtained in some cases, e.g., 3-3.8:1
â/R from the dibenzoyladenine derivative, 15:1 from the N-benzoyl-
cytidine derivative, and 100: 0 from the thymidine derivative. (a)
Wackernagel, F.; Schwitter, U.; Giese, B. Tetrahedron Lett. 1997, 38,
2657. (b) Giese, B.; Erdmann, P.; Giraud, L.; Gobel, T.; Petretta, M.;
Schafer, T.; Von Raumer, M. Tetrahedron Lett. 1994, 35, 2683. (c)
Giese, B.; Dussy, A.; Elie, C.; Erdmann, P.; Schwitter, U. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1861. (d) Giese, B.; Erdmann, P.;
Scha¨fer, T.; Schwitter, U. Synthesis 1994, 1310.
analogous methyl ester,6 we found that it was necessary
(10) (a) Crich, D.; Hao, X. J . Org. Chem. 1999, 64, 4016. (b) Crich,
D.; Hao, X. J . Org. Chem. 1998, 63, 3796.
(11) (a) Moss, G. P.; Reese, C. B.; Schofield, K.; Shapiro, R.; Todd,
L. J . Chem. Soc. 1963, 1149. (b) Harmon, R. E.; Zenarosa, C. V.; Gupta,
C. V. Chem. Ind. (London) 1969, 1141. (c) Hutchison, A. J .; Williams,
M.; de J esus, R.; Yokoyama, R.; Oei, H. H.; Ghai, G. R.; Webb, R. L.;
Zoganas, H. C.; Stone, G. A.; J arvis, M. F. J . Med. Chem. 1990, 33,
1919. (d) Olsson, R. A.; Kusachi, S.; Thompson, R. D.; Ukena, D.;
Padgett, W.; Daly, J . W. J . Med. Chem. 1986, 29, 1683. (e) Teng, K.;
Cook, P. D. J . Org. Chem. 1994, 59, 278. (f) Barton, D. H. R.; Gero, S.
D.; Quicletsire, B.; Samadi, M. J . Chem. Soc., Perkin Trans. 1 1991,
981.
(12) Epp, J . B.; Widlanski, T. S. J . Org. Chem. 1999, 64, 293.

2626 J . Org. Chem., Vol. 66, No. 8, 2001
J ung and Toyota
Sch em e 2
Ta ble 1. Ster eoselectivity of Ad d ition of Electr op h iles
(E+) to Ester En ola tes
overall yield. Silylation of the 3′-hydroxyl, removal of the
MMTr group, TEMPO-BAIB oxidation as before, forma-
tion of the methyl ester with trimethylsilyldiazomethane,
and final desilylation with TBAF afforded the desired
substrate 9 in 86% overall yield.
ester
E
R-product
â-product
3
3
3
3
9
9
9
9
9
D
2.4
1
1
0
1
9.3
7.3
8.7
1
1
11.4
3.8
1
1.6
1
1
1
0
SePh
allyl
F
Deprotonation of the ester 9 under the same conditions
as for 3, namely excess LDA (5.4 equiv) followed by
reformation of the LDA with tert-butyllithium (to give
the more reactive unchelated lithium salt) and deutera-
tion, gave mainly the â-deuterio thymidylate 11a (53%)
along with a smaller amount of the R-isomer 10a (21%).
This is again in general agreement with our earlier
results in which the deuterium atom is introduced mostly
cis to the existing hydroxyl group. However, when the
lithium anion of 9 was trapped with other electrophiles,
the R product was the major isomer isolated, e.g.,
phenylselenenyl chloride gave mainly 10b (56%) along
with a small amount of the R-isomer 11b (6%), and
methyl iodide gave mostly the R-isomer 10c (44% and
an additional 14% of the O-methyl derivative) with 8%
of the â-isomer 11c being produced. Allyl bromide af-
forded a similar mixture with the â-isomer 10d greatly
predominating (52%) over the R-isomer (6%). Again, use
of the strong fluorinating agent (NFSI) as the electrophile
afforded mainly the â-fluoro 3′-sulfonate 10e in 49% yield
(under different conditions, one can isolate the free
alcohol 10f in 30% yield along with 15% of 10e). The
structures of the products 10bcd were again proven by
reduction of the esters to the corresponding primary
alcohols 12bcd with LiBH4 followed by formation of the
acetonides 13bcd with acidic dimethoxypropane.15 Once
more, control experiments showed that the trans-oriented
diol did not form an acetonide under these conditions.
The results of the addition of electrophiles to the trianion
of 9 are shown in Table 1.
D
SePh
allyl
Me
F
in 21% yield along with 19% of 5d ). The structures of
the products 5bc were proven by reduction of the esters
to the corresponding primary alcohols 6bc with lithium
borohydride followed by formation of the acetonides 7bc
with acidic dimethoxypropane.15 Control experiments
showed that the trans-oriented diol did not form an
acetonide under these conditions therefore proving that
the ester group in 5 was cis to the hydroxyl group. The
results of the addition of electrophiles to the trianion
derived from 3 are shown in Table 1.
We also investigated deprotonations and functional-
izations of the 3′-epimer of thymidylic esters, namely the
methyl ester 9.16 This substrate was prepared as follows.
First, inversion of the 3′-hydroxyl of 1 was carried out
by a four-step sequence involving initial MMTr protection
of the 5′-hydroxyl of 1 followed by mesylation, formation
of the anhydro nucleoside, and hydrolysis to give 8 in 86%
(15) The diols derived from the fluoro nucleosides, e.g., 6d and 12e,
did not give clean acetonides under these conditions. Their structures
were assigned by the pattern of coupling constants in the proton NMR,
3
especially the J H-F, and by analogy to the formation of the other
derivatives.
(16) We were unable to prepare the corresponding tert-butyl ester
due to steric hindrance caused by the large tert-butyldiphenylsilyl
(TPS) ether at the 3′â position. Normally the methyl ester is not
preferred since side products can arise via attack of some nucleophilic
species (the ester enolate or LDA itself) on the methyl ester. However,
presumably due to the steric hindrance around this methyl ester, we
do not observe a significant amount of side products of the sort
mentioned above during the formation and reaction of the trianion.
Trapping of the anions of nucleosides having carbonyl
groups at the 4′-position with the 3′R-hydroxyl protected
with electrophiles are known and generally give mostly
the â products.14 We believe that the selectivity observed

Preparation of 4′-Substituted Thymidines
J . Org. Chem., Vol. 66, No. 8, 2001 2627
Sch em e 3. Obser ved (Top ) a n d Ca lcu la ted
Sch em e 5. P r esu m ed Tr a n sition Sta tes for
Electr op h ilic Ad d ition s to th e En ola tes of 3 a n d 9
(Bottom ) J Va lu es in 1H NMR Sp ectr a of 3 a n d 9
by assuming that the anions adopt conformations similar
to those calculated for the dimethylketene acetals I-IV.
Thus, we expect the trianion of 3 to adopt the conforma-
tion shown in V (analogous to I) while the trianion of 9
adopts the conformation shown in VI (analogous to II).
The stereochemical course of the reaction can then be
explained by assuming that the electrophilic agents
approach the carbanionic center from the face opposite
the 3′-alkoxide group which is in a pseudoaxial arrange-
ment in both V and VI. Attack of the enolate on the
electrophile would occur in the staggered axial orienta-
tion due to torsional strain, e.g., on the top face of V and
on the bottom face of VI as shown. This “conformational
transmission of chirality” via staggered axial attack on
an sp2 carbon center has been postulated to account for
the high diastereoselectivity seen in additions to other
half-chair conformations.18
Sch em e 4. Ma cr om od el 5.0 Str a in En er gy
Ca lcu la tion s
The deuteration results can be rationalized by assum-
ing that there is a small amount of net complexation of
the deuterium source with the 3′-alkoxide group prior to
protonation and this leads to a small preference for
protonation cis to the alkoxy group, 2.4:1 and 1.6:1 for
the trianions of 3 and 9 respectively.
We have just begun to examine the further chemistry
of these novel 4′-substituted nucleoside derivatives, e.g.,
the transformation of the products into other useful
nucleoside derivatives. The results of those experiments
will be reported in due course. The preparation and
testing of these and other novel nucleoside analogues is
currently underway in our laboratories.
here is due to the conformation adopted by the nucleo-
side in its trianionic form. We have analyzed the confor-
mations of the precursor esters 3 and 9 by coupling
constant analysis and by molecular mechanics calcula-
tions (Macromodel 5.0). These two molecules exist in
opposite half-chair conformations, with 3 preferring the
3′-exo conformation and 9 existing in the 3′-endo confor-
mation, as shown in Scheme 3.17 The key coupling
constants are as follows: (a) the one between H3′ and
H4′, which is very small (∼0 Hz) in 3 and medium (4.2
Hz) in 9; (b) the one between H1′ and H2′â, which is large
(9.3 Hz) in 3 and small (2.6 Hz) in 9. The corresponding
calculated values for the minimized structures (both
methyl esters) are also given in Scheme 3 for comparison
purposes. The overall match is quite good. Thus, both
molecules prefer conformations in which the hydroxyl
group prefers a pseudoaxial position. We have also
calculated the preferred conformations of the dimethyl-
ketene acetals I-IV as models for the lithium enolates
of the esters 3 and 9 in the two possible half-chair
conformations (Scheme 4). For the enolate derived from
the ester 3, the 3′-exo conformation I is greatly favored
over the corresponding 3′-endo conformation III (by about
4 kcal/mol), while for the enolate derived from the ester
9, the 3′-endo conformation II is greatly favored over the
corresponding 3′-exo conformation IV (by about 5 kcal/
mol). Presumably, this difference is due in part to the
steric repulsion of the pseudoequatorial hydroxyl group
with the alkoxy group on the alkene.
Con clu sion
We have shown that electrophilic trapping of the
lithium trianion of tert-butyl thymidylate 3 occurs
stereoselectively from either the R- or â-face depending
on the electrophile (Scheme 1). Deuterioacetic acid in
deuteriomethanol affords mainly the R-deuterated prod-
uct (4a /4b ) 2.4:1) while all other electrophiles, e.g.,
phenylselenenyl chloride, allyl bromide, and N-fluoro-
benzenesulfonimide (NFSI), give predominately (or com-
pletely) the products of attack from the â-face (5bcd /4bcd
) 3.7:1 to 100:0). The structures of the products were
determined by coupling constant analysis of both the
initial compounds and the diols 6bcd prepared by ester
reduction and by formation of the acetonides 7bc. In
similar fashion, electrophilic trapping of the lithium
trianion of the methyl ester of the 3′-epimer of thymidylic
acid 9 also occurs stereoselectively with attack on either
the R- or â-face depending on the electrophile (Scheme
2). Again deuterioacetic acid in deuteriomethanol affords
mainly the â-deuterated product (11a /10a ) 1.6:1) while
all other electrophiles, e.g., phenylselenenyl chloride,
methyl iodide, allyl bromide, and NFSI, gave predomi-
nately (or completely) the product of attack from the
We rationalize the diastereoselectivity of the alkylation
of the trianions of 3 and 9 as shown in Scheme 5, namely
(17) Altona, C.; Sundaralingam, M. J . Am. Chem. Soc. 1972, 94,
8205.
(18) Lucero, M. J .; Houk, K. N. J . Am. Chem. Soc. 1997, 119, 826
and references therein.

2628 J . Org. Chem., Vol. 66, No. 8, 2001
J ung and Toyota
1-[(2R,4S,5R)-5-[bis(4-methoxyphenyl)phenylmethoxymethyl]-
4-hydroxytetrahydrofuran-2-yl]-5-methyl-1H-pyrimidine-2,4-
dione (498 mg, 0.968 mmol) in DMF (3.5 mL) were added
imidazole (315 mg, 4.63 mmol) and TBDPSCl (0.40 mL, 1.54
mmol) at room temperature, and the mixture was stirred at
the same temperature for 54 h. After being quenched with
water, the mixture was extracted with Et2O (3 × 25 mL) and
dried over MgSO4. After removal of the solvent, the residue
was purified by flash chromatography (hexane/ethyl acetate
) 3:1) to give 1-[(2R,4S,5R)-5-[bis(4-methoxyphenyl)phenyl-
methoxymethyl]-4-(tert-butyldiphenylsilanyloxy)tetrahydrofuran-
2-yl]-5-methyl-1H-pyrimidine-2,4-dione (726 mg, 100%) as a
colorless foam: [R]21D ) +41° (c ) 0.58, CHCl3); IR (neat) 3056,
2955, 2932, 1692, 1510, 1472, 1449, 1428, 1273, 1252, 1181,
R-face (8.7:1 to 100:0). Again, the structures of the
products were determined by coupling constant analysis
of both the initial compounds and the diols 12b-e were
prepared by reduction of the ester and by formation of
the acetonides 13bcd . A rationale has been developed
using molecular mechanics calculations to explain the
diastereoselectivity, which involves staggered axial at-
tack on the sp2 carbon opposite to the pseudoaxial alkoxy
group in the most stable half-chair conformation of the
enolates, as shown in Schemes 3-5.
Exp er im en ta l Section
1
1113, 1065, 1034, 999, 826, 756, 702, 613 cm-1; 400 MHz H
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
NMR (CDCl3) δ 1.06 (9H, s), 1.38 (3H, s), 2.09 (1H, ddd, J )
13.5, 7.5, 6.3 Hz), 2.40 (1H, dd, J ) 13.5, 5.5 Hz), 2.92 (1H,
dd, J ) 10.5, 2.2 Hz), 3.24 (1H, dd, J ) 10.5, 2.2 Hz), 3.79
(3H, s), 4.09 (1H, s), 4.57 (1H, m), 6.52 (1H, dd, J ) 7.5, 5.5
Hz), 6.77 (2H, d, J ) 8.5 Hz), 7.15 (2H, d, J ) 8.5 Hz), 7.2-7.3
(12H, m), 7.35-7.47 (4H, m), 7.50 (1H, s), 7.56 (2H, d, J ) 7.4
Hz), 7.63 (2H, d, J ) 7.4 Hz), 9.09 (1H, br s); 100 MHz 13C
NMR (CDCl3) δ 11.72 (C5-Me), 19.03 (CMe3), 26.89 (CMe3),
41.16 (C2′), 55.27 (OCH3), 63.44 (C5′), 73.96 (C3′), 88.87 (C4′),
86.77 (C1′), 87.07 (CAr3), 111.11 (C5), 113.23 (o-C × 2 of
MeOAr), 127.16 (1C of Ph), 127.20 (1C of Ph), 127.87 (2C of
Ph), 127.91 (2C of Ph), 127.96 (2C of Ph), 127.97 (2C of Ph),
128.31 (2C of Ph), 128.35 (2C of Ph), 130.00 (1C of Ph), 130.06
(1C of Ph), 130.35 (2C of Ph), 133.06 (1C of Ph), 133.09 (1C of
Ph), 134.79 (p-C of MeOAr), 135.67 (2C of Ph), 135.72 (2C of
Ph), 135.72 (C4), 143.75 (m-C of MeOAr), 143.84 (m-C of
MeOAr), 150.46 (C6), 158.72 (C-OMe), 163.98 (C2).
on Bruker spectrometers at 200 or 400 MHz for proton and at
50 or 100 MHz for carbon and are so indicated. H NMR and
1
13C NMR data are reported in parts per million (δ) downfield
from tetramethylsilane. The following abbreviations are
used: s ) singlet, d ) doublet, t ) triplet, q ) quartet, m )
multiplet, br ) broad. Infrared spectra were recorded on a
Nicolet 510 infrared spectrophotometer as a liquid film or as
a thin crystalline film. All IR data are reported in wave-
numbers (cm-1).
Thin-layer chromatography (TLC) was performed using
Merck silica gel 60 F254 0.25 mm plates. Visualization was
accomplished using ultraviolet light or one of the following
stains: Anisaldehyde (2 mL), acetic acid (1 mL), or sulfuric
acid (2 mL) in 95% ethanol (85 mL). Flash chromatography
was carried out using ICN Biomedicals silica gel 60 (230-400
mesh). Solvent systems are reported as volume percent
mixtures. Concentration or evaporation of solvent refers to
removal at reduced pressure using a Bu¨chi rotary evaporator
and a Bu¨chi aspirator pump. All inorganic solutions are
aqueous and concentrations are indicated in percent weight,
except for saturated sodium chloride and saturated sodium
bicarbonate.
1-[(2R,4S,5R)-4-(ter t-Bu t yld ip h en ylsila n yloxy)-5-h y-
d r oxym eth yltetr a h yd r ofu r a n -2-yl]-5-m eth yl-1H-p yr im i-
d in e-2,4-d ion e. To
a solution of 1-[(2R,4S,5R)-5-[bis(4-
methoxyphenyl)phenylmethoxymethyl]-4-(tert-butyldiphenyl-
silanyloxy)tetrahydrofuran-2-yl]-5-methyl-1H-pyrimidine-2,4-dione
(90 mg, 0.12 mmol) in MeOH (6 mL) was added Amberlyst
15-H (53 mg) at room temperature, and the mixture was
stirred for 30 h. After filtration, the solvent was evaporated
in vacuo. The residue was purified by flash chromatography
(hexane/ethyl acetate ) 1:1-1:2) to give 1-[(2R,4S,5R)-4-(tert-
butyldiphenylsilanyloxy)-5-hydroxymethyltetrahydrofuran-2-
yl]-5-methyl-1H-pyrimidine-2,4-dione (58 mg, 100%) as a
colorless foam: [R]22D ) +39° (c ) 0.60, CHCl3); IR (neat) 3440,
3071, 2932, 2859, 1690, 1472, 1428, 1364, 1275, 1198, 1105,
1061, 1032, 960, 824, 756, 741, 702, 612 cm-1; 400 MHz 1H
NMR (CDCl3) δ 1.09 (9H, s), 1.82 (3H, s), 2.14 (1H, ddd, J )
13.5, 8, 6 Hz), 2.26 (1H, ddd, J ) 13.5, 6, 3 Hz), 2.45 (1H, br),
3.25 (1H, dd, J ) 12, 2.5 Hz), 3.63 (1H, dd, J ) 12, 2.5 Hz),
3.98 (1H, dt, J ) 3, 2.5 Hz), 4.45 (1H, ddd, J ) 6, 3 Hz), 6.26
(1H, dd, J ) 8, 6 Hz), 7.30 (1H, s), 7.35-7.5 (6H, m), 7.62-
7.66 (4H, m), 9.20 (1H, br); 100 MHz 13C NMR (CDCl3) δ 12.47
(C5-Me), 19.04 (CMe3), 26.91 (CMe3), 40.27 (C2′), 62.02 (C5′),
73.01 (C3′), 86.67 (C4′), 87.72 (C1′), 110.95 (C5), 127.92 (4C of
Ph), 130.11 (1C of Ph), 130.15 (1C of Ph), 133.10 (1C of Ph),
133.24 (1C of Ph), 135.72 (2C of Ph), 135.77 (2C of Ph), 136.91
(C4), 150.45 (C6), 163.94 (C2).
(2S,3S,5R)-3-(ter t-Bu tyld ip h en ylsila n yloxy)-5-(5-m eth -
yl-2,4-d ioxo-3,4-d ih yd r o-2H-p yr im id in -1-yl)-tetr a h yd r o-
fu r a n -2-ca r boxylic Acid (2). To a solution of 1-[(2R,4S,5R)-
4-(tert-butyldiphenylsilanyloxy)-5-hydroxymethyltetrahydro-
furan-2-yl]-5-methyl-1H-pyrimidine-2,4-dione (124 mg, 0.258
mmol) in CH2Cl2 (1.3 mL) were added 2,2,6,6-tetramethyl-1-
piperidinyloxy, free radical (TEMPO) (9 mg, 0.06 mmol), and
iodobenzene diacetate (BAIB) (184 mg, 0.570 mmol) at room
temperature. After the mixture was stirred for 2 h, a mixture
of MeCN-water (1:1) (0.014 mL) was added to the reaction
mixture, and the mixture was stirred for 24 h. After removal
of the solvent, the residue was purified by flash chromatog-
raphy (CHCl3-MeOH ) 10:1) to give (2S,3S,5R)-3-(tert-
butyldiphenylsilanyloxy)-5-(5-methyl-2,4-dioxo-3,4-dihydro-
2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid 2 (128
mg, 100%) as a colorless foam: [R]22D ) +72° (c ) 0.60, CHCl3-
MeOH ) 10:1); IR (neat) 3071, 2957, 2932, 2859, 1713, 1674,
The following solvents and reagents were distilled from the
indicated agent under argon: tetrahydrofuran (THF) and
diethyl ether from sodium benzophenone ketyl; dichloromethane
and triethylamine from calcium hydride. All reactions were
performed under argon unless otherwise noted.
1-[(2R,4S,5R)-5-[Bis(4-m eth oxyph en yl)ph en ylm eth oxy-
m eth yl]-4-h ydr oxytetr ah ydr ofu r an -2-yl]-5-m eth yl-1H-pyr -
im id in e-2,4-d ion e. To a solution of thymidine (157 mg, 0.648
mmol) in DMF (1.5 mL) were added triethylamine (0.23 mL,
1.65 mmol), DMAP (6 mg, 0.05 mmol), and 4-monomethoxy-
trityl chloride (400 mg, 1.30 mmol) at room temperature, and
the mixture was stirred at the same temperature for 3.5 h.
After being quenched with water, the mixture was extracted
with CH2Cl2 (3 × 15 mL) and dried over MgSO4. After removal
of the solvent, the residue was purified by flash chromatog-
raphy (hexane/ethyl acetate ) 1:2, ethyl acetate) to give
1-[(2R,4S,5R)-5-[bis(4-methoxyphenyl)phenylmethoxymethyl]-
4-hydroxytetrahydrofuran-2-yl]-5-methyl-1H-pyrimidine-2,4-
dione (330 mg, 99%) as a colorless foam: [R]22 ) +10° (c )
D
0.33, CHCl3); IR (neat) 3058, 1690, 1609, 1510, 1470, 1449,
1271, 1252, 1181, 1092, 1059, 1034, 831, 737, 702 cm-1; 400
MHz 1H NMR (CDCl3) δ 1.45 (3H, d, J ) 1.1 Hz), 2.31 (1H,
ddd, J ) 13.6, 8, 6 Hz), 2.44 (1H, ddd, J ) 13.6, 5.8, 2.5 Hz),
3.10 (1H, d, J ) 4.4 Hz), 3.37 (1H, dd, J ) 10.5, 3 Hz), 3.45
(1H, dd, J ) 10.5, 3 Hz), 3.78 (3H, s), 4.08 (1H, dt, J ) 2.8, 2.8
Hz), 4.58 (1H, m), 6.44 (1H, dd, J ) 8, 5.8 Hz), 6.84 (2H, m),
7.22-7.32 (8H, m), 7.38-7.43 (4H, m),7.60 (1H, d, J ) 1.1 Hz),
9.41 (1H, br s); 100 MHz 13C NMR (CDCl3) δ 11.86 (C5-Me),
40.98 (C2′), 55.28 (OCH3), 63.75 (C5′), 72.52 (C3′), 84.81 (C4′),
86.29 (C1′), 87.20 (CAr3), 111.36 (C5), 113.31 (o-C × 2 of
MeOAr), 127.30 (1C of Ph), 127.31 (1C of Ph), 128.04 (4C of
Ph), 128.38 and 30.42 (2C of Ph), 134.87 (p-C of MeOAr),
135.73 (C4), 143.82 (m-C of MeOAr), 143.90 (m-C of MeOAr),
150.67 (C6), 158.80 (C-OMe), 164.02 (C2).
1-[(2R,4S,5R)-5-[Bis(4-m eth oxyph en yl)ph en ylm eth oxy-
m eth yl]-4-(ter t-bu tyldiph en ylsilan yloxy)tetr ah ydr ofu r an -
2-yl]-5-m eth yl-1H-p yr im id in e-2,4-d ion e. To a solution of

Preparation of 4′-Substituted Thymidines
J . Org. Chem., Vol. 66, No. 8, 2001 2629
1472, 1428, 1279, 1227, 1107, 1084, 741, 702, 610 cm-1; 200
MHz 1H NMR (CDCl3-CD3OD ) 10:1) δ 1.00 (9H, s), 1.67 (1H,
ddd, J ) 13.5, 9.5, 4.4 Hz), 1.78 (3H, s), 2.13 (1H, dd, J ) 13.5,
5 Hz), 4.48 (1H, s), 4.52 (1H, d, J ) 4.4 Hz), 6.53 (1H, dd, J )
9.5, 5 Hz), 7.29 (6H, m), 7.56 (4H, m), 8.04 (1H, s); 50 MHz
13C NMR (CDCl3-CD3OD ) 10:1) δ 16.25 (C5-Me), 22.92
(CMe3), 30.65 (CMe3), 43.28 (C2′), 80.65 (C3′), 89.30 (C4′), 90.62
(C1′), 114.86 (C5), 131.74 (2C of Ph), 131.80 (2C of Ph), 133.92
(1C of Ph), 134.00 (1C of Ph), 136.47 (1C of Ph), 136.67 (1C of
Ph), 139.60 (2C of Ph), 139.66 (2C of Ph), 141.07 (C4), 154.65
(C6), 168.54 (C2), 177.8 (C5′).
purified by flash chromatography (hexane/ethyl acetate ) 2:3-
1:2) to give a 7:1 mixture of 4a and 3 (14 mg, 50%) and a 7:1
mixture of 5a and the C4′-stereoisomer of 3 (5.2 mg, 18%).
(2S,3S,5R)-4-Deuterio-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid
tert-butyl ester 4a (colorless foam): [R]21 ) +27° (c ) 0.29,
D
CHCl3-MeOH ) 20:1); IR (neat) 3386, 3241, 1732, 1717, 1655,
1
1476, 1372, 1294, 1273, 1204, 1088 cm-1; 400 MHz H NMR
(CDCl3-CD3OD ) 20:1) δ 1.45 (9H, s), 1.90 (1H, ddd, J ) 13.5,
9.2, 4.3 Hz), 1.90 (3H, d, J ) 1.2 Hz), 2.33 (1H, ddd, J ) 13.5,
5.1, 1 Hz), 4.43 (1H, d, J ) 4.3 Hz), 6.43 (1H, dd, J ) 9.2, 5.1
Hz), 8.11 (1H, d, J ) 1.2 Hz); 13C NMR (CDCl3-CD3OD ) 20:
1) δ 16.41 (C5-Me), 31.83 (CMe3), 42.94 (C2′), 78.38 (C3′), 86.79
(CMe3), 89.25 (small peak, C4′), 90.37 (C1′), 115.10 (C5), 140.46
(C4), 154.77 (C6), 168.34 (C2), 174.51 (C5′).
(2S,3S,5R)-3-(ter t-Bu tyld ip h en ylsila n yloxy)-5-(5-m eth -
yl-2,4-d ioxo-3,4-d ih yd r o-2H -p yr im id in -1-yl)t et r a h yd r o-
fu r a n -2-ca r boxylic Acid ter t-Bu tyl Ester . To a solution of
2 (430 mg, 0.870 mmol) in CH2Cl2 (3.2 mL) were added t-BuOH
(0.80 mL, 8.37 mmol), DMAP (304 mg, 2.49 mmol), and 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
(1.05 g, 5.48 mmol) at 0 °C, and the mixture was stirred at 0
°C for 30 min and room temperature for 23 h. After being
quenched with water, the mixture was extracted with CH2Cl2
and dried over MgSO4. After removal of the solvent, the
residue was purified by flash chromatography (hexane/ethyl
acetate ) 3:1) to give (2S,3S,5R)-3-(tert-butyldiphenylsilanyl-
oxy)-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetra-
hydrofuran-2-carboxylic acid tert-butyl ester (333 mg, 100%)
as a colorless foam: [R]22D ) +65° (c ) 0.70, CHCl3); IR (neat)
3071, 2961, 2932, 1738, 1696, 1472, 1427, 1279, 1221, 1130,
(2R,3S,5R)-4-Deuterio-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid
tert-butyl ester 5a (colorless foam): [R]22 ) +32° (c ) 0.20,
D
CHCl3-MeOH ) 20:1); IR (neat) 3455, 3208, 1742, 1723, 1673,
1
1267, 1105, 1086 cm-1; 400 MHz H NMR (CDCl3-CD3OD )
20:1) δ 1.46 (9H, s), 1.85 (3H, d, s), 2.29 (1H, ddd, J ) 13.5,
7.3, 5.7 Hz), 2.46 (1H, ddd, J ) 13.5, 6.5, 2 Hz), 4.68 (1H, dd,
J ) 5.7, 2 Hz), 4.73 (1/7 H, d, J ) 4.4 Hz), 6.20 (1H, dd, J )
7.3, 6.5 Hz), 7.09 (1H, s); 13C NMR (CDCl3-CD3OD ) 20:1) δ
16.21 (C5-Me), 31.88 (CMe3), 44.06 (C2′), 76.05 (C3′), 85,19
(small peak, C4′), 86.77 (CMe3), 92.49 (C1′), 114.81 (C5), 140.53
(C4), 154.25 (C6), 168.25 (C2), 172.19 (C5′).
1
1105, 1084, 739, 702, 608 cm-1; 400 MHz H NMR (CDCl3) δ
(2S,4S,5R)-3-Hydr oxy-5-(5-m eth yl-2,4-dioxo-3,4-dih ydr o-
2H-p yr im id in -1-yl)-2-(p h en ylselen en yl)tetr a h yd r ofu r a n -
2-ca r boxylic Acid ter t-Bu tyl Ester (5b). The ester 3 (8 mg)
was coevaporated with benzene, dried in vacuo, dissolved in
THF (1.0 mL)-HMPA (0.13 mL), and dried under molecular
sieves 4A (three pieces) with stirring for 1 h. To the solution
of 3 (7.5 mg, 0.024 mmol) was added lithium diisopropylamide
mono(tetrahydrofuran) (LDA) (Aldrich, 1.5 M in cyclohexane,
0.090 mL, 0.14 mmol) at -78 °C, and the mixture was stirred
at -78 °C for 5 min, -78 °C f room temperature for 10 min,
and room temperature for 30 min. tert-Butyllithium (1.7 M in
pentane, 0.065 mL, 0.11 mmol) was added to the solution at
-78 °C, and the mixture was stirred at -78 °C for 1 h. To the
solution was added phenylselenenyl chloride (52 mg, 0.27
mmol) in THF (0.1 mL) at -78 °C, and the mixture was stirred
at the same temperature for 1 h. After the reaction was
quenched with MeOH (0.09 mL)-AcOH (0.03 mL), the solvent
was evaporated in vacuo. The residue was purified by flash
chromatography (hexane/ethyl acetate ) 2:3) to give (2S,4S,5R)-
3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-
yl)-2-(phenylselenenyl)tetrahydrofuran-2-carboxylic acid tert-
butyl ester 5b (6.4 mg, 57%) as a colorless foam and (2R,3S,5R)-
3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-
yl)-2-(phenylselenenyl)tetrahydrofuran-2-carboxylic acid tert-
butyl ester 4b (0.6 mg, 5%) as a colorless foam.
1.10 (9H, s), 1.36 (9H, s), 1.77 (1H, ddd, J ) 13.5, 9.6, 5 Hz),
1.94 (3H, d, J ) 1 Hz), 2.25 (1H, dd, J ) 13.5, 5 Hz), 4.47 (1H,
s), 4.49 (1H, d, J ) 5 Hz), 6.68 (1H, dd, J ) 9.6, 5 Hz), 7.38-
7.5 (6H, m), 7.66 (4H, m), 8.11 (1H, d, J ) 1 Hz), 9.3 (1H, br);
13C NMR (CDCl3-CD3OD ) 10:1) δ 12.69 (C5-Me), 19.14
(CMe3), 26.85 (CMe3), 27.91 (CMe3), 39.38 (C2′), 76.60 (C3′),
82.61 (CMe3), 85.49 (C4′), 86.44 (C1′), 111.17 (C5), 127.94 (2C
of Ph), 128.00 (2C of Ph), 130.12 (1C of Ph), 130.19 (1C of Ph),
132.61 (1C of Ph), 132.72 (1C of Ph), 135.71 (2C of Ph), 135.73
(2C of Ph), 136.48 (C4), 150.64 (C6), 164.14 (C2), 170.34 (C5′).
(2S,3S,5R)-3-Hydr oxy-5-(5-m eth yl-2,4-dioxo-3,4-dih ydr o-
2H-pyr im idin-1-yl)tetr ah ydr ofu r an -2-car boxylic Acid ter t-
Bu tyl Ester (3). To (2S,3S,5R)-3-(tert-butyldiphenylsilanyloxy)-
5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydro-
furan-2-carboxylic acid tert-butyl ester (333 mg, 0.605 mmol)
in THF (6.8 mL) was added TBAF (1 M in THF, 0.60 mL) at
0 °C, and the mixture was stirred at the same temperature
for 1.5 h. After being quenched with water, the mixture was
extracted with CH2Cl2 and dried over MgSO4. After removal
of the solvent, the residue was purified by flash chromatog-
raphy (hexane/ethyl acetate ) 1:2-1:4) to give 3 (184 mg, 97%)
as a colorless foam: [R]22 ) +23° (c ) 0.32, CHCl3-MeOH )
D
20:1); IR (neat) 3389, 3241, 1734, 1717, 1657, 1476, 1372, 1333,
1292, 1275, 1213, 1161, 1121, 1096, 1071, 621 cm-1; 400 MHz
1H NMR (CDCl3-CD3OD ) 20:1) δ 1.44 (9H, s), 1.89 (1H, ddd,
J ) 13.5, 9.3, 4.6 Hz), 1.89 (3H, d, J ) 1.2 Hz), 2.33 (1H, ddd,
J ) 13.5, 5.1, 0.7 Hz), 4.35 (1H, s), 4.42 (1H, d, J ) 4.6 Hz),
6.43 (1H, dd, J ) 9.3, 5.1 Hz), 8.11 (1H, d, J ) 1.2 Hz); 13C
NMR (CDCl3-CD3OD ) 20:1) δ 16.41 (C5-Me), 31.82 (CMe3),
42.93 (C2′), 78.44 (C3′), 86.79 (CMe3), 89.25 (C4′), 90.38 (C1′),
115.09 (C5), 140.50 (C4), 154.81 (C6), 168.43 (C2), 174.53 (C5′).
(2S,3S,5R)-4-Deu ter io-3-h yd r oxy-5-(5-m eth yl-2,4-d ioxo-
3,4-d ih yd r o-2H -p yr im id in -1-yl)t et r a h yd r ofu r a n -2-ca r -
boxylic Acid ter t-Bu tyl Ester (4a ). The ester 3 (30 mg) was
coevaporated with benzene, dried in vacuo, dissolved in THF
(3.9 mL)-HMPA (0.48 mL), and dried under molecular sieves
4 Å with stirring for 1 h. To the solution of 3 (28 mg, 0.090
mmol) was added lithium diisopropylamide mono(tetrahydro-
furan) (LDA) (Aldrich, 1.5 M in cyclohexane, 0.35 mL, 0.53
mmol) at -78 °C, and the mixture was stirred at -78 °C for
5 min, -78 °C f room temperature for 10 min, and at room
temperature for 30 min. tert-Butyllithium (1.7 M in pentane,
0.25 mL, 0.43 mmol) was added to the solution at -78 °C, and
the mixture was stirred at -78 °C for 1 h. To the solution were
added CD3OD (0.34 mL) and CD3CO2D (0.11 mL) at -78 °C,
and the mixture was stirred at -78 °C f room temperature
for 30 min. After removal of the solvent, the residue was
(2S,4S,5R)-3-Hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-
pyrimidin-1-yl)- 2-(phenylselenenyl)tetrahydrofuran-2-carbox-
ylic acid tert-butyl ester 5b: [R]22D ) +84° (c ) 0.5, CHCl3); IR
(neat) 3400, 1698, 1474, 1370, 1273, 1159, 1084, 1063, 747,
1
667 cm-1; 400 MHz H NMR (CDCl3) δ 1.35 (9H, s), 1.89 (3H,
d, J ) 1.2 Hz), 2.50 (1H, ddd, J ) 13.5, 9.2, 4.3 Hz), 2.57 (1H,
ddd, J ) 13.5, 6, 1.2 Hz), 3.31 (1H, br s), 4.71 (1H, m), 6.86
(1H, dd, J ) 9.2, 6 Hz), 7.33 (2H, m), 7.39 (1H, m), 7.62 (3H,
m), 8.74 (1H, br s); 13C NMR (CDCl3) δ 12.61 (C5-Me), 27.81
(CMe3), 37.55 (C2′), 71.11 (C3′), 84.28 (CMe3), 87.64 (C4′), 92.97
(C1′), 111.97 (C5), 126.88 (p-C of Ph), 129.28 (C-Se), 129.31
(2C of Ph), 135.71 (2C of Ph), 135.91 (C4), 150.28 (C6), 163.39
(C2), 167.23 (C5′).
(2R,3S,5R)-3-Hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-
pyrimidin-1-yl)-2-(phenylselenenyl)tetrahydrofuran-2-carbox-
1
ylic acid tert-butyl ester 4b: 400 MHz H NMR (CDCl3) δ 1.35
(9H, s), 1.92 (3H, d, J ) 1.2 Hz), 2.29 (1H, ddd, J ) 13.7, 7.6,
5.2 Hz), 2.65 (1H, ddd, J ) 13.6, 7.4, 6.8 Hz), 3.25 (1H, br s),
4.76 (1H, m), 6.38 (1H, dd, J ) 7.4, 5.2 Hz), 7.33 (2H, m), 7.39
(1H, m), 7.62 (3H, m), 8.74 (1H, br s).
1-(2R,4S,5R)-4-H yd r oxy-5-h yd r oxym et h yl-5-p h en yl-
selen en yltetr a h yd r ofu r a n -2-yl)-5-m eth yl-1H-p yr im id in e-
2,4-d ion e (6b). To a solution of 5b (12 mg, 0.026 mmol) in

2630 J . Org. Chem., Vol. 66, No. 8, 2001
J ung and Toyota
THF (0.8 mL) was added LiBH4 (2 mg, 0.092 mmol) at room
temperature, and the mixture was stirred for 1 h. After the
reaction was quenched with EtOH (0.25 mL) for 0.5 h and
neutralized with AcOH (0.01 mL) for 0.5 h, the solvent was
evaporated in vacuo. The residue was purified by flash
chromatography (hexane/ethyl acetate ) 1:2 to ethyl acetate)
to give 1-(2R,4S,5R)-4-hydroxy-5-hydroxy-methyl-5-phenyl-
selenenyltetrahydrofuran-2-yl)-5-methyl-1H-pyrimidine-2,4-
(1H, m), 6.35 (1H, dd, J ) 6.6, 6.6 Hz), 7.19 (1H, d, J ) 1 Hz),
8.70 (1H, br s); 13C NMR (CDCl3) δ 12.60 (C5-Me), 28.11
(CMe3), 39.00 (C2′), 40.64 (allyl), 75.46 (C3′), 83.45 (CMe3),
86.20 (C4′), 89.81 (C1′), 111.08 (C5), 119.91 and 131.64 (vinyl
of allyl), 135.84 (C4), 149.99 (C6), 163.58 (C2), 170.33 (C5′).
(2R,3S,5R)-2-Methyl-3-(2-propenyloxy)-5-(5-methyl-2,4-dioxo-
3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid
tert-butyl ester 5c′ (colorless foam): 400 MHz 1H NMR (CDCl3)
δ 1.49 (9H, s), 1.91 (3H, d, J ) 1.2 Hz), 2.18 (1H, ddd, J )
13.5, 6.8, 6.5 Hz), 2.54 (2H, m), 2.47 (1H, dd, J ) 13.5, 6.6
Hz), 4.05 (2H, m), 4.15 (1H, m), 5.15-5.35 (4H, m), 5.75-5.95
(2H, m), 6.32 (1H, dd, J ) 6.6, 6.5 Hz), 7.19 (1H, d, J ) 1.2
Hz), 8.16 (1H, br).
(2S,3S,5R)-3-Hydroxy-2-methyl-5-(5-methyl-2,4-dioxo-3,4-di-
hydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid tert-
butyl ester 4c (colorless foam): 400 MHz 1H NMR (CDCl3) δ
1.50 (9H, s), 1.96 (3H, d, J ) 1.2 Hz), 2.03 (1H, ddd, J ) 13.5,
8.8, 5 Hz), 2.46 (1H, ddd, J ) 13.5, 5, 2 Hz), 2.66 (2H, m), 4.59
(1H, dd, J ) 5, 1.8 Hz), 4.46 (1H, m), 5.19 (2H, m), 5.84 (1H,
m), 6.43 (1H, dd, J ) 8.8, 5 Hz), 8.02 (1H, d, J ) 1.2 Hz), 8.22
(1H, br).
dione 6b (7 mg, 68%) as a colorless foam: [R]22 ) +181° (c )
D
0.15, CHCl3); IR (neat) 3397, 2924, 2853, 1692, 1468, 1275,
1042, 741 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.94 (3H, s), 2.56
(2H, m), 3.29 (1H, br), 3.87 (1H, d, J ) 13 Hz), 3.92 (1H, d, J
) 13 Hz), 4.26 (1H, br s), 4.68 (1H, br s), 6.82 (1H, dd, J )
7.9, 7.4 Hz), 7.31 (2H, dd, J ) 7.7, 7.1 Hz), 7.38 (1H, m), 7.56
(2H, m), 7.84 (1H, d, J ) 1.2 Hz), 9.17 (1H, br s); 13C NMR
(CDCl3) δ: 12.60 (C5-Me), 39.37 (C2′), 64.27 (C5′), 78.07 (C3′),
87.21 (C1′), 97.85 (C4′), 112.14 (C5), 126.08 (p-C of Ph), 129.22
(C-Se), 129.54 (2C of Ph), 135.88 (2C of Ph), 136.19 (C4), 150.77
(C6), 163.61 (C2).
1-[(4a R,6R,7a S)-2,2-Dim et h yl-4a -p h en ylselen en ylt et -
r a h yd r ofu r o[3,2-d ][1,3]d ioxin -6-yl]-5-m eth yl-1H-p yr im i-
d in e-2,4-d ion e (7b). To a solution of 6b (9 mg, 0.023 mmol)
in 2,2-dimethoxypropane (0.33 mL)-DMF (0.08 mL) was
added pyridinium p-toluenesulfonate (<1 mg) at room tem-
perature, and the mixture was stirred for 48 h. After removal
of the solvent, the residue was purified by preparative thin-
layer chromatography (ethyl acetate) to give 1-(4aR,6R,7aS)-
2,2-dimethyl-4a-phenylselenenyltetrahydrofuro[3,2-d][1,3]dioxin-
6-yl)-5-methyl-1H-pyrimidine-2,4-dione 7b (6.5 mg, 65%) as a
colorless foam: [R]21D ) +57° (c ) 0.15, CHCl3); IR (neat) 3183,
2926, 1694, 1470, 1375, 1267, 1078, 999, 866 cm-1; 400 MHz
1H NMR (CDCl3) δ 1.23 (3H, s), 1.35 (3H, s), 1.96 (3H, s), 2.51
(2H, m), 3.94 (1H, d, J ) 12.9 Hz), 4.23 (1H, d, J ) 12.9 Hz),
4.61 (1H, br s), 6.77 (1H, dd, J ) 8, 7 Hz), 7.35 (2H, dd, J )
7.5, 7.3 Hz), 7.42 (1H, dd, J ) 7.5, 7.5 Hz), 7.65 (1H, d, J )
7.3 Hz), 7.86 (1H, s), 8.34 (1H, br s); 13C NMR (CDCl3) δ 12.64
(C5-Me), 19.45 and 27.91 (Me2C), 37.92 (C2′), 66.31 (C5′), 75.00
(C3′), 87.61 (C1′), 88.88 (Me2C), 98.35 (C4′), 111.74 (C5), 125.80
(p-C of Ph), 129.47 (C-Se), 129.59 (2C of Ph), 136.11 (C4),
136.47 (2C of Ph), 150.23 (C6), 163.29 (C2).
(2R,3S,5R)-3-Hyd r oxy-2-m eth yl-5-(5-m eth yl-2,4-d ioxo-
3,4-d ih yd r o-2H -p yr im id in -1-yl)t et r a h yd r ofu r a n -2-ca r -
boxylic Acid ter t-Bu tyl Ester (5c). The ester 3 (8 mg) was
coevaporated with benzene, dried in vacuo, dissolved in THF
(1.0 mL)-HMPA (0.13 mL), and dried under molecular sieves
4A (three pieces) with stirring for 1 h. To the solution of 3
(7.5 mg, 0.024 mmol) was added lithium diisopropylamide
mono(tetrahydrofuran) (LDA) (Aldrich, 1.5 M in cyclohexane,
0.090 mL, 0.14 mmol) at -78 °C, and the mixture was stirred
at -78 °C for 5 min, -78 °C f room temperature for 10 min,
and at room temperature for 30 min. tert-Butyllithium (1.7 M
in pentane, 0.065 mL, 0.11 mmol) was added to the solution
at -78 °C, and the mixture was stirred at -78 °C for 1 h. To
the solution was added allyl bromide (0.035 mL, 0.40 mmol)
at -78 °C, and the mixture was stirred at -78 °C f -30 °C
for 1 h and at 0 °C for 40 min. After the reaction was quenched
with MeOH (0.09 mL)-AcOH (0.03 mL), the solvent was
evaporated in vacuo. The residue was purified by flash
chromatography (hexane/ethyl acetate ) 1:1-1:2) to give
(2R,3S,5R)-2-methyl-3-(2-propenyloxy)-5-(5-methyl-2,4-dioxo-
3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid
tert-butyl ester 5c′ (1.5 mg, 16%), (2R,3S,5R)-3-hydroxy-2-
methyl-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-
tetrahydrofuran-2-carboxylic acid tert-butyl ester 5c (2.9 mg,
34%), and (2S,3S,5R)-3-hydroxy-2-methyl-5-(5-methyl-2,4-di-
oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic
acid tert-butyl ester 4c (0.8 mg, 9%).
1-[(2R ,4S ,5S )-4-H yd r oxy-5-h yd r oxym e t h yl-5-(2-p r o-
pen yl)tetr ah ydr ofu r an -2-yl]-5-m eth yl-1H-pyr im idin e-2,4-
d ion e (6c). To a solution of 5c (4.2 mg, 0.012 mmol) in THF
(0.4 mL) was added LiBH4 (1 mg, 0.046 mmol) at room
temperature, and the mixture was stirred for 3 h. After the
reaction was quenched with EtOH (0.25 mL) for 0.5 h and
neutralized with AcOH (0.01 mL) for 0.5 h, the solvent was
evaporated in vacuo. The residue was purified by flash
chromatography (ethyl acetate) to give 1-(2R,4S,5S)-4-hydroxy-
5-hydroxymethyl-5-(2-propenyl)tetrahydrofuran-2-yl)-5-meth-
yl-1H-pyrimidine-2,4-dione 6c (3 mg, 89%) as a colorless
foam: [R]22 ) +18° (c ) 0.10, CHCl3); IR (neat) 3413, 2926,
D
1684, 1472, 1271, 1053 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.91
(3H, d, J ) 1.1 Hz), 2.21 (1H, ddd, J ) 14, 7.2, 7.1 Hz), 2.39
(1H, dd, J ) 14, 6.9 Hz), 2.44 (1H, dd, J ) 14, 7.3 Hz), 2.51
(1H, ddd, J ) 14, 6.2, 3.3 Hz), 3.44 (1H, br s, OH), 3.82 (1H,
d, J ) 13 Hz), 3.85 (1H, d, J ) 13 Hz), 3.98 (1H, d, J ) 5.4 Hz,
OH), 4.44 (1H, m), 5.21 (2H, m), 5.84 (1H, m), 6.40 (1H, dd, J
) 7.2, 6.2 Hz), 7.25 (1H, d, J ) 1.1 Hz), 9.43 (1H, br s); 13C
NMR (CDCl3) δ: 12.61 (C5-Me), 40.49 and 40.70 (C2′ and
allyl), 65.26 (C5′), 75.61 (C3′), 84.97 (C4′), 87.71 (C1′), 111.41
(C5), 119.80 and 132.36 (vinyl of allyl), 135.41 (C4), 150.72
(C6), 163.89 (C2).
5-Meth yl-1-[(4aS,6R,7a S)-2,2-d im eth yl-4a -(2-p r op en yl)-
tetr a h yd r ofu r o[3,2-d ][1,3]d ioxin -6-yl]-1H-p yr im id in e-2,4-
d ion e (7c). To a solution of 6c (8 mg, 0.028 mmol) in 2,2-
dimethoxypropane (0.28 mL)-DMF (0.08 mL) was added
pyridinium p-toluenesulfonate (<1 mg) at room temperature,
and the mixture was stirred for 35 h. After removal of the
solvent, the residue was purified by preparative thin-layer
chromatography (ethyl acetate) to give 5-methyl-1-(4aS,6R,7aS)-
2,2-dimethyl-4a-(2-propenyl)tetrahydrofuro[3,2-d][1,3]dioxin-
6-yl)-1H-pyrimidine-2,4-dione 7c (5.6 mg, 62%) as a colorless
foam: [R]21 ) +32° (c ) 0.17, CHCl3); IR (neat) 3187, 2928,
D
1692, 1468, 1373, 1264, 851, 756 cm-1; 400 MHz 1H NMR
(CDCl3) δ 1.37 (6H, s), 1.92 (3H, s), 2.00 (1H, ddd, J ) 13, 8.5,
5.5 Hz), 2.41 (1H, dd, J ) 13, 4.5 Hz), 2.50 (2H, m), 3.64 (1H,
d, J ) 11.7 Hz), 3.69 (1H, d, J ) 11.7 Hz), 4.21 (1H, d, J ) 5
Hz), 5.26 (2H, m), 5.86 (1H, m), 6.38 (1H, dd, J ) 9, 4.5 Hz),
7.31 (1H, s), 8.37 (1H, br s); 13C NMR (CDCl3) δ: 12.65 (C5-
Me), 22.48 and 25.62 (Me2C), 37.77 and 40.94 (C2′ and allyl),
63.90 (C5′), 73.90 (C3′), 84.03 (C4′), 85.79 (C1′), 99.47 (Me2C),
111.11 (C5), 120.11 and 131.89 (vinyl of allyl), 134.97 (C4),
150.05 (C6), 163.35 (C2).
(2S,3S,5R)-3-Ben zen esu lfon yloxy-2-flu or o-5-(5-m eth yl-
2,4-dioxo-3,4-dih ydr o-2H-pyr im idin -1-yl)tetr ah ydr ofu r an -
2-ca r boxylic Acid ter t-Bu tyl Ester (5d ). The ester 3 (16 mg)
was coevaporated with benzene, dried in vacuo, dissolved in
THF (2.0 mL)-HMPA (0.25 mL), and dried under molecular
sieves 4A (eight pieces) with stirring for 1 h. To the solution
of 3 (14.5 mg, 0.046 mmol) was added lithium diisopropylamide
mono(tetrahydrofuran) (LDA) (Aldrich, 1.5 M in cyclohexane,
0.18 mL, 0.27 mmol) at -78 °C, and the mixture was stirred
at -78 °C for 5 min, -78 °C f room temperature for 10 min,
(2R,3S,5R)-3-Hydroxy-2-methyl-5-(5-methyl-2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid
tert-butyl ester 5c (colorless foam): [R]22 ) +33° (c ) 0.22,
D
CHCl3); IR (neat) 3492, 2930, 1740, 1709, 1674, 1476, 1370,
1275, 1235, 1140, 1086 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.52
(9H, s), 1.92 (3H, s), 2.25 (1H, ddd, J ) 13.7, 6.8, 6.5 Hz), 2.47
(1H, ddd, J ) 13.5, 6.5, 4.4 Hz), 2.54 (1H, dd, J ) 14, 7 Hz),
2.82 (1H, dd, J ) 14, 7.2 Hz), 4.46 (1H, m), 5.22 (2H, m), 5.83

Preparation of 4′-Substituted Thymidines
J . Org. Chem., Vol. 66, No. 8, 2001 2631
and room temperature for 30 min. tert-Butyllithium (1.7 M in
pentane, 0.13 mL, 0.22 mmol) was added to the solution at
-78 °C, and the mixture was stirred at -78 °C for 1 h. To the
solution was added N-fluorobenzenesulfonimide (NFSI) (155
mg, 0.490 mmol) in THF (0.42 mL) at -78 °C, and the mixture
was stirred at -78 °C f -25 °C for 1 h and at -25 °C f 0 °C
for 5 min. After the reaction was quenched with MeOH (0.18
mL)-AcOH (0.06 mL), the solvent was evaporated in vacuo.
The residue was purified by flash chromatography (hexane/
ethyl acetate ) 1:1-1:2) to give (2S,3S,5R)-3-benzenesulfonyl-
oxy-2-fluoro-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-
tetrahydrofuran-2-carboxylic acid tert-butyl ester 5d (10.3 mg,
48%) and the 3′-O-benzenesulfonyl derivative of 3 (3.4 mg,
16%).
CHCl3-MeOH ) 20:1); IR (neat) 3397, 1701, 1474, 1283, 1071
1
cm-1; 400 MHz H NMR (CDCl3-CD3OD ) 20:1) δ 1.88 (3H,
s), 2.16 (1H, m), 2.43 (1H, dd, J ) 14, 6 Hz), 3.86 (1H, dd, J )
18, 12.6 Hz), 3.91 (1H, dd, J ) 23, 12.6 Hz), 4.48 (1H, dd, J )
3, 3 Hz), 6.69 (1H, ddd, J ) 8.3, 8.3, 6 Hz), 7.28 (1H, s); 13C
NMR (CDCl3-CD3OD ) 20:1) δ 16.42 (C5-Me), 41.18 (C2′),
64.57 (C5′, d, J ) 129 Hz), 77.73 (C3′, d, J ) 157 Hz), 90.85
(C1′, d, J ) 13 Hz), 116.05 (C5), 124.94 (C4′, d, J ) 906 Hz),
138.79 (C4, d, J ) 24 Hz), 154.60 (C6), 167.86 (C2).
Meth a n esu lfon ic Acid (2R,3S,5R)-2-[Bis(4-m eth oxy-
ph en yl)ph en ylm eth oxym eth yl]-5-(5-m eth yl-2,4-dioxo-3,4-
d ih yd r o-2H-p yr im id in -1-yl)tetr a h yd r ofu r a n -3-yl Ester .
To a solution of 1-[(2R,4S,5R)-5-[bis(4-methoxyphenyl)phenyl-
methoxymethyl]-4-hydroxytetrahydrofuran-2-yl]-5-methyl-1H-
pyrimidine-2,4-dione (56 mg, 0.11 mmol) in pyridine (0.3 mL)
was added methanesulfonyl chloride (0.011 mL, 0.14 mmol)
at 0 °C, and the mixture was stirred for 6 h at the same
temperature and refrigerated for 12 h. After the reaction was
quenched with ice-water (5 mL), the mixture was extracted
with CH2Cl2 and dried over MgSO4. After removal of the
solvent, the residue was purified by flash chromatography
(hexane/ethyl acetate ) 1:2) to give methanesulfonic acid
(2R,3S,5R)-2-[bis(4-methoxyphenyl)phenylmethoxymethyl]-5-
(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydro-
furan-3-yl ester (61 mg, 94%) as a colorless foam: [R]22D ) +21°
(c ) 0.45, CHCl3); IR (neat) 3031, 1694, 1510, 1360, 1252, 1177,
756 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.46 (3H, d, J ) 1.1
Hz), 2.48 (1H, ddd, J ) 14.5, 8.7, 6.5 Hz), 2.68 (1H, ddd, J )
14.5, 5.5, 1.4 Hz), 3.02 (3H, s), 3.45 (1H, dd, J ) 10.8, 2.5 Hz),
3.54 (1H, dd, J ) 10.8, 2.8 Hz), 3.79 (3H, s), 4.32 (1H, m), 4.09
(1H, s), 5.40 (1H, m), 6.44 (1H, dd, J ) 8.7, 5.5 Hz), 6.86 (2H,
m), 7.24-7.35 (8H, m), 7.37-7.4 (4H, m), 7.54 (1H, d, J ) 1.1
Hz), 9.36 (1H, s); 13C NMR (CDCl3) δ 11.84 (C5-Me), 38.47
(C2′), 38.66 (MeS), 55.31 (OCH3), 63.03 (C5′), 79.91 (C3′), 83.77
(C4′), 84.29 (C1′), 87.64 (CAr3), 111.89 (C5), 113.44 (o-C × 2
of MeOAr), 127.49 (2C of Ph), 128.16 (4C of Ph), 128.29 (2C of
Ph), 128.34 (2C of Ph), 130.38 (2C of Ph), 134.45 (p-C of
MeOAr), 135.04 (C4), 143.52 (m-C × 2 of MeOAr), 150.53 (C6),
158.96 (C-OMe), 163.78 (C2).
(2S,3S,5R)-3-Benzenesulfonyloxy-2-fluoro-5-(5-methyl-2,4-
dioxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-car-
boxylic acid tert-butyl ester 5d (colorless foam): [R]24 ) +19°
D
(c ) 0.43, CHCl3); IR (neat) 1759, 1713, 1474, 1451, 1373, 1335,
1260, 1194, 1117, 1051, 1001, 918, 899, 835, 781, 752, 689,
1
588 cm-1; 200 MHz H NMR (CDCl3) δ 1.49 (9H, s), 1.92 (3H,
d, J ) 0.9 Hz), 2.29 (1H, m), 2.64 (1H, dd, J ) 15, 6 Hz), 5.38
(1H, dd, J ) 3.7, 3.7 Hz), 6.80 (1H, ddd, J ) 8.5, 8.5, 6 Hz),
7.14 (1H, s), 7.61 (2H, m), 7.70 (1H, m), 7.92 (2H, m), 8.42
(1H, br); 13C NMR (CDCl3) δ: 12.67 (C5-Me), 27.61 (CMe3),
35.10 (C2′), 81.29 (C3′, d, J ) 169 Hz), 85.51 (CMe3), 87.22
(C1′), 112.80 (C5), 112.95 (C4′, d, J ) 936 Hz), 127.91 (2C of
Ph), 129.67 (2C of Ph), 133.74 (1C of Ph), 134.76 (1C of Ph),
135.82 (C4), 149.92 (C6), 160.17 (C5′, d, J ) 130 Hz), 162.92
(C2).
(2S,3S,5R)-2-F lu or o-3-h yd r oxy-5-(5-m et h yl-2,4-d ioxo-
3,4-d ih yd r o-2H -p yr im id in -1-yl)t et r a h yd r ofu r a n -2-ca r -
boxylic Acid ter t-Bu tyl Ester (5e). The ester 3 (52 mg) was
coevaporated with benzene, dried under vacuo, dissolved in
THF (6.5 mL)-HMPA (0.81 mL), and dried under molecular
sieves 4A (25 pieces) with stirring for 1 h. To the solution of 3
(51 mg, 0.16 mmol) was added lithium diisopropylamide mono-
(tetrahydrofuran) (LDA) (Aldrich, 1.5 M in cyclohexane, 0.61
mL, 0.92 mmol) at -78 °C, and the mixture was stirred at
-78 °C for 5 min, -78 °C f room temperature for 15 min,
and room temperature for 27 min. tert-Butyllithium (1.7 M in
pentane, 0.44 mL, 0.75 mmol) was added to the solution at
-78 °C, and the mixture was stirred at -78 °C for 1 h. To the
solution was added N-fluorobenzenesulfonimide (NFSI) (545
mg, 1.73 mmol) in THF (1.5 mL) at -78 °C, and the mixture
was stirred at -78 °C for 10 min. After the reaction was
quenched with MeOH (0.63 mL)-AcOH (0.19 mL), the solvent
was evaporated in vacuo. The residue was purified by flash
chromatography (hexane/ethyl acetate ) 1:1) to give (2S,
3S,5R)-2-fluoro-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-
2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid tert-butyl
ester 5e (10.9 mg, 21%) and 5d (14 mg, 19%).
(2S,3S,5R)-2-Fluoro-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-di-
hydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid tert-
butyl ester 5e (colorless foam): [R]22D ) +34° (c ) 0.08, CHCl3);
IR (neat) 3463, 3204, 2928, 1755, 1725, 1682, 1478, 1335, 1279,
1115 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.56 (9H, s), 1.95 (3H,
d, J ) 1.2 Hz), 2.21 (1H, m), 2.56 (1H, dd, J ) 14, 6 Hz), 3.48
(1H, br s, OH), 4.66 (1H, m), 6.94 (1H, ddd, J ) 8.9, 8.9, 6
Hz), 7.22 (1H, dd, J ) 1.2, 1.2 Hz), 8.57 (1H, br); 13C NMR
(CDCl3) δ 12.72 (C5-Me), 27.84 (CMe3), 36.47 (C2′, d, J ) 10
Hz), 75.66 (C3′, d, J ) 143 Hz), 85.52 (CMe3), 87.79 (C1′, d, J
) 12 Hz), 112.59 (C5), 113.89 (C4′, d, J ) 941 Hz), 134.43 (C4,
d, J ) 22 Hz), 150.38 (C6), 163.43 (C2), 163.28 (C5′, d, J )
139 Hz).
(1 R ,9 R ,1 0 R )-1 0 -[[(4 -M e t h o x y p h e n y l )d i p h e n y l ]-
m et h oxym et h yl]-4-m et h yl-8,11-d ioxa -2,6-d ia za t r icyclo-
[7.2.1.02,7]d od eca -3,6-d ien -5-on e. To a solution of methane-
sulfonic acid (2R,3S,5R)-2-[bis(4-methoxyphenyl)phenylmethoxy-
methyl]-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)tetra-
hydrofuran-3-yl ester (1.58 g, 2.67 mmol) in EtOH (267 mL)
were added 1 N aqueous NaOH (2.67 mL) and water (19.2 mL)
at room temperature, and the mixture was refluxed for 2 h.
After removal of the solvent, the residue was purified by flash
chromatography (CHCl3-MeOH ) 10:1) to give (1R,9R,10R)-
10-[[(4-methoxyphenyl)diphenyl]methoxymethyl]-4-methyl-
8,11-dioxa-2,6-diazatricyclo[7.2.1.02,7]dodeca-3,6-dien-5-one (1.19
g, 91%) as a colorless foam: [R]22D ) +4° (c ) 0.45, CHCl3); IR
(neat) 1661, 1634, 1532, 1472, 1136, 1078, 880, 704 cm-1; 400
1
MHz H NMR (CDCl3) δ 1.89 (3H, s), 2.34 (1H, ddd, J ) 12.8,
3.3, 3 Hz), 2.65 (1H, d, J ) 12.8 Hz), 3.30 (1H, dd, J ) 10, 6
Hz), 3.34 (1H, dd, J ) 10, 7 Hz), 3.77 (3H, s), 4.24 (1H, ddd, J
) 7, 6, 2 Hz), 5.10 (1H, s), 5.47 (1H, d, J ) 3.3 Hz), 6.80 (2H,
m), 6.93 (1H, s), 7.15-7.3 (10H, m), 7.41 (4H, m); 13C NMR
(CDCl3) δ 13.44 (C5-Me), 33.64 (C2′), 55.27 (OCH3), 62.28 (C5′),
76.80 (C3′), 84.54 (C4′), 87.00 (CAr3), 87.53 (C1′), 113.22 (o-C
× 2 of MeOAr), 118.31 (C5), 127.04 (2C of Ph), 127.91 (2C of
Ph), 127.93 (2C of Ph), 128.25 (2C of Ph), 128.29 (2C of Ph),
130.38 (2C of Ph), 134.84 (p-C of MeOAr), 135.19 (C4), 143.84
(m-C of MeOAr), 143.97 (m-C of MeOAr), 153.31 (C6), 158.68
(C-OMe), 171.70 (C2).
1-[(2R,4S,5R)-5-F lu or o-4-h yd r oxy-5-h yd r oxym eth yltet-
r ah ydr ofu r an -2-yl)-5-m eth yl-1H-pyr im idin e-2,4-dion e (6d).
To a solution of 5d (9.5 mg, 0.029 mmol) in THF (1.0 mL) was
added LiBH4 (3 mg, 0.14 mmol) at room temperature, and the
mixture was stirred for 2 h. After the reaction was quenched
with EtOH (0.5 mL) for 10 min and neutralized with AcOH
(0.02 mL) for 10 min, the solvent was evaporated in vacuo.
The residue was purified by flash chromatography (ethyl
acetate) to give 1-[(2R,4S,5R)-5-fluoro-4-hydroxy-5-hydroxy-
methyltetrahydrofuran-2-yl]-5-methyl-1H-pyrimidine-2,4-dione
(2R,4R,5R)-1-[5-[Bis(4-m et h oxyp h en yl)p h en ylm et h -
oxym eth yl]-4-h ydr oxytetr ah ydr ofu r an -2-yl]-5-m eth yl-1H-
p yr im id in e-2,4-d ion e (8). To a solution of (1R,9R,10R)-10-
[[(4-methoxyphenyl)diphenyl]methoxymethyl]-4-methyl-8,11-
dioxa-2,6-diazatricyclo[7.2.1.02,7]dodeca-3,6-dien-5-one (1.19 g,
2.40 mmol) in EtOH (240 mL) were added 1 N aqueous NaOH
(5.4 mL) and water (40 mL) at room temperature, and the
mixture was refluxed for 3 h. After removal of the solvent, the
residue was purified by flash chromatography (ethyl acetate)
to give (2R,4R,5R)-5-[[bis(4-methoxyphenyl)phenylmethoxy-
6d (6.2 mg, 82%) as a colorless foam: [R]22 ) +0° (c ) 0.1,
D

2632 J . Org. Chem., Vol. 66, No. 8, 2001
J ung and Toyota
methyl]-4-hydroxytetrahydrofuran-2-yl]-5-methyl-1H-pyrimidine-
[4-(tert-Butyldiphenylsilanyloxy)-5-hydroxymethyltetrahydro-
furan-2-yl]-5-methyl-1H-pyrimidine-2,4-dione (864 mg, 1.80
mmol) in CH2Cl2 (8.5 mL) were added 2,2,6,6-tetramethyl-1-
piperidinyl-oxy, free radical (TEMPO) (62 mg, 0.39 mmol), and
iodobenzene diacetate (BAIB) (1.28 g, 3.97 mmol) at room
temperature. After the mixture was stirred for 2 h, a mixture
of MeCN-water (1:1) (0.1 mL) was added to the reaction
mixture, and the mixture was stirred for 24 h. After removal
of the solvent, the residue was purified by flash chromatog-
raphy (CHCl3-MeOH ) 10:1) to give (2S,3R,5R)-3-(tert-
butyldiphenylsilanyloxy)-5-(5-methyl-2,4-dioxo-3,4-dihydro-
2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid (890 mg,
2,4-dione 8 (1.25 g, 100%) as a colorless foam: [R]22 ) +18°
D
(c ) 0.35, CHCl3); IR (neat) 3391, 3026, 1698, 1509, 1271, 1252,
1069, 756 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.77 (3H, s), 2.20
(1H, dd, J ) 14.5, 2 Hz), 2.56 (1H, ddd, J ) 14.5, 8, 5 Hz),
3.50 (1H, dd, J ) 10, 5.4 Hz), 3.64 (1H, dd, J ) 10, 5.3 Hz),
3.80 (3H, s), 4.05 (1H, ddd, J ) 5.4, 5.3, 3 Hz), 4.46 (1H, ddd,
J ) 5, 3, 3 Hz), 6.19 (1H, dd, J ) 8, 2 Hz), 6.86 (2H, m), 7.22-
7.36 (8H, m), 7.45-7.5 (4H, m), 7.65 (1H, d, J ) 1.2 Hz), 9.21
(1H, br s); 400 MHz 13C NMR (CDCl3) δ: 12.53 (C5-Me), 40.81
(C2′), 55.27 (OCH3), 61.99 (C5′), 70.96 (C3′), 82.84 (C4′), 85.22
(C1′), 87.24 (CAr3), 110.11 (C5), 113.37 (o-C × 2 of MeOAr),
127.24 (1C of Ph), 127.26 (1C of Ph), 128.09 (2C of Ph), 128.10
(2C of Ph), 128.21 (2C of Ph), 128.25 (2C of Ph), 130.29 (2C of
Ph), 134.85 (p-C of MeOAr), 137.22 (C4), 143.78 (m-C of
MeOAr), 143.86 (m-C of MeOAr), 150.75 (C6), 158.81 (C-OMe),
164.06 (C2).
100%) as a colorless foam: [R]21 ) -3° (c ) 0.25, CHCl3-
D
MeOH ) 40:1); IR (neat) 2932, 1686, 1474, 1428, 1277, 1113,
1076, 704, 612 cm-1; 400 MHz 1H NMR (CDCl3-CD3OD ) 40:
1) δ 0.96 (9H, s), 1.90 (3H, s), 2.07 (1H, ddd, J ) 14.5, 2, 2
Hz), 2.17 (1H, ddd, J ) 14.5, 6.5, 5.2 Hz), 4.59 (1H, d, J ) 4.4
Hz), 4.75 (1H, m), 6.00 (1H, dd, J ) 6.5, 2 Hz), 7.3-7.45 (6H,
m), 7.49 (2H, m), 7.62 (2H, m), 8.38 (1H, s); 13C NMR (CDCl3-
CD3OD ) 40:1) δ 16.45 (C5-Me), 22.88 (CMe3), 30.62 (CMe3),
44.18 (C2′), 76.74 (C3′), 87.87 (C4′), 90.79 (C1′), 113.41 (C5),
131.68 (2C of Ph), 131.75 (2C of Ph), 133.98(1C of Ph), 134.11
(1C of Ph), 135.50 (1C of Ph), 136.55 (1C of Ph), 139.47 (2C of
Ph), 139.89 (2C of Ph), 141.67 (C4), 154.13 (C6), 168.70 (C2),
174.78 (C5′).
(2R,4R,5R)-1-[5-[Bis(4-m et h oxyp h en yl)p h en ylm et h -
oxym eth yl]-4-(ter t-bu tyld ip h en ylsila n yloxy)tetr a h yd r o-
fu r a n -2-yl]-5-m eth yl-1H-p yr im id in e-2,4-d ion e. To a solu-
tion of 8 (1.06 g, 2.06 mmol) in DMF (15.4 mL) were added
imidazole (1.83 g, 26.9 mmol) and TBDPSCl (2.31 mL, 8.88
mmol) at room temperature, and the mixture was gently
refluxed for 1.5 h. After the reaction was quenched with water,
the mixture was extracted with Et2O and dried over MgSO4.
After removal of the solvent, the residue was purified by flash
chromatography (hexane/ethyl acetate ) 2:1) to give (2R,4R,
5R)-1-[5-[bis(4-methoxyphenyl)phenylmethoxymethyl]-4-
(tert-butyldiphenylsilanyloxy)tetrahydrofuran-2-yl]-5-methyl-
1H-pyrimidine-2,4-dione (1.46 g, 94%) as a colorless foam:
(2S,3R,5R)-3-(ter t-Bu tyld ip h en ylsila n yloxy)-5-(5-m eth -
yl-2,4-d ioxo-3,4-d ih yd r o-2H -p yr im id in -1-yl)t et r a h yd r o-
fu r a n -2-ca r boxylic Acid Meth yl Ester . To a solution of
(2S,3R,5R)-3-(tert-butyldiphenylsilanyloxy)-5-(5-methyl-2,4-di-
oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carbox-
ylic acid (74 mg, 0.15 mmol) in benzene (2 mL)-MeOH (1.6
mL) was added (trimethylsilyl)diazomethane (2 M in hexane,
0.17 mL, 3.4 mmol) at room temperature, and the mixture was
stirred for 10 h. After removal of the solvent, the residue was
purified by flash chromatography (hexane/ethyl acetate ) 1:1)
to give (2S,3R,5R)-3-(tert-butyldiphenylsilanyloxy)-5-(5-meth-
yl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-
carboxylic acid methyl ester (70 mg, 92%) as a colorless foam:
[R]22 ) +36° (c ) 0.52, CHCl3); IR (neat) 2932, 1686, 1510,
D
1472, 1269, 1252, 1115, 1071, 741, 704 cm-1; 400 MHz 1H NMR
(CDCl3) δ 0.89 (9H, s), 1.84 (3H, d, J ) 1 Hz), 2.06 (1H, dd, J
) 15, 1.8 Hz), 2.38 (1H, ddd, J ) 15, 7.7, 5.5 Hz), 3.04 (1H,
dd, J ) 10.7, 2 Hz), 3.73 (1H, dd, J ) 10.7, 9 Hz), 3.79 (3H, s),
4.06 (1H, ddd, J ) 9, 3, 2 Hz), 4.18 (1H, dd, J ) 5, 3 Hz), 6.17
(1H, dd, J ) 7.6, 1.8 Hz), 6.76 (2H, m), 7.15-7.5 (22H, m),
7.17 (1H, d, J ) 1 Hz), 9.05 (1H, br s); 13C NMR (CDCl3) δ
12.56 (C5-Me), 19.06 (CMe3), 26.85 (CMe3), 41.94 (C2′), 55.23
(OCH3), 64.08 (C5′), 72.49 (C3′), 84.91 (C4′), 85.77 (C1′), 86.69
(CAr3), 109.67 (C5), 113.14 (o-C × 2 of MeOAr), 126.88 (1C of
Ph), 126.94 (1C of Ph), 127.67 (2C of Ph), 127.89 (2C of Ph),
127.91 (2C of Ph), 127.94 (2C of Ph), 128.31 (2C of Ph), 128.54
(2C of Ph), 129.96 (1C of Ph), 130.30 (1C of Ph), 130.47 (2C of
Ph), 131.99 (1C of Ph), 132.40 (1C of Ph), 135.29 (p-C of
MeOAr), 135.63 (2C of Ph), 135.89 (2C of Ph), 136.51 (C4),
143.96 (m-C of MeOAr), 144.49 (m-C of MeOAr), 150.35 (C6),
158.57 (C-OMe), 164.13 (C2).
[R]22 ) +4° (c ) 0.35, CHCl3); IR (neat) 2953, 1759, 1694,
D
1472, 1429, 1277, 1219, 1113, 1051, 941, 702 cm-1; 400 MHz
1H NMR (CDCl3) δ 0.99 (9H, s), 1.96 (3H, d, J ) 1.2 Hz), 2.12
(1H, ddd, J ) 14.2, 3.9, 3.6 Hz), 2.20 (1H, ddd, J ) 14.2, 6.5,
5.3 Hz), 4.59 (1H, d, J ) 5 Hz), 4.75 (1H, ddd, J ) 5.3, 5, 3.6
Hz), 6.04 (1H, dd, J ) 6.5, 3.9 Hz), 7.35-7.5 (6H, m), 7.53 (2H,
m), 7.59 (2H, m), 8.30 (1H, d, J ) 1.2 Hz), 8.87 (1H, br); 13C
NMR (CDCl3) δ 12.77 (C5-Me), 19.00 (CMe3), 26.78 (CMe3),
39.87 (C2′), 52.28 (ester Me), 72.81 (C3′), 83.10 (C4′), 86.13
(C1′), 110.08 (C5), 127.92 (2C of Ph), 128.02 (2C of Ph), 130.25
(1C of Ph), 130.43 (1C of Ph), 131.82 (1C of Ph), 132.34 (1C of
Ph), 135.68 (2C of Ph), 135.80 (2C of Ph), 137.01 (C4), 150.26
(C6), 164.02 (C2), 169.28 (C5′).
(2R,4R,5R)-1-[4-(ter t-Bu t yld ip h en ylsila n yloxy)-5-h y-
d r oxym eth yltetr a h yd r ofu r a n -2-yl]-5-m eth yl-1H-p yr im i-
d in e-2,4-d ion e. To a solution of (2R,4R,5R)-1-[5-[bis(4-meth-
oxyphenyl)phenylmethoxymethyl]-4-(tert-butyldiphenylsilanyl-
oxy)tetrahydrofuran-2-yl]-5-methyl-1H-pyrimidine-2,4-dione
(1.50 g, 1.92 mmol) in MeOH (100 mL) was added Amberlyst
15-H (1.03 g) at room temperature, and the mixture was
stirred for 37 h. After filtration, the solvent was evaporated
in vacuo. The residue was purified by flash chromatography
(hexane/ethyl acetate ) 1:2-1:4) to give (2R,4R,5R)-1-[4-(tert-
butyldiphenylsilanyloxy)-5-hydroxymethyltetrahydrofuran-2-
yl]-5-methyl-1H-pyrimidine-2,4-dione (923 mg, 100%) as a
colorless foam: [R]20D ) -21° (c ) 0.48, CHCl3); IR (neat) 2932,
1686, 1472, 1428, 1271, 1113, 1074, 702, 611 cm-1; 400 MHz
1H NMR (CDCl3) δ 1.08 (9H, s), 1.93 (3H, s), 2.01 (1H, ddd, J
) 14.6, 3.8, 2 Hz), 2.41 (1H, ddd, J ) 14.6, 7.4, 6.6 Hz), 3.77
(1H, dd, J ) 12, 3 Hz), 3.88 (1H, m), 4.01 (1H, dd, J ) 12, 5.4
Hz), 4.54 (1H, m), 6.09 (1H, dd, J ) 7.4, 3.8 Hz), 7.35-7.5 (6H,
m), 7.56 (2H, m), 7.64 (2H, m), 7.81 (1H, s), 9.08 (1H, br); 13C
NMR (CDCl3) δ: 12.63 (C5-Me), 19.16 (CMe3), 26.99 (CMe3),
41.67 (C2′), 62.02 (C5′), 72.45 (C3′), 83.82 (C4′), 83.85 (C1′),
110.65 (C5), 128.07 (2C of Ph), 128.17 (2C of Ph), 130.48 (1C
of Ph), 130.49 (1C of Ph), 132.07 (1C of Ph), 132.35 (1C of Ph),
135.75 (4C of Ph), 136.21 (C4), 150.43 (C6), 164.02 (C2).
(2S,3R,5R)-3-(ter t-Bu tyld ip h en ylsila n yloxy)-5-(5-m eth -
yl-2,4-d ioxo-3,4-d ih yd r o-2H -p yr im id in -1-yl)t et r a h yd r o-
fu r a n -2-ca r b oxylic Acid . To a solution of (2R,4R,5R)-1-
(2S,3R5R)-3-Hydr oxy-5-(5-m eth yl-2,4-dioxo-3,4-dih ydr o-
2H-p yr im id in -1-yl)tetr a h yd r ofu r a n -2-ca r boxylic Acid
Meth yl Ester (9). To (2S,3R,5R)-3-(tert-butyldiphenylsilanyl-
oxy)-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)tetra-
hydrofuran-2-carboxylic acid methyl ester (800 mg, 1.57 mmol)
in THF (17 mL) was added TBAF (1 M in THF, 1.6 mL) at 0
°C, and the mixture was stirred at the same temperature for
1.5 h. After the reaction was quenched with water, the mixture
was extracted with CH2Cl2 and dried over MgSO4. After
removal of the solvent, the residue was purified by flash chro-
matography (ethyl acetate/MeOH ) 50:1) to give (2S,3R,5R)-
3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-
yl)tetrahydrofuran-2-carboxylic acid methyl ester 9 (424 mg,
100%) as a colorless foam: [R]23 ) +18° (c ) 0.45, CHCl3-
D
MeOH ) 10:1); IR (neat) 3381, 1746, 1686, 1476, 1279, 1221,
1
1100 cm-1; 200 MHz H NMR (CDCl3-CD3OD ) 10:1) δ 1.84
(3H, s), 2.14 (1H, dm, J ) 14.5 Hz), 2.49 (1H, ddd, J ) 14.5,
7, 5.5 Hz), 3.77 (3H, s), 4.53 (1H, d, J ) 4.2 Hz), 4.60 (1H, m),
6.08 (1H, dd, J ) 7.4, 2.6 Hz), 8.03 (1H, s); 13C NMR (CDCl3-
CD3OD ) 10:1) δ 16.16 (C5-Me), 44.50 (C2′), 56.04 (ester Me),
74.44 (C3′), 87.70 (C4′), 90.34 (C1′), 113.66 (C5), 141.87 (C4),
154.89 (C6), 169.09 (C2), 173.28 (C5′).
(2R,3R,5R)-2-Deu ter io-3-h ydr oxy-5-(5-m eth yl-2,4-dioxo-
3,4-d ih yd r o-2H-p yr im id in -1-yltetr a h yd r ofu r a n -2-ca r box-

Preparation of 4′-Substituted Thymidines
J . Org. Chem., Vol. 66, No. 8, 2001 2633
ylic Acid Meth yl Ester (11a ) a n d (2S,3R,5R)-2-Deu ter io-
3 -h y d r o x y -5 -(5 -m e t h y l -2 ,4 -d i o x o -3 ,4 -d i h y d r o -2H -
pyr im idin -1-yl)tetr ah ydr ofu r an -2-car boxylic Acid Meth yl
Ester (10a ). The ester 9 (29 mg) was coevaporated with
benzene, dried in vacuo, dissolved in THF (4.3 mL)-HMPA
(0.52 mL), and dried under molecular sieves 4A (18 pieces)
with stirring for 1 h. To the solution of 9 (28.0 mg, 0.104 mmol)
was added lithium diisopropylamide mono(tetrahydrofuran)
(LDA) (Aldrich, 1.5 M in cyclohexane, 0.40 mL, 0.60 mmol) at
-78 °C, and the mixture was stirred at -78 °C for 5 min, -78
°C f room temperature for 10 min, and room temperature
for 10 min. tert-Butyllithium (1.7 M in pentane, 0.30 mL, 0.51
mmol) was added to the solution at -78 °C, and the mixture
was stirred at -78 °C for 1 h. To the solution were added
CD3OD (0.38 mL) and CD3CO2D (0.12 mL) at -78 °C, and the
mixture was stirred at -78 °C f room temperature for 30 min.
After removal of the solvent, the residue was purified by flash
chromatography (hexane/ethyl acetate ) 1:2 to ethyl acetate)
to give (2R,3R,5R)-2-deuterio-3-hydroxy-5-(5-methyl-2,4-dioxo-
3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid
methyl ester 11a (15 mg, 53%) and (2S,3R,5R)-2-deuterio-3-
hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-
tetrahydrofuran-2-carboxylic acid methyl ester 10a (6 mg,
21%), both as colorless foams.
dd, J ) 15, 3.2 Hz), 3.08 (1H, ddd, J ) 15, 8.5, 6 Hz), 3.71
(1H, s), 3.75 (1H, br s), 4.70 (1H, dd, J ) 6, 3.4 Hz), 6.50 (1H,
dd, J ) 8.5, 3.2 Hz), 7.35 (2H, m), 7.42 (1H, m), 7.56 (1H, d, J
) 1.2 Hz), 7.62 (2H, m), 8.90 (1H, br s); 13C NMR (CDCl3) δ:
12.61 (C5-Me), 38.02 (C2′), 52.94 (ester Me), 75.92 (C3′), 85.60
(C4′), 93.20 (C1′), 111.87 (C5), 125.59 (p-C of Ph), 129.35 (2C
of Ph), 129.86 (C-Se), 137.04 (C4), 137.25 (2C of Ph), 150.44
(C6), 163.64 (C2), 168.02 (C5′).
1-(2R,4R,5S)-4-H yd r oxy-5-h yd r oxym et h yl-5-p h en yl-
selen en yltetr a h yd r ofu r a n -2-yl)-5-m eth yl-1H-p yr im id in e-
2,4-d ion e (12b ). To a solution of (2R,3R,5R)-3-hydroxy-5-
(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-(phenyl-
selenenyl)tetrahydrofuran-2-carboxylic acid methyl ester 10b
(24 mg, 0.056 mmol) in THF (0.75 mL)-EtOH (1.0 mL) was
added LiBH4 (3 mg, 0.14 mmol) at room temperature, and the
mixture was stirred for 1 h. After the mixture was neutralized
with AcOH (0.015 mL) for 30 min, the solvent was evaporated
in vacuo. The residue was purified by flash chromatography
(hexane/ethyl acetate ) 1:2) to give 1-(2R,4R,5S)-4-hydroxy-
5-hydroxymethyl-5-phenylselenenyltetrahydrofuran-2-yl)-5-
methyl-1H-pyrimidine-2,4-dione 12b (14 mg, 63%) as a color-
less foam: [R]22 ) -158° (c ) 0.08, CHCl3); IR (neat) 3386,
D
2926, 1686, 1474, 1279, 1057, 741, 693 cm-1; 400 MHz 1H NMR
(CDCl3) δ 1.89 (3H, s), 2.16 (1H, dd, J ) 15, 3 Hz), 2.93 (1H,
br s, OH), 3.10 (1H, ddd, J ) 15, 8.5, 7 Hz), 3.88 (2H, m), 4.08
(1H, br s, OH), 4.54 (1H, s), 6.55 (1H, dd, J ) 8.5, 3 Hz), 7.35
(2H, dd, J ) 7, 7 Hz), 7.40 (1H, dd, J ) 7, 7 Hz), 7.59 (1H, s),
7.62 (2H, d, J ) 7 Hz), 8.31 (1H, br s); 13C NMR (CDCl3) δ:
12.55 (C5-Me), 39.37 (C2′), 63.45 (C5′), 77.02 (C3′), 85.97 (C1′),
98.23 (C4′), 111.88 (C5), 125.30 (p-C of Ph), 129.36 (C-Se),
129.40 (2C of Ph), 137.13 (2C of Ph), 137.44 (C4), 150.27 (C6),
163.34 (C2).
(2R,3R,5R)-2-Deuterio-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid
methyl ester 11a : [R]21 ) - 21° (c ) 0.25, CHCl3); IR (neat)
D
3401, 2928, 1744, 1694, 1472, 1277, 1103, 756 cm-1; 400 MHz
1H NMR (CDCl3-CD3OD ) 8:1) δ 1.86 (3H, d, J ) 1.1 Hz),
2.17 (1H, ddd, J ) 14.7, 3, 2 Hz), 2.68 (1H, ddd, J ) 14.7, 7.4,
5.5 Hz), 3.80 (3H, s), 4.28 (1H, dd, J ) 5.5, 2 Hz), 6.15 (1H,
dd, J ) 7.4, 3 Hz), 8.00 (1H, s); 13C NMR (CDCl3-CD3OD )
8:1) δ 16.23 (C5-Me), 42.99 (C2′), 56.43 (ester Me), 76.92 (C3′),
91.24 (C1′), 114.49 (C5), 141.56 (C4), 154.80 (C6), 168.50 (C2),
174.90 (C5′).
1-(4a S,6R,7a R)-2,2-Dim et h yl-4a -p h en ylselen en ylt et -
r a h yd r ofu r o[3,2-d ][1,3]d ioxin -6-yl)-5-m eth yl-1H-p yr im i-
d in e-2,4-d ion e (13b). To a solution of 12b (3 mg, 0.0076
mmol) in 2,2-dimethoxypropane (0.24 mL)-DMF (0.06 mL)
was added pyridinium p-toluenesulfo-nate (<1 mg) at room
temperature, and the mixture was stirred for 30 h. After
removal of the solvent, the residue was purified by preparative
thin-layer chromatography (ethyl acetate) to give 1-(4aS,6R,
7aR)-2,2-dimethyl-4a-phenylselenenyltetrahydrofuro[3,2-d]-
[1,3]dioxin-6-yl)-5-methyl-1H-pyrimidine-2,4-dione 13b (3.3
mg, 100%) as a colorless foam: [R]22D ) -78° (c ) 0.14, CHCl3);
IR (neat) 2924, 1692, 1468, 1283, 1202, 1117 cm-1; 400 MHz
1H NMR (CDCl3) δ 1.32 (3H, s), 1.36 (3H, s), 1.92 (3H, d, J )
1.2 Hz), 2.04 (1H, dd, J ) 15, 2.2 Hz), 3.08 (1H, ddd, J ) 15,
8.5, 5 Hz), 4.08 (1H, d, J ) 13.4 Hz), 4.38 (1H, d, J ) 13.4
Hz), 4.52 (1H, d, J ) 5 Hz), 6.40 (1H, dd, J ) 8.5, 2.2 Hz),
7.35 (2H, m), 7.42 (1H, m), 7.67 (2H, m), 7.94 (1H, d, J ) 1.2
Hz), 8.13 (1H, br); 13C NMR (CDCl3) δ: 12.59 (C5-Me), 18.68
and 28.64 (Me2C), 39.39 (C2′), 65.94 (C5′), 73.96 (C3′), 84.80
(C1′), 88.05 (Me2C), 98.55 (C4′), 110.48 (C5), 125.05 (p-C of
Ph), 129.40 (2C of Ph), 129.56 (C-Se), 137.17 (C4), 137.42 (2C
of Ph), 150.20 (C6), 163.45 (C2).
(2S,3R,5R)-3-Hyd r oxy-2-m eth yl-5-(5-m eth yl-2,4-d ioxo-
3,4-d ih yd r o-2H -p yr im i-d in -1-yl)t et r a h yd r ofu r a n -2-ca r -
boxylic Acid Meth yl Ester (10c). The ester 9 (34 mg) was
coevaporated with benzene, dried in vacuo, dissolved in THF
(5.0 mL)-HMPA (0.61 mL), and dried under molecular sieves
4A (15 pieces) with stirring for 1 h. To the solution of 9 (33
mg, 0.12 mmol) was added lithium diisopropylamide mono-
(tetrahydrofuran) (LDA) (Aldrich, 1.5 M in cyclohexane, 0.45
mL, 0.68 mmol) at -78 °C, and the mixture was stirred at
-78 °C for 5 min, -78 °C f room temperature for 10 min,
and room temperature for 10 min. tert-Butyllithium (1.7 M in
pentane, 0.34 mL, 0.58 mmol) was added to the solution at
-78 °C, and the mixture was stirred at -78 °C for 1 h. To the
solution were added iodomethane (0.12 mL, 1.93 mmol) at -78
°C and the mixture was stirred at -78 °C for 20 min and at
-78 °C f -20 °C for 1 h. After the reaction was quenched
with MeOH (0.42 mL)-AcOH (0.14 mL), the solvent was
evaporated in vacuo. The residue was purified by flash
chromatography (ethyl acetate) to give (2S,3R,5R)-3-hydroxy-
2-methyl-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-
yl)tetrahydrofuran-2-carboxylic acid methyl ester 10c (15 mg,
(2S,3R,5R)-2-Deuterio-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid
methyl ester 10a : IR (neat) 1281, 1103, 758 cm-1; 400 MHz
1H NMR (CDCl3-CD3OD ) 5:1) δ 1.81 (3H, s), 2.11 (1H, dm,
J ) 14.5 Hz), 2.47 (1H, ddd, J ) 14.5, 6, 6 Hz), 3.74 (3H, s),
4.55 (1H, d, J ) 6 Hz), 6.06 (1H, dm, J ) 6 Hz), 8.03 (1H, s);
13C NMR (CDCl3-CD3OD ) 5:1) δ 16.20 (C5-Me), 44.47 (C2′),
56.14 (ester Me), 74.39 (C3′), 90.39 (C1′), 113.73 (C5), 141.75
(C4), 154.75 (C6), 169.00 (C2), 173.21 (C5′).
(2R,3R,5R)-3-Hyd r oxy-5-(5-m eth yl-2,4-d ioxo-3,4-d ih y-
d r o-2H-p yr im id in -1-yl)-2-(p h en ylselen en yl)tetr a h yd r o-
fu r a n -2-ca r boxylic Acid Meth yl Ester (10b). The ester 9
(7.3 mg) was coevaporated with benzene, dried in vacuo,
dissolved in THF (1.1 mL)-HMPA (0.14 mL), and dried under
molecular sieves 4A (three pieces) with stirring for 1 h. To the
solution of 9 (6.7 mg, 0.025 mmol) was added lithium diiso-
propylamide mono(tetrahydrofuran) (LDA) (Aldrich, 1.5 M in
cyclohexane, 0.093 mL, 0.14 mmol) at -78 °C, and the mixture
was stirred at -78 °C for 5 min, -78 °C f room temperature
for 5 min, and room temperature for 11 min. tert-Butyllithium
(1.7 M in pentane, 0.075 mL, 0.12 mmol) was added to the
solution at -78 °C, and the mixture was stirred at -78 °C for
1 h. To the solution was added phenylselenenyl chloride (55
mg, 0.29 mmol) in THF (0.15 mL) at -78 °C, and the mixture
was stirred at the same temperature for 1 h. After the reaction
was quenched with MeOH (0.09 mL)-AcOH (0.03 mL), the
solvent was evaporated in vacuo. The residue was purified by
flash chromatography (hexane/ethyl acetate ) 1:1) to give
(2R,3R,5R)-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-
2H-pyrimidin-1-yl)-2-(phenylselenenyl)tetrahydrofuran-2-car-
boxylic acid methyl ester 10b (6 mg, 56%) together with
recovery of 9 (1 mg, 15%) and (2S,3R,5R)-3-hydroxy-5-(5-
methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)- 2-(phenyl-
selenenyl)tetrahydrofuran-2-carboxylic acid methyl ester 11b
(0.6 mg, 6%), all as colorless foams.
(2R,3R,5R)-3-Hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydro-
2H-pyrimidin-1-yl)-2-(phenylselenenyl)tetrahydrofuran-2-car-
boxylic acid methyl ester 10b: [R]22D ) -153° (c ) 0.27, CHCl3);
IR (neat) 3063, 1686, 1476, 1279, 1090, 742, 692 cm-1; 400
MHz 1H NMR (CDCl3) δ 1.87 (3H, d, J ) 1.2 Hz), 2.19 (1H,

2634 J . Org. Chem., Vol. 66, No. 8, 2001
J ung and Toyota
44%) as a colorless foam: [R]22 ) -98° (c ) 0.33, CHCl3); IR
13C NMR (CDCl3) δ: 12.48 (C5-Me), 39.89 (C2′), 40.60 (allyl),
52.53 (ester Me), 75.00 (C3′), 87.23 (C4′), 94.76 (C1′), 109.14
(C5), 119.90 and 130.97 (vinyl of allyl), 138.19 (C4), 150.92
(C6), 164.70 (C2), 170.57 (C5′).
D
(neat) 3399, 1740, 1690, 1476, 1281, 1107 cm-1; 400 MHz H
1
NMR (CDCl3) δ 1.48 (3H, s), 1.81 (3H, s), 2.51 (1H, dm, J )
15 Hz), 2.72 (1H, ddd, J ) 15, 7, 6 Hz), 3.86 (3H, s), 4.00 (1H,
br s), 4.39 (1H, d, J ) 4.4 Hz), 6.19 (1H, d, J ) 7 Hz), 8.03
(1H, s), 9.86 (1H, br s); 13C NMR (CDCl3) δ 12.49 (C5-Me),
22.67 (C4′-Me), 39.30 (C2′), 52.52 (ester Me), 75.65 (C3′), 85.74
(C4′), 90.56 (C1′), 109.94 (C5), 137.66 (C4), 150.66 (C6), 164.60
(C2), 171.90 (C5′).
1-(2R ,4R ,5R )-4-H yd r oxy-5-h yd r oxym e t h yl-5-(2-p r o-
pen yl)tetr ah ydr ofu r an -2-yl)-5-m eth yl-1H-pyr im idin e-2,4-
d ion e (12d ). To a solution of 10d (15 mg, 0.048 mmol) in THF
(1 mL) was added LiBH4 (10 mg, 0.46 mmol) at room temper-
ature, and the mixture was stirred for 18 h. After the mixture
was stirred with EtOH (1 mL) for 30 min and neutralized with
AcOH (0.06 mL) for 30 min, the solvent was evaporated in
vacuo. The residue was purified by flash chromatography
(ethyl acetate) to give 1-[(2R,4R,5R)-4-hydroxy-5-hydroxy-
methyl-5-(2-propenyl)tetrahydrofuran-2-yl]-5-methyl-1H-pyrim-
1-(2R,4R,5R)-4-H yd r oxy-5-h yd r oxym et h yl-5-m et h yl-
tetr a h yd r ofu r a n -2-yl)-5-m eth yl-1H-p yr im id in e-2,4-d ion e
(12c). To a solution of 10c (11.5 mg, 0.040 mmol) in THF (1.1
mL) was added LiBH4 (2 mg, 0.092 mmol) at room tempera-
ture, and the mixture was stirred for 1 h. After the mixture
was stirred with EtOH (0.33 mL) for 15 min and neutralized
with AcOH (0.013 mL) for 30 min, the solvent was evaporated
in vacuo. The residue was purified by flash chromatography
(ethyl acetate) to give 1-(2R,4R,5R)-4-hydroxy-5-hydroxy-
methyl-5-methyltetrahydrofuran-2-yl)-5-methyl-1H-pyrimidine-
2,4-dione 12c (7.5 mg, 73%) as a colorless foam: [R]22D ) -14°
(c ) 0.10, CHCl3-MeOH ) 20:1); IR (neat) 3407, 1690, 1476,
idine-2,4-dione 12d (6.9 mg, 51%) as a colorless foam: [R]22
D
) -24° (c ) 0.10, CHCl3); IR (neat) 3403, 1686, 1474, 1277,
1076 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.91 (3H, s), 2.27 (3H,
m), 2.78 (1H, ddd, J ) 14.7, 7.7, 7 Hz), 3.03 (1H, br, s, OH),
3.89 (2H, s), 4.37 (1H, m), 5.17 (2H, m), 5.81 (1H, m), 6.04
(1H, dd, J ) 7, 6 Hz), 7.71 (1H, s), 8.77 (1H, br s); 13C NMR
(CDCl3) δ 12.54 (C5-Me), 39.88 (C2′), 40.29 (allyl), 65.07 (C5′),
75.28 (C3′), 85.44 (C4′), 88.07 (C1′), 111.08 (C5), 119.70 and
131.96 (vinyl of allyl), 137.82 (C4), 150.53 (C6), 163.77 (C2).
5-Meth yl-1-[(4a R,6R,7aR)-2,2-dim eth yl-4a-(2-pr open yl)-
t et r a h yd r ofu r o[3,2-d ] [1,3]d ioxin -6-yl]-1H -p yr im id in e-
2,4-d ion e (13d ). To a solution of 12d (5 mg, 0.018 mmol) in
2,2-dimethoxypropane (0.28 mL)-DMF (0.06 mL) was added
pyridinium p-toluenesulfonate (<1 mg) at room temperature,
and the mixture was stirred for 30 h. After removal of the
solvent, the residue was purified by preparative thin-layer
chromatography (ethyl acetate) to give 5-methyl-1-[(4aR,6R,
7aR)-2,2-dimethyl-4a-(2-propenyl)tetrahydrofuro[3,2-d][1,3]-
dioxin-6-yl]-1H-pyrimidine-2,4-dione 13d (5 mg, 86%) as a
colorless foam: [R]22D ) -29° (c ) 0.15, CHCl3); IR (neat) 1686,
1470, 1279, 1202, 1096 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.39
(3H, s), 1.44 (3H, s), 1.95 (3H, s), 2.08 (1H, d, J ) 15.4 Hz),
2.15 (1H, dd, J ) 14, 7.8 Hz), 2.23 (1H, dd, J ) 14, 6.5 Hz),
2.79 (1H, ddd, J ) 15.4, 8, 5 Hz), 3.93 (1H, d, J ) 14.5 Hz),
3.95 (1H, d, J ) 14.5 Hz), 4.25 (1H, d, J ) 5 Hz), 5.18 (2H, m),
5.79 (1H, m), 6.22 (1H, d, J ) 8 Hz), 8.04 (1H, s), 8.25 (1H,
br); 13C NMR (CDCl3) δ 12.60 (C5-Me), 19.41 and 28.12 (Me2C),
39.74 (C2′), 39.96 (allyl), 63.96 (C5′), 72.22 (C3′), 81.91 (C4′),
84.21 (C1′), 98.05 (Me2C), 109.66 (C5), 120.08 and 130.97 (vinyl
of allyl), 137.31 (C4), 150.38 (C6), 163.75 (C2).
1
1279, 1055 cm-1; 400 MHz H NMR (CDCl3-CD3OD ) 20:1)
δ 1.09 (3H, s), 1.82 (3H, d, J ) 1.1 Hz), 1.97 (1H, ddd, J )
14.7, 3.9, 2.6 Hz), 2.70 (1H, ddd, J ) 14.7, 7.8, 6 Hz), 3.69
(1H, d, J ) 11.6 Hz), 3.76 (1H, d, J ) 11.6 Hz), 4.12 (1H, dd,
J ) 6, 2.6 Hz), 6.09 (1H, dd, J ) 7.8, 3.9 Hz), 7.84 (1H, d, J )
1.1 Hz); 13C NMR (CDCl3) δ: 16.24 (C5-Me), 25.57 (C4′-Me),
44.50 (C2′), 69.45 (C5′), 79.36 (C3′), 87.67 (C4′), 90.82 (C1′),
114.49 (C5), 141.46 (C4), 154.87 (C6), 168.67 (C2).
5-Meth yl-1-[(4a S,6R,7a R)-2,2,4a -tr im eth yltetr a h yd r o-
fu r o[3,2-d][1,3]dioxin -6-yl]-1H-pyr im idin e-2,4-dion e (13c).
To a solution of 12c (7 mg, 0.027 mmol) in 2,2-dimethoxypro-
pane (0.28 mL)-DMF (0.08 mL) was added pyridinium p-
toluenesulfonate (<1 mg) at room temperature, and the
mixture was stirred for 50 h. After removal of the solvent, the
residue was purified by preparative thin-layer chromatography
(ethyl acetate) to give 5-methyl-1-[(4aS,6R,7aR)-2,2,4a-tri-
methyltetrahydrofuro[3,2-d][1,3]dioxin-6-yl]-1H-pyrimidine-2,4-
dione 13c (8 mg, 100%) as a colorless foam: [R]22 ) -3° (c )
D
0.15, CHCl3); IR (neat) 3189, 1694, 1472, 1379, 1283, 1094,
1028 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.12 (3H, s), 1.40 (3H,
s), 1.46 (3H, s), 1.95 (3H, s), 2.07 (1H, d, J ) 15.4 Hz), 2.79
(1H, ddd, J ) 15.4, 7.8, 4.6 Hz), 3.88 (1H, d, J ) 13.3 Hz),
4.01 (1H, d, J ) 13.3 Hz), 4.19 (1H, d, J ) 4.6 Hz), 6.19 (1H,
d, J ) 7.8 Hz), 8.06 (1H, s), 8.53 (1H, br); 13C NMR (CDCl3) δ:
12.61 (C5-Me), 18.82 and 21.24 (Me2C), 28.53 (C4′-Me), 39.66
(C2′), 65.08 (C5′), 73.17 (C3′), 79.60 (C4′), 83.92 (C1′), 98.01
(Me2C), 109.55 (C5), 137.44 (C4), 150.46 (C6), 163.91 (C2).
(2S,3R,5R)-3-H yd r oxy-2-(2-p r op en yl)-5-(5-m et h yl-2,4-
d ioxo-3,4-d ih yd r o-2H-p yr im id in -1-yl)tetr a h yd r ofu r a n -2-
ca r boxylic Acid Meth yl Ester (10d ). The ester 9 (9 mg) was
coevaporated with benzene, dried in vacuo, dissolved in THF
(1.3 mL)-HMPA (0.17 mL), and dried under molecular sieves
4A (5 pieces) with stirring for 1 h. To the solution of 9 (8.5
mg, 0.031 mmol) was added lithium diisopropylamide mono-
(tetrahydrofuran) (LDA) (Aldrich, 1.5 M in cyclohexane, 0.12
mL, 0.17 mmol) at -78 °C, and the mixture was stirred at
-78 °C for 5 min, -78 °C f room temperature for 5 min, and
room temperature for 10 min. tert-Butyllithium (1.7 M in
pentane, 0.09 mL, 0.15 mmol) was added to the solution at
-78 °C, and the mixture was stirred at -78 °C for 1 h. To the
solution was added allyl bromide (0.042 mL, 0.49 mmol) at
-78 °C, and the mixture was stirred at -78 °C for 30 min
and at -78 °C f -15 °C for 1.5 h. After the reaction was
quenched with MeOH (0.11 mL)-AcOH (0.036 mL), the
solvent was evaporated in vacuo. The residue was purified by
flash chromatography (ethyl acetate) to give (2S,3R,5R)-3-
hydroxy-2-(2-propenyl)-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-
pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid methyl ester
(2R,3R,5R)-3-Ben zen esu lfon yloxy-2-flu or o-5-(5-m et h -
yl-2,4-d ioxo-3,4-d ih yd r o-2H -p yr im id in -1-yl)t et r a h yd r o-
fu r a n -2-ca r boxylic Acid Meth yl Ester (10e). The ester 9
(9.5 mg) was coevaporated with benzene, dried in vacuo,
dissolved in THF (1.4 mL)-HMPA (0.17 mL), and dried under
molecular sieves 4A (five pieces) with stirring for 1 h. To the
solution of 9 (9 mg, 0.033 mmol) was added lithium diisopro-
pylamide mono(tetrahydrofuran) (LDA) (Aldrich, 1.5 M in
cyclohexane, 0.13 mL, 0.19 mmol) at -78 °C, and the mixture
was stirred at -78 °C for 5 min, -78 °C f room temperature
for 5 min, and room temperature for 10 min. tert-Butyllithium
(1.7 M in pentane, 0.095 mL, 0.16 mmol) was added to the
solution at -78 °C, and the mixture was stirred at -78 °C for
1 h. To the solution was added N-fluorobenzenesulfonimide
(NFSI) (110 mg, 0.35 mmol) in THF (0.3 mL) at -78 °C, and
the mixture was stirred at -78 °C f 30 °C for 1 h and at -30
°C f 0 °C for 15 min. After the reaction was quenched with
MeOH (0.12 mL)-AcOH (0.04 mL), the solvent was evaporated
in vacuo. The residue was purified by flash chromatography
(hexane/ethyl acetate ) 1:2) to give (2R,3R,5R)-3-benzene-
sulfonyloxy-2-fluoro-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-
pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid methyl ester
10e (7 mg, 49%) as a colorless foam: [R]24 ) -16° (c ) 0.4,
D
CHCl3); IR (neat) 2924, 1771, 1696, 1451, 1377, 1285, 1194,
1115, 743, 586 cm-1; 400 MHz 1H NMR (CDCl3) δ 1.84 (3H, d,
J ) 1.2 Hz), 2.37 (1H, ddd, J ) 16, 2.5, 1 Hz), 2.99 (1H, dddd,
J ) 16, 7.5, 5.5, 1.4 Hz), 3.78 (3H, s), 5.26 (1H, ddd, J ) 5.5,
5.5, 1 Hz), 6.60 (1H, ddd, J ) 7.5, 2.5, 2.5 Hz), 7.46 (1H, d, J
) 1.2 Hz), 7.60 (2H, m), 7.74 (1H, m), 7.85 (2H, m), 8.90 (1H,
br); 13C NMR (CDCl3) δ 12.64 (C5-Me), 35.98 (C2′), 53.75 (ester
Me), 79.70 (C3′, d, J ) 165 Hz), 86.49 (C1′, d, J ) 8 Hz), 111.95
10d (5 mg, 52%) as a colorless foam: [R]24 ) -21° (c ) 0.20,
D
CHCl3); IR (neat) 3370, 2930, 1752, 1696, 1474, 1281, 1101
cm-1; 200 MHz 1H NMR (CDCl3) δ 1.88 (3H, d, J ) 0.9 Hz),
2.32 (1H, m), 2.32 (1H, m), 2.34 (1H, m), 2.67 (2H, m), 3.20
(1H, br s), 3.85 (3H, s), 4.44 (1H, m), 5.16 (2H, m), 5.75 (1H,
m), 6.23 (1H, dd, J ) 7.6, 2.8 Hz), 7.92 (1H, s), 8.68 (1H, br s);

Preparation of 4′-Substituted Thymidines
J . Org. Chem., Vol. 66, No. 8, 2001 2635
(C5), 113.28 (C4′, d, J ) 939 Hz), 127.73 (2C of Ph), 129.69
(2C of Ph), 134.72 (1C of Ph), 134.96 (1C of Ph), 135.45 (C4),
150.04 (C6), 162.25 (C5′, d, J ) 129 Hz), 163.30 (C2).
(2R,3R,5R)-2-F lu or o-3-h yd r oxy-5-(5-m eth yl-2,4-d ioxo-
3,4-d ih yd r o-2H -p yr im i-d in -1-yl)t et r a h yd r ofu r a n -2-ca r -
boxylic Acid Meth yl Ester (10f). The ester 9 (13 mg) was
coevaporated with benzene, dried in vacuo, dissolved in THF
(1.9 mL)-HMPA (0.24 mL), and dried under molecular sieves
4A (eight pieces) with stirring for 1 h. To the solution of 9 (12.5
mg, 0.046 mmol) was added lithium diisopropylamide mono-
(tetrahydrofuran) (LDA) (Aldrich, 1.5 M in cyclohexane, 0.18
mL, 0.27 mmol) at -78 °C, and the mixture was stirred at
-78 °C for 5 min, -78 °C f room temperature for 7 min, and
room temperature for 10 min. tert-Butyllithium (1.7 M in
pentane, 0.13 mL, 0.22 mmol) was added to the solution at
-78 °C, and the mixture was stirred at -78 °C for 1 h. To the
solution were added N-fluorobenzenesulfonimide (NFSI) (156
mg, 0.495 mmol) in THF (0.48 mL) at -78 °C, and the mixture
was stirred at -78 °C for 20 min. After the reaction was
quenched with MeOH (0.2 mL)-AcOH (0.045 mL), the solvent
was evaporated in vacuo. The residue was purified by flash
chromatography (hexane/ethyl acetate ) 1:2) to give 10e (3
mg, 15%) and (2R,3R,5R)-2-fluoro-3-hydroxy-5-(5-methyl-2,4-
dioxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-car-
boxylic acid methyl ester 10f (4.6 mg, 30%), both as colorless
foams.
Hz), 111.35 (C5), 114.99 (C4′, d, J ) 930 Hz), 137.53 (C4),
150.48 (C6), 163.68 (C2), 164.33 (C5′, d, J ) 130 Hz).
1-(2R ,4R ,5S )-5-F lu or o-4-h yd r oxy-5-h yd r oxym e t h yl-
tetr a h yd r ofu r a n -2-yl)-5-m eth yl-1H-p yr im id in e-2,4-d ion e
(12e). To a solution of 10f (3.5 mg, 0.012 mmol) in THF (0.2
mL) was added LiBH4 (1 mg, 0.046 mmol) at room tempera-
ture, and the mixture was stirred for 2.5 h. After the mixture
was stirred with EtOH (0.2 mL) for 10 min and neutralized
with AcOH (0.01 mL) for 10 min, the solvent was evaporated
in vacuo. The residue was purified by flash chromatography
(ethyl acetate) to give 1-(2R,4R,5S)-5-fluoro-4-hydroxy-5-hy-
droxymethyltetrahydrofuran-2-yl)-5-methyl-1H-pyrimidine-
2,4-dione 12e (2.5 mg, 80%) as a colorless foam: [R]23D ) -40°
(c ) 0.05, CHCl3-MeOH ) 20:1); IR (neat) 3382, 2926, 1689,
1472, 1285, 1140, 1067 cm-1; 400 MHz 1H NMR (CDCl3-
CD3OD ) 20:1) δ 1.90 (3H, d, J ) 1.2 Hz), 2.04 (1H, ddd, J )
15, 2.7 Hz), 2.86 (1H, dddd, J ) 15, 9.0, 6.4, 1.4 Hz), 3.93 (1H,
dd, J ) 12.6, 10.2 Hz), 4.00 (1H, dd, J ) 22.5, 12.6 Hz), 4.46
(1H, dd, J ) 5.4, 5.3 Hz), 6.43 (1H, ddd, J ) 8.8, 2.4, 2.4 Hz),
7.65 (1H, d, J ) 1.2 Hz); 13C NMR (CDCl3) δ: 12.39 (C5-Me),
36.64 (C2′), 60.80 (C5′, d, J ) 124 Hz), 72.20 (C3′, d, J ) 159
Hz), 86.04 (C1′, d, J ) 13 Hz), 111.58 (C5), 120.75 (C4′, d, J )
920 Hz), 137.14 (C4), 150.65 (C6), 163.94 (C2).
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM47228) and the Universitywide
AIDS Research Program (R97-LA-139) for generous
financial support.
(2R,3R,5R)-2-Fluoro-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-di-
hydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid
methyl ester 10f: [R]24D ) -32° (c ) 0.2, CHCl3); IR (neat) 2926,
1761, 1694, 1472, 1318, 1285, 1115, 756 cm-1; 400 MHz 1H
NMR (CDCl3) δ 1.88 (3H, s), 2.39 (1H, dm, J ) 15 Hz), 2.87
(1H, ddd, J ) 15, 8.5, 6 Hz), 3.94 (3H, s), 4.28 (br s), 4.62 (1H,
m), 6.42 (1H, ddd, J ) 8.5, 2.5, 2.5 Hz), 7.67 (1H, s), 9.29 (1H,
br); 13C NMR (CDCl3) δ: 12.53 (C5-Me), 36.16 (C2′), 53.57
(ester Me), 74.11 (C3′, d, J ) 145 Hz), 88.30 (C1′, d, J ) 10
Su p p or tin g In for m a tion Ava ila ble: Proton and carbon
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O001223A