Stereoselectivity in the synthesis of 3′-deoxy-3′-C-(hydroxymethyl)uridines by hydroboration and conversion into a building block for various 3′-deoxy-3′-C-(methylene)uridine analogues

Article abstract of DOI:10.1002/1099-0690(200111)2001:22<4305::AID-EJOC4305>3.0.CO;2-9

The stereoselectivity in hydroboration of 3′-deoxy-3′-C-(methylene)uridine derivatives has been studied. Hydroboration of 3′-deoxy-3′-C-(methylene)uridine derivatives gave two 3′-deoxy-3′-C-hydroxymethyl stereoisomers (with ribo or xylo configuration). The influence of reagent (BH₃·Me₂S, or 9-borabicyclo[3.3.1]nonane (9-BBN-H)) and solvent (THF, toluene, or hexane) was investigated. Use of BH₃·Me₂S gave the xylo isomer as the main product. The highest preference for the ribo isomer was obtained by use of 9-BBN-H in hexane. Furthermore, 4-methoxytrityl protection of the hydroxy function at the 5′-position resulted in better stereoselectivity than that obtained by tert-butyldimethylsilyl protection, when 9-BBN-H was used as reagent. At best, hydroboration of 1-[2-O-(tert-butyldimethylsilyl)-3-deoxy-3-C-methylene-5-O-(4-methoxytrityl)- β-D-erythro-pentofuranosyl]uracil (3b) using 9-BBN-H in hexane gave a ribo to xylo (4b to 5b) isomer ratio of 82:18. The ribo isomer was converted into the corresponding mesylate 6 to allow for further functionalization. Subsequent substitution with azide and reduction afforded 1-[3-C-aminomethyl-2-O-(tert-butyldimethylsilyl)-3-deoxy-5-O-(4-methoxytrityl)- β-D-ribo-pentofuranosyl]uracil (8) in good overall yield (43% over 6 steps). Wiley-VCH Verlag GmbH, 2001.

Full text of DOI:10.1002/1099-0690(200111)2001:22<4305::AID-EJOC4305>3.0.CO;2-9

FULL PAPER
Stereoselectivity in the Synthesis of 3Ј-Deoxy-3Ј-C-(hydroxymethyl)uridines
by Hydroboration and Conversion into a Building Block for Various
3Ј-Deoxy-3Ј-C-(methylene)uridine Analogues
Anna Winqvist[a] and Roger Strömberg*[a]
Keywords: Enantioselectivity / Hydroboration / Nucleosides
The stereoselectivity in hydroboration of 3Ј-deoxy-3Ј-C-
than that obtained by tert-butyldimethylsilyl protection,
(methylene)uridine derivatives has been studied. Hydrobor- when 9-BBN-H was used as reagent. At best, hydroboration
ation of 3Ј-deoxy-3Ј-C-(methylene)uridine derivatives gave of 1-[2-O-(tert-butyldimethylsilyl)-3-deoxy-3-C-methylene-
two 3Ј-deoxy-3Ј-C-hydroxymethyl stereoisomers (with ribo or
xylo configuration). The influence of reagent (BH3·Me2S, or
9-borabicyclo[3.3.1]nonane (9-BBN-H)) and solvent (THF,
toluene, or hexane) was investigated. Use of BH3·Me2S gave
the xylo isomer as the main product. The highest preference
5-O-(4-methoxytrityl)-β-D-erythro-pentofuranosyl]uracil (3b)
using 9-BBN-H in hexane gave a ribo to xylo (4b to 5b) iso-
mer ratio of 82:18. The ribo isomer was converted into the
corresponding mesylate 6 to allow for further functionaliz-
ation. Subsequent substitution with azide and reduction af-
for the ribo isomer was obtained by use of 9-BBN-H in hex- forded 1-[3-C-aminomethyl-2-O-(tert-butyldimethylsilyl)-3-
ane. Furthermore, 4-methoxytrityl protection of the hydroxy
deoxy-5-O-(4-methoxytrityl)-β-D-ribo-pentofuranosyl]uracil
function at the 5Ј-position resulted in better stereoselectivity
(8) in good overall yield (43% over 6 steps).
Introduction
analogues containing 3Ј-N-modified (phosphoramid-
ates[12,13]
) and 3Ј-C-branched internucleoside linkages
[amide linkages[14Ϫ19] or methylene methylimino (MMI)
linkages[20,21]] have shown that they display enhanced bind-
ing to complementary RNA. Analysis of these modifica-
tions suggest that a substituent less electronegative than
oxygen in the 3Ј-position gives a sugar conformation typical
of A-type helixes.[12,16,22,23]
To the best of our knowledge, only a little work has been
done with 3Ј-C-branched analogues with 2Ј-hydroxyl func-
tions.[19] To investigate oligoribonucleotide analogues con-
taining 3Ј-C-branched internucleoside linkages further, de-
velopment of a convenient synthesis of a general building
block capable of being converted into differently func-
tionalized 3Ј-deoxy-3Ј-C-methylene ribonucleoside ana-
logues would be valuable. In this paper, a novel method
for preparation of a uridine analogue with its 3Ј-hydroxyl
function replaced by a hydroxymethyl group and further
conversion into the corresponding mesylate is presented.
Furthermore, conversion into the corresponding aminome-
thyl analogue, which is a building block for synthesis of the
3Ј-C-branched internucleoside amide linkage, is described.
Antisense oligonucleotides are oligonucleotide analogues
typically intended to bind to RNA (such as a mRNA of a
disease-related protein) in a sequence-specific fashion
through WatsonϪCrick base-pairing, to suppress gene ex-
pression.[1,2,3] In the design of antisense oligonucleotides
with good pharmacological properties, several aspects have
to be considered. Two important properties are resistance
to degradation by nucleases and high hybridization affinity
towards complementary RNA. From a general point of
view, RNA:RNA duplexes, which give rise to a helix of A-
type, are thermodynamically more stable than DNA:RNA
duplexes. Hence, a more stable duplex is in general obtained
if the antisense oligonucleotides are of RNA type. The first
generation antisense oligonucleotides were, however, of
the DNA type, in the form of phosphorothioate
oligodeoxyribonucleotides.[1Ϫ7]
In order to increase duplex stability, conformational pre-
organisation in a single-stranded antisense oligonucleotide
can be achieved through structural modification. One ap-
proach is to introduce a modification into the furanose moi-
eties. The gauche-effect from an electronegative group at
the 2Ј-position has been shown to shift the conformational
equilibrium toward the North conformers (largely 3Ј-
endo),[8,9] which in general results in oligonucleotide ana-
logues with increased hybridization affinity towards com-
plementary RNA.[10,11] Recent studies of oligonucleotide
Results and Discussion
Several synthetic strategies have been used in the past to
introduce a hydroxymethyl group as a substitute for the 3Ј-
hydroxyl function in deoxyribonucleosides[24Ϫ27] and ribon-
ucleosides.[28] This paper evaluates a strategy involving in-
troduction of the hydroxymethyl group by hydroboration of
3Ј-deoxy-3Ј-C-(methylene)uridine analogues. This strategy
also provides for early introduction of appropriate pro-
tecting groups prior to synthesis of building blocks for oli-
[a]
Division of Organic and Bioorganic Chemistry, MBB, Scheele
Laboratory, Karolinska Institutet,
171 77 Stockholm, Sweden
E-mail: Roger.Stromberg@mbb.ki.se
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the author.
Eur. J. Org. Chem. 2001, 4305Ϫ4311
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1122Ϫ4305 $ 17.50ϩ.50/0
4305

A. Winqvist, R. Strömberg
FULL PAPER
gomer synthesis: the 4-methoxytrityl (MMT) group for pro- 3b when treated with NaH, and is suggested to be the cor-
tection of the 5Ј-hydroxyl function and the tert-butyldime- responding 3Ј-hydroxy-3Ј-C-methyltriphenylphosphonium
thylsilyl (TBDMS) group for protection of the 2Ј-hydroxyl salt.
function.
The influence of reagent and solvent on the stereoselect-
Stereoselectivity and yield of the hydroboration step were ivity (Table 1) of the hydroboration step (Scheme 2) was in-
conceivable limiting features, due to the possibility of the vestigated for 3a using 9-borabicyclo[3.3.1]nonane (9-BBN-
formation of two stereoisomers with ribo or xylo pentofur- H) and BH3·Me2S in THF, toluene, or hexane. Subsequent
anosyl configurations. Influences on stereoselectivity oxidative treatment was carried out using NaBO3·4H2O,
through the use of different boranes and solvents were in- since the use of H2O2 in alkaline solution caused side reac-
vestigated for the 5Ј-O-TBDMS-protected 3Ј-deoxy-3Ј-C- tions, in particular the loss of TBDMS protecting groups.
methylene derivative 3a, with the goal of obtaining the ribo The use of H2O2 as oxidizing agent also gave an unidenti-
isomer in an adequate ratio over the xylo isomer. The best fied, UV-inactive side product. However, this problem was
conditions were then used for hydroboration of the 5Ј-O- negligible when NaBO3·4H2O was used. Oxidative treat-
MMT-protected derivative 3b.
ment with NaBO3·4H2O was complete within 30 hours;
In view of the fact that the stereoselectivity in hydrobor- after longer reaction times partial loss of the TBDMS
ation reactions can be directed by steric influences, we as- groups was observed. This problem was most noticeable
sumed that a large protecting group, such as the TBDMS with the primary TBDMS group.
group, for protection of the 2Ј-hydroxyl functions of 3a and
Hydroboration of the 5Ј-O-TBDMS-protected derivative
3b would increase the steric hindrance at the Re face, and 3a using BH3·Me2S in THF, toluene, or hexane gave the
consequently direct the borane reagent to the Si face. A xylo isomer 5a as the main product (entries 1Ϫ3). On the
disadvantage in the use of the TBDMS group or the MMT other hand, treatment with 9-BBN-H gave a considerably
group for protection of the hydroxyl function at the 5Ј-posi- higher proportion of the ribo isomer 4a. Furthermore, when
tions of 3a and 3b is that a large group can reduce stereo- 9-BBN-H was used as reagent, a solvent effect was observed
selectivity by shielding the Si face. However, initial protec- on changing from THF to toluene or hexane (entries 4Ϫ6).
tion by the MMT group, which is commonly used in oligon- A less polar solvent favored the formation of isomer 4a. In
ucleotide synthesis, provides for a substantial advantage in conclusion, then, 9-BBN-H in hexane was the best com-
the synthesis of building blocks.
bination in the synthesis of the ribo isomer; 4a and 5a were
Compounds 3a and 3b were prepared essentially accord- obtained in a ratio of 61:39 (entry 6). The desired product
ing to the procedure of Samano et al.[29] Oxidation of the 4a was isolated by silica gel chromatography in a yield of
2Ј,5Ј-O-protected uridines 1a and 1b (Scheme 1) gave 2a 35%.
and 2b in yields of 76% and 91%, respectively. Wittig reac-
Hydroboration of the 5Ј-O-MMT-protected derivative
tions were then carried out on 2a and 2b, using n-butylli- 3b, using 9-BBN-H in hexane and subsequent oxidative
thium and methyltriphenylphosphonium bromide in THF, treatment with NaBO3·4H2O, resulted in further improved
to afford the corresponding 3Ј-deoxy-3Ј-C-methylene deriv- stereoselectivity; isomers 4b and 5b were obtained in a ratio
atives 3a (96%) and 3b (95%). It is worth mentioning that of 82:18 (entry 8). The ribo isomer 4b was isolated by silica
no less than equimolar amounts of base relative to phos- gel chromatography in a yield of 64%. The configurations
phonium salt are preferred. When an excess of phosphon- of isomers 4a/4b and 5a/5b were established by rotating-
ium salt was used, a polar side product was obtained; this frame Overhauser effect spectroscopy (ROESY) experi-
did not decompose to give the 3Ј-deoxy-3Ј-C-methylene de- ments. Selected ROE contacts are outlined in Figure 1.
rivative, even upon heating. Similarly to results reported by
A comparison of the results from hydroboration of 3a
Matsuda et al.,[30] the polar side product converted into 3a/ and 3b using 9-BBN-H in THF or hexane suggests that
even switching between two relatively large protecting
groups for the hydroxyl function at the 5Ј-position has a
significant effect on the stereoselectivity (entry 4 vs.7 and
entry 6 vs. 8). A relatively small 5Ј-O-protecting group
might then be expected to improve the selectivity even fur-
ther. However, as stated earlier, this would imply a strategy
with extra protection and deprotection steps, which would
be less desirable overall.
Conversion of the hydroxyl function in 4b into a leaving
group enables further functionalization to be achieved
through substitution. Different nucleophiles can be used in
order to obtain building blocks for various 3Ј-C-branched
backbone modified oligoribonucleotides, such as amide-
linked nucleosides etc. Treatment of 4b with methanesul-
fonyl chloride gave the mesylate 6 in 88% yield. Treatment
of 6 with lithium azide in DMF gave 7 (94%), and sub-
Scheme 1
4306
sequent reduction of the azide using triphenylphosphane in
Eur. J. Org. Chem. 2001, 4305Ϫ4311

Synthesis of 3Ј-Deoxy-3Ј-C-(hydroxymethyl)uridines
FULL PAPER
Table 1. Results from hydroboration of 3a and 3b with BH3·Me2S or 9-BBN-H in various solvents.
Entry
Reaction of
compound
Reagent
Reaction conditions
Ratio of ribo and
xylo isomers[a]
Yield of the ribo
isomer 4 (a or b)[b]
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3b
3b
BH3·Me2S
BH3·Me2S
BH3·Me2S
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
THF, 0 °C, 120 h.
Toluene, 0 °C, 120 h
Hexane, 0 °C, 120 h
THF, 20 °C, 20 h
Toluene, 20 °C, 20 h
Hexane, 20 °C, 20 h
THF, 20 °C, 20 h
7:93
13:87
9:91
46:54
53:47
61:39
75:25
82:18
6%
7%
8%
41%
43%
45% (35%)[c]
63%
Hexane, 20 °C, 20 h
71% (64%)[c]
[a]
1
Isomeric ratios of ribo and xylo isomers, established by H NMR experiments on crude product mixtures after oxidative treatment
[b]
1
with NaBO3·4H2O and workup. Ϫ
material and side products into account. Ϫ Isolated yield after purification by silica gel chromatography.
Yield of the ribo isomer 4 (a or b), established by H NMR, taking traces of remaining starting
[c]
Scheme 3
Conclusions
We have developed an efficient method, involving highly
stereoselective hydroboration of 2Ј,5Ј-O-protected 3Ј-deoxy-
3Ј-C-(methylene)uridine derivatives, for preparation of a ur-
idine analogue with its 3Ј-hydroxyl function replaced by a
hydroxymethyl group. A study of the stereoselectivity of the
hydroboration showed that by changing to 9-BBN-H and a
less polar solvent, the proportion of ribo isomer could be
increased from 7 to 61%. A change in the 5Ј-protection fur-
ther increased the proportion of ribo isomer to 82%. The
overall method proved to be fully compatible with the
standard protecting group strategy normally adopted in oli-
goribonucleotide synthesis, thus avoiding further protecting
group manipulation. The synthesis of the hydroxymethyl
analogue requires only three additional steps compared to
that of a ribonucleoside bearing the same standard RNA
synthesis protection, and it is produced in good yield. Con-
version of the hydroxymethyl group of 4b into the corres-
ponding mesylate readily allowed further functionalization
through substitution, and this derivative is therefore valu-
able as a general building block in the synthesis of various
3Ј-C-branched uridine analogues. As an example, substitu-
Scheme 2
Figure 1. Informative ROE contacts observed for compounds 4a,
4b, 5a, and 5b, which confirms the total configurations.
dioxane and aqueous ammonia afforded the 3Ј-deoxy-3Ј-C- tion with azide and reduction afforded 3Ј-C-aminomethyl-
aminomethyl derivative 8 in a yield of 94% (Scheme 3). The 3Ј-deoxy derivative 8, part of the building block for amide-
overall yield of 8, over 6 steps from 1b, was a respectable linked nucleotides, in good overall yield. Use of this strategy
43%.
for synthesis of other 3Ј-C-branched nucleoside analogues,
Eur. J. Org. Chem. 2001, 4305Ϫ4311
4307

A. Winqvist, R. Strömberg
FULL PAPER
was stirred at 0 °C for 1 h. Ethyl acetate (100 mL) was added with
vigorous stirring. The mixture was filtered through silica gel (6 cm
layer packed in a minimum volume of ethyl acetate), into saturated
aqueous NaHCO3 (250 mL), which gave a colorless filtrate. The
silica gel was carefully washed with ethyl acetate (ca 500 mL) until
no remaining product could be observed by TLC analysis. The or-
ganic layer was separated and washed with saturated aqueous
NaHCO3 (250 mL). The organic layer was dried (Na2SO4), concen-
trated (Ͻ 25 °C to avoid depyrimidination). The residue was further
dried by evaporation of added toluene, and was then purified by
silica gel column chromatography (toluene/ethyl acetate, 2:1, v/v)
to give crystalline 2b (9.35 g, 91%): Rf ϭ 0.31 (toluene/ethyl acetate,
5:1, v/v). Ϫ 1H NMR (CD3CN, 20 °C, δ ϭ 1.94): δ ϭ 9.25 (s, 1 H,
NH), 7.62 (d, J5,6 ϭ 8.2 Hz, 1 H, H-6), 7.39Ϫ7.24 and 6.89 (14 H,
MMT), 6.13 (d, J1Ј,2Ј ϭ 7.8 Hz, 1 H, H-1Ј), 5.59 (d, 1 H, H-5), 4.58
(d, 1 H, H-2Ј), 4.39 (m, 1 H, H-4Ј), 3.77 (s, 3 H, OCH3), 3.48 (dd,
and extension of the methodology for the other common
ribonucleosides, is in progress.
Experimental Section
General Remarks and Methods: NMR spectra were recorded using
1
a Bruker AVANCE DRX 400 instrument (400.13 MHz in H and
100.62 MHz in 13C). Chemical shifts are given in ppm, downfield
from external TMS. Most assignments in 1H and 13C NMR spectra
1
1
were made by standard H-1H-COSY and H-13C-HMQC experi-
ments; uridine numbering is used. ROESY experiments were car-
ried out in CD3CN at 20 °C, using a mixing time of 250 ms. Ϫ
Silica gel column chromatography was generally carried out using
˚
Matrex silica, 60A (35Ϫ70 µm, Amicron). Isomeric mixtures were
purified by column chromatography on silica gel 60 (40Ϫ63 µm,
Merck). Ϫ TLC analysis was carried out on pre-coated 60 F254
silica gel plates (Merck), with detection by UV light and/or by char-
ring with 8% sulfuric acid in methanol. Solutions were concen-
trated under reduced pressure using temperatures not exceeding 40
°C, unless otherwise stated. Reagents and solvents were of ordinary
commercial grade unless otherwise stated. THF was distilled at at-
mospheric pressure over CaH2 prior to use. DMF was distilled over
J5Јa,5Јb ϭ 10.8 Hz, J4Ј,5Јa ϭ 3.7 Hz, 1 H, H-5Јa), 3.30 (dd, J4Ј,5Јb
ϭ
2.0 Hz, 1 H, H-5Јb), 0.89 [s, 9 H, SiC(CH3)3], 0.15 (s, 3 H, SiCH3),
0.09 (s, 3 H, SiCH3). Ϫ 13C NMR (CD3CN, 20 °C, δ ϭ 118.41 and
1.40): δ ϭ 209.8 (C-3Ј), 163.6, 160.1, 151.7, 145.1, 144.9, 140.6 (C-
6), 135.6, 131.4, 129.3, 129.2, 129.1, 128.5, 128.4, 114.4, 104.4 (C-
5), 88.1, 86.5 (C-1Ј), 81.6 (C-4Ј), 77.3 (C-2Ј), 64.2 (C-5Ј), 56.1
(OCH3), 25.9 [SiC(CH3)3], 19.0 [SiC(CH3)3], Ϫ4.33 (SiCH3),
Ϫ4.92 (SiCH3).
˚
CaH2 at reduced pressure and was stored over 4-A molecular
sieves. Acetonitrile (Labscan p.a.) and methanol were dried over 3-
1-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-3-C-methylene-β-D-
˚
A molecular sieves. Hexane, pyridine (Labscan p.a.), and CH2Cl2
erythro-pentofuranosyl]uracil (3a): n-Butyllithium in hexane (2 ,
5.55 mL, 11.1 mmol, 3 equiv.) was added to a slurry of methyltri-
phenylphosphonium bromide (3.97 g, 11.1 mmol, 3 equiv.) in dry
THF (20 mL). The mixture was stirred for 2 h and then cooled to
0 °C. A solution of 2a (1.74 g, 3.7 mmol) in dry THF (20 mL) was
added dropwise. The reaction mixture was stirred at room temper-
ature for 18 h, and was then poured into saturated aqueous ammo-
nium chloride (100 mL) and extracted with ethyl acetate (200 mL).
The organic layer was washed with brine (100 mL). The combined
water layers were washed with ethyl acetate (50 mL). The combined
organic layers were dried (Na2SO4) and concentrated. The crude
product was purified by silica gel column chromatography (step-
wise gradient of 10Ϫ20% v/v ethyl acetate in toluene) to give 3a
(1.66 g, 96%): Rf ϭ 0.33 (toluene/ethyl acetate, 5:1, v/v); NMR
spectroscopic data were in agreement with published data.[29]
˚
were dried over 4-A molecular sieves. Toluene was dried with and
stored over sodium. 2Ј-O-(tert-Butyldimethylsilyl)-5Ј-O-(4-methox-
ytrityl)-uridine (1b) was synthesized essentially according to stand-
ard procedures.[31] LiN3 was prepared as follows: a solution of
NaN3 (1.8 equiv.) in 0.16  aqueous Li2SO4 (135 mL) was stirred
at 40 °C until a clear solution was obtained. Ethanol (96%, 675
mL) was added dropwise. The mixture was filtered to remove the
precipitate and the filtrate was concentrated. The residue was fur-
ther dried by evaporation of added toluene, and was then dried
over P2O5 at 40 °C in vacuum.
1-[2,5-Bis-O-(tert-butyldimethylsilyl)-β-D-erythro-3-pentofuran-3-
ulosyl]uracil (2a): A solution of 2Ј,5Ј-bis-O-(tert-butyldimethylsilyl)-
uridine[32] (1a, 4.55 g, 9.63 mmol) in dry CH2Cl2 (60 mL) was ad-
ded to a mixture of CrO3 (4.33 g, 43.3 mmol, 4.5 equiv.), acetic
anhydride (4.36 mL, 46.2 mmol, 4.8 equiv.), and dry pyridine (7.78
mL, 96.3 mmol, 10 equiv.) in dry CH2Cl2 (60 mL). The reaction
mixture was stirred at room temperature for 40 minutes. Ethyl acet-
ate (60 mL) was added with vigorous stirring. The mixture was
filtered through silica gel (5 cm layer packed in a minimum volume
of ethyl acetate), into saturated aqueous NaHCO3 (150 mL), which
gave a colorless filtrate. The silica gel was carefully washed with
ethyl acetate (ca 300 mL) until no additional product could be ob-
served by TLC analysis. The organic layer was separated and
washed with saturated aqueous NaHCO3 (150 mL). The organic
layer was dried (Na2SO4) and concentrated (Ͻ25 °C to avoid depy-
rimidination). The residue was taken up in diethyl ether (10 mL)
and was then triturated by addition of hexane (100 mL) to give
2a (3.45 g, 76%): Rf ϭ 0.27 (toluene/ethyl acetate, 5:1, v/v); NMR
spectroscopic data were in agreement with published data.[33]
1-[2-O-(tert-Butyldimethylsilyl)-3-deoxy-5-O-(4-methoxytrityl)-3-C-
methylene-β-D-erythro-pentofuranosyl]uracil (3b): n-Butyllithium in
hexane (2 , 21.2 mL, 42.4 mmol, 3 equiv.) was added to a slurry
of methyltriphenylphosphonium bromide (15.13 g, 42.4 mmol, 3
equiv.) in dry THF (80 mL). The mixture was stirred for 2 h, and
then cooled to 0 °C. A solution of compound 2b (8.88 g,
14.12 mmol) in dry THF (80 mL) was added dropwise. The reac-
tion mixture was stirred at room temperature for 20 h, and was
then poured into saturated aqueous ammonium chloride (200 mL)
and extracted with ethyl acetate (400 mL). The organic layer was
washed with brine (200 mL). The combined water layers were
washed with ethyl acetate (100 mL). The combined organic layers
were dried (Na2SO4) and concentrated. The crude product was
purified by silica gel column chromatography (stepwise gradient of
10Ϫ50% v/v ethyl acetate in toluene) to give 3b (8.45 g, 95%): Rf ϭ
1
1-[2-O-(tert-Butyldimethylsilyl)-5-O-(4-methoxytrityl)-β-
3-pentofuran-3-ulosyl]uracil (2b):
72 mmol, 4.5 equiv.), Ac2O (7.26 mL, 76.9 mmol, 4.8 equiv.), and H-6), 7.44Ϫ7.13, 6.89 (14 H, MMT), 5.79 (d, J1Ј,2Ј ϭ 6.9 Hz, 1 H,
dry pyridine (12.93 mL, 160 mmol, 10 equiv.) in dry CH2Cl2 (100 H-1Ј), 5.39 (d, 1 H, H-5), 5.33 (br. s, 1 H, 3Ј-CH2), 5.21 (br. s, 1
mL) was cooled to °C and solution of 2Ј-O-(tert- H, 3Ј-CH2), 4.84 (m, 1 H, H-2Ј), 4.74 (m, 1 H, H-4Ј), 3.78 (s, 3 H,
butyldimethylsilyl)-5Ј-O-(4-methoxytrityl)uridine (1b, 10.10 g, OCH3), 3.42 (dd, J5Јa,5Јb ϭ 10.5 Hz, J4Ј,5Јa ϭ 3.8 Hz, 1 H, H-5Јa),
D-erythro- 0.31 (toluene/ethyl acetate, 5:1, v/v). Ϫ H NMR (CD3CN, 20 °C,
A
mixture of CrO3 (7.2 g, δ ϭ 1.94): δ ϭ 9.16 (br. s, 1 H, NH), 7.68 (d, J5,6 ϭ 8.1 Hz, 1 H,
0
a
16 mmol) in dry CH2Cl2 (100 mL) was added. The reaction mixture
3.21 (dd, J4Ј,5Јb ϭ 2.5 Hz, H-5Јb), 0.91 [s, 9 H, SiC(CH3)3], 0.14 (s,
4308
Eur. J. Org. Chem. 2001, 4305Ϫ4311

Synthesis of 3Ј-Deoxy-3Ј-C-(hydroxymethyl)uridines
FULL PAPER
3 H, SiCH3), 0.04 (s, 3 H, SiCH3). Ϫ 13C NMR (CD3CN, 20 °C,
was stirred at 20 °C for 20 hours. The mixture was concentrated
δ ϭ 118.41 and 1.40): δ ϭ 163.8, 160.0, 151.8, 148.4, 145.6, 145.2, and the residue was dissolved in dry THF (10 mL). The solution
141.2 (C-6), 136.0, 131.5, 129.3, 129.08, 129.06, 128.80, 128.76,
was cooled to 0 °C, and methanol (4 mL) was added dropwise.
128.29, 128.27, 114.3, 109.9 (3Ј-CH2), 103.6 (C-5), 88.3 (C-1Ј), 87.9, When gas evolution had ceased, water (6 mL) was added, followed
80.4 (C-4Ј), 77.1 (C-2Ј), 67.3 (C-5Ј), 56.1 (OCH3), 26.1 [SiC(CH3)3], by NaBO3·4H2O (2.91 g, 18.9 mmol, 24 equiv.). The ice-water bath
18.8 [SiC(CH3)3], Ϫ4.36 (SiCH3), Ϫ4.66 (SiCH3).
Ϫ
was removed and the mixture was stirred vigorously at room tem-
C36H42N2O6Si: calcd. C 68.98, H 6.75, N 4.47; found C 68.82, H perature for 30 hours. The mixture was filtered to remove the pre-
6.67, N 4.42.
cipitate. The filtrate was diluted with ethyl acetate (50 mL) and
washed with brine (2ϫ 25 mL). The organic layer was dried
(Na2SO4) and concentrated. The residue was purified by silica gel
column chromatography (CHCl3/methanol, 98:2, v/v, containing
0.1% v/v triethylamine) to give the product as an isomeric mixture.
The two isomers were separated by column chromatography on
silica gel (30 g, Merck 40Ϫ63 µm) using a stepwise gradient of
0Ϫ3% (v/v) acetone in CHCl3 containing 0.8Ϯ 0.2% v/v ethanol
and 0.1% v/v triethylamine (the acetone concentration was in-
creased by 0.5% v/v per 100 mL eluent), to give 4b (330 mg, 64%)
and 5b (81 mg, 16%). 4b: Rf ϭ 0.14 (acetone/CHCl3 containing
0.8Ϯ 0.2% v/v ethanol, 5:95 v/v). Ϫ 1H NMR (CD3CN, 20 °C, δ ϭ
1.94): δ ϭ 8.88 (s, 1 H, NH), 7.90 (d, J5,6 ϭ 8.1 Hz, 1 H, H-6),
7.48Ϫ7.26 and 6.90 (14 H, MMT), 5.63 (d, J1Ј,2Ј ϭ 1.5 Hz, 1 H, H-
1Ј), 5.12 (dd, 1 H, H-5), 4.44 (dd, J2Ј,3Ј ϭ 4.8 Hz, 1 H, H-2Ј), 4.14
(m, 1 H, H-4Ј), 3.78 (s, 3 H, OCH3), 3.69 (m, 1 H, CH2OH), 3.53
(m, 1 H, CH2OH), 3.47 (dd, J5Јa,5Јb ϭ 2.2, Hz, J4Ј,5Јa ϭ 11.2 Hz,
1 H, H-5Јa), 3.40 (dd, J4Ј,5Јb ϭ 3.7 Hz, 1 H, H-5Јb), 2.71 (t, 1 H,
CH2OH), 2.45 (m, 1 H, H-3Ј), 0.90 [s, 9 H, SiC(CH3)3], 0.17 (s, 3
H, SiCH3), 0.09 (s, 3 H, SiCH3). Ϫ 13C NMR (CD3CN, 20 °C, δ ϭ
118.41 and 1.40): δ ϭ 164.3, 160.0, 151.5, 145.6, 145.3, 141.5 (C-
6), 136.1, 131.6, 129.5, 129.1, 128.3, 114.3, 101.9 (C-5), 92.4 (C-
1Ј), 88.0, 83.1 (C-4Ј), 78.5 (C-2Ј), 64.3 (C-5Ј), 59.1 (CH2OH), 56.1
(OCH3), 45.4 (C-3Ј), 26.3 [SiC(CH3)3], 18.8 [SiC(CH3)3], Ϫ4.26
(SiCH3), Ϫ5.07 (SiCH3). Ϫ C36H44N2O7Si: calcd. C 67.05, H 6.88,
N 4.34; found C 66.93, H 6.77, N 4.32.
1-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-3-C-hydroxymethyl-
β-D-ribo-pentofuranosyl]uracil (4a): A solution of compound 3a
(0.29 g, 0.62 mmol) in dry hexane (8 mL) was cooled to 0 °C, and
9-BBN-H (0.43 g, 3.71 mmol, 6 equiv.) was added. The reaction
mixture was left on a melting ice-water bath, and was then stirred
at 20 °C for 20 hours. The mixture was concentrated and the res-
idue was dissolved in dry THF (8 mL). The solution was cooled to
0 °C, and methanol (3.2 mL) was added dropwise. When gas evolu-
tion had ceased, water (4.8 mL) was added, followed by
NaBO3·4H2O (2.33 g, 11.1 mmol, 24 equiv.). The ice-water bath
was removed and the mixture was stirred vigorously at room tem-
perature for 30 hours. The mixture was filtered to remove the pre-
cipitate. The filtrate was diluted with ethyl acetate (50 mL) and
washed with brine (2ϫ 25 mL). The organic layer was dried
(Na2SO4) and concentrated. The residue was purified by silica gel
column chromatography (CHCl3/methanol, 98:2, v/v) to give the
product as an isomeric mixture. The two isomers were separated
by column chromatography on silica gel (30 g, Merck 40Ϫ63 µm)
using a stepwise gradient of 5%-40% v/v ethyl acetate in toluene
(the ethyl acetate concentration was increased by 5% v/v per 100
mL eluent), to give 4a (106 mg, 35%) and 5a (94 mg, 31%). 4a:
1
Rf ϭ 0.33 (hexane/ethyl acetate, 6:4, v/v). Ϫ H NMR (CDCl3, 20
°C, δ ϭ 7.26): δ ϭ 9.96 (s, 1 H, NH), 8.08 (d, J5,6 ϭ 8.2 Hz, 1 H,
H-6), 5.88 (d, J1Ј,2Ј ϭ 1.1, 1 H, H-1Ј), 5.62 (d, 1 H, H-5), 4.39 (dd,
J2Ј,3Ј ϭ 4.9 Hz, 1 H, H-2Ј), 4.25 (m, 1 H, H-4Ј), 4.07 (dd, J5Јa,5Јb ϭ
11.6 Hz, J4Ј,5Јa ϭ 2.3 Hz, 1 H, H-5Јa), 3.83Ϫ3.72 (m, 3 H, H-5Јb
and CH2OH), 2.39 (br. s, 1 H, CH2OH), 2.32 (m, 1 H, H-3Ј), 0.90
[s, 9 H, SiC(CH3)3], 0.88 [s, 9 H, SiC(CH3)3], 0.19 (s, 3 H, SiCH3),
0.10 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3), 0.08 (s, 3 H, SiCH3). Ϫ
13C NMR (CDCl3, 20 °C, δ ϭ 77.01): δ ϭ 163.8 (C-4), 150.4 (C-
2), 140.3 (C-6), 101.3 (C-5), 91.0 (C-1Ј), 82.8 (C-4Ј), 78.4 (C-2Ј),
62.6 (C-5Ј), 58.9 (CH2OH), 43.1 (C-3Ј), 25.8 [SiC(CH3)3], 25.6
[SiC(CH3)3], 18.3 [SiC(CH3)3], 17.9 [SiC(CH3)3], Ϫ4.06, Ϫ5.00 and
Ϫ5.08 (4 ϫ SiCH3). Ϫ C22H42N2O6Si2: calcd. C 54.29, H 8.70, N
5.76; found C 54.29, H 8.84, N 5.70.
1-[2-O-(tert-Butyldimethylsilyl)-3-deoxy-3-C-hydroxymethyl-5-O-
(4-methoxytrityl)-β-D-xylo-pentofuranosyl]uracil (5b): Rf ϭ 0.18
(acetone/CHCl3 containing 0.8Ϯ 0.2% v/v ethanol, 5:95 v/v). Ϫ 1H
NMR (CD3CN, 20 °C, δ ϭ 1.94): δ ϭ 9.00 (s, 1 H, NH), 7.55 (d,
J5,6 ϭ 8.1 Hz, 1 H, H-6), 7.44Ϫ7.24 and 6.89 (14 H, MMT), 5.74
(d, J1Ј,2Ј ϭ 5.3 Hz, 1 H, H-1Ј), 5.32 (dd, 1 H, H-5), 4.43 (m, 1 H,
H-4Ј), 4.25 (m, 1 H, H-2Ј), 3.78 (s, 3 H, OCH3), 3.60 (m, 1 H,
CH2OH), 3.52 (m, 1 H, CH2OH), 3.42Ϫ3.41 (ABX, 2 H, H-5Јa
and b), 2.80 (t, 1 H, CH2OH), 2.47 (m, 1 H, H-3Ј), 0.86 [s, 9 H,
SiC(CH3)3], 0.07 (s, 3 H, SiCH3), 0.02 (s, 3 H, SiCH3). Ϫ 13C NMR
(CD3CN, 20 °C, δ ϭ 118.41 and 1.40): δ ϭ 163.8, 160.0, 151.8,
145.4, 145.3, 141.5 (C-6), 136.1, 131.6, 129.5, 129.1, 128.3, 114.3,
102.9 (C-5), 90.6 (C-1Ј), 88.3, 79.8 (C-4Ј), 77.2 (C-2Ј), 64.4 (C-5Ј),
59.9 (CH2OH), 56.1 (OCH3), 50.7 (C-3Ј), 26.0 [SiC(CH3)3], 18.5
[SiC(CH3)3], Ϫ4.46 (SiCH3), Ϫ4.47 (SiCH3).
1-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-3-C-hydroxymethyl-
β-D-xylo-pentofuranosyl]uracil (5a): Rf ϭ 0.28 (hexane/ethyl acetate,
1
6:4, v/v). Ϫ H NMR (CDCl3, 20 °C, δ ϭ 7.26): δ ϭ 9.62 (s, 1 H,
NH), 7.74 (d, J5,6 ϭ 8.1 Hz, 1 H, H-6), 5.86 (d, J1Ј,2Ј ϭ 6.0 Hz,
1 H, H-1Ј), 5.71 (d, 1 H, H-5), 4.23 (m, 1 H, H-4Ј), 4.25 (t, 1 H,
H-2Ј), 3.95 (dd, J5Јa,5Јb ϭ 11.7 Hz, J4Ј,5Јa ϭ 3.0 Hz, 1 H, H-5Јa),
3.88Ϫ3.74 (m, 3 H, H-5Јb and CH2OH), 3.06 (dd, 1 H, CH2OH),
2.59 (m, 1 H, H-3Ј), 0.92 [s, 9 H, SiC(CH3)3], 0.82 [s, 9 H,
SiC(CH3)3], 0.124 (s, 3 H, SiCH3), 0.116 (s, 3 H, SiCH3), Ϫ0.01 (s,
3 H, SiCH3), Ϫ0.10 (s, 3 H, SiCH3). Ϫ 13C NMR (CDCl3, 20 °C,
δ ϭ 77.01): δ ϭ 163.3 (C-4), 150.6 (C-2), 140.5 (C-6), 102.6 (C-5),
88.8 (C-1Ј), 78.8, 75.3, 62.9 (C-5Ј), 59.6 (CH2OH), 49.7 (C-3Ј), 25.7
[SiC(CH3)3], 25.4 [SiC(CH3)3], 18.1 [SiC(CH3)3], 17.6 [SiC(CH3)3],
Ϫ4.23, Ϫ4.27 and Ϫ4.93 (4ϫ SiCH3).
1-[2-O-(tert-Butyldimethylsilyl)-3-deoxy-3-C-methanesulfomethyl-5-
O-(4-methoxytrityl)-β-D-ribo-pentofuranosyl]uracil (6): Compound
4b (130 mg, 0.20 mmol) was dissolved in dry acetonitrile/pyridine,
9:1 (2 mL) and the solution was cooled to 0 °C. Methanesulfonyl
chloride (18.6 µL, 0.24 mmol, 1.2 equiv.) was added. The ice-water
bath was removed and the reaction mixture was stirred at room
temperature for 20 hours. The reaction mixture was partitioned
between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (50 mL).
The water layer was washed with CH2Cl2 (20 mL). The combined
1-[2-O-(tert-Butyldimethylsilyl)-3-deoxy-3-C-hydroxymethyl-5-O- organic layers were dried (Na2SO4) and concentrated. The residue
(4-methoxytrityl)-β-
compound 3b (0.50 g, 0.798 mmol) in dry hexane (10 mL) was co-
D
-ribo-pentofuranosyl]uracil (4b): A solution of
was further dried by evaporation of added toluene. The crude prod-
uct was purified by silica gel column chromatography (toluene/ethyl
oled to 0 °C, and 9-BBN-H (0.58 g, 4.79 mmol, 6 equiv.) was ad- acetate, 2:1 v/v), to give crystalline 6 (128 mg, 88%): Rf ϭ 0.08
1
ded. The reaction mixture was left on a melting ice-water bath, and
(toluene/ethyl acetate, 5:1, v/v). Ϫ H NMR (CD3CN, 20 °C, δ ϭ
Eur. J. Org. Chem. 2001, 4305Ϫ4311
4309

A. Winqvist, R. Strömberg
1.94): δ ϭ 9.66 (s, 1 H, NH), 7.86 (d, J5,6 ϭ 8.1, 1 H, H-6), Ϫ5.07 (SiCH3). Ϫ C36H45N3O6Si: calcd. C 67.16, H 7.04, N 6.53;
FULL PAPER
7.47Ϫ7.26 and 6.90 (14 H, MMT), 5.64 (d, J1Ј,2Ј ϭ 0.9 Hz, 1 H, H-
1Ј), 5.14 (d, 1 H, H-5), 4.53 (dd, J2Ј,3Ј ϭ 4.9 Hz, 1 H, H-2Ј), 4.37
(dd, J ϭ 7.0, 2J ϭ 10.1 Hz, 1 H, CH2OMs), 4.23 (dd, J ϭ 6.3, 2J ϭ
10.1 Hz, 1 H, CH2OMs), 4.20 (m, 1 H, H-4Ј), 3.78 (s, 3 H, OCH3),
3.49 (dd, J5Јa,5Јb ϭ 11.3 Hz, J5Јa,4Ј ϭ 2.3 Hz, 1 H, H-5Јa), 3.43 (dd,
J5Јb,4Ј ϭ 3.5 Hz, 1 H, H-5Јb), 2.98 [s, 3 H, CH3S(O)2O], 2.80 (m, 1
H, H-3Ј), 0.91 [s, 9 H, SiC(CH3)3], 0.19 (s, 3 H, SiCH3), 0.14 (s, 3
H, SiCH3). Ϫ 13C NMR (CD3CN, 20 °C, δ ϭ 118.41 and 1.40):
δ ϭ 164.2, 160.1, 151.6, 145.5, 145.2, 141.4 (C-6), 135.9, 131.7,
129.5, 129.2, 129.1, 128.8, 114.4, 102.1 (C-5), 92.4 (C-1Ј), 88.1, 82.4
(C-4Ј), 80.0 (C-2Ј), 67.7 (CH2OMs), 63.8 (C-5Ј), 56.1 (OCH3), 42.9
(C-3Ј), 37.8 [CH3S(O)2O], 26.3 [SiC(CH3)3], 18.8 [SiC(CH3)3],
Ϫ4.12 (SiCH3), Ϫ5.10 (SiCH3). Ϫ C37H46N2O9SSi: calcd. C 61.47,
H 6.41, N 3.88, S 4.44; found C 61.58, H 6.58, N 3.77, S 4.56.
found C 66.72, H 7.19, N 6.35.
Experimental Procedure for the Determination of the Stereoselectiv-
ity in Hydroboration of 3a and 3b with Different Reagents
(BH3·Me2S or 9-BBN-H) in Various Solvents (THF, toluene, or hex-
ane): Test reactions for hydroboration by BH3·Me2S (3 equiv.) were
carried out on a 43 µmol scale (of 3a) in 0.51 mL of THF, toluene,
and hexane. The reaction mixtures were kept at 0 °C for 120 h. Test
reactions for hydroboration by 9-BBN-H (6 equiv.) were carried
out on a 43 µ mol scale of the 1-[2,5-O-protected 3-deoxy-3-C-
methylene-β--erythro-pentofuranosyl]uracil derivatives (3a and
3b) in 0.51 mL THF, toluene, and hexane. The reaction mixtures
were stirred at 20 °C for 20 h. All reaction mixtures were concen-
trated. Subsequent oxidative treatments of the reactions with
NaBO3·4H2O (18 equiv.) in 1.2 mL THF/methanol/H2O (5:2:3
v/v). The mixtures were stirred vigorously for 30 h at 20 °C, and
were then centrifuged. The supernatant was removed, diluted with
ethyl acetate, extracted with brine, and the organic layers were then
concentrated. The residues were further dried by evaporation of
1-[3-C-Azidomethyl-2-O-(tert-butyldimethylsilyl)-3-deoxy-5-O-(4-
methoxytrityl)-β-D-ribo-pentofuranosyl]uracil (7): Compound 6
(25 mg, 0.035 mmol) was dissolved in dry DMF (1 mL). LiN3
(10.1 mg, 0.207 mmol, 6 equiv.) was added and the reaction mixture
was stirred at 60 °C for 20 hours. The reaction mixture was diluted
with ethyl acetate (15 mL) and washed with water (2ϫ 15 mL) and
brine (15 mL). The organic layer was dried (Na2SO4) and concen-
trated. The residue was purified by silica gel column chromato-
graphy (stepwise gradient of 0Ϫ35% v/v ethyl acetate in toluene)
to give 7 (22 mg, 94%): Rf ϭ 0.29 (toluene/ethyl acetate, 5:1, v/v).
1
added acetonitrile, and were then analyzed by H NMR. Isomeric
ratios were determined by integration of signals originating from
H-6 in the respective isomers. The chemical shifts for H-6 of the
products 4a, 5a, 4b, and 5b are given above.
Acknowledgments
We thank the Swedish Natural Science Research Council and the
Swedish Research Council for Engineering Sciences for financial
support.
Ϫ
1H NMR (CD3CN, 20 °C, δ ϭ 1.94): δ ϭ 9.09 (s, 1 H, NH),
7.92 (d, J5,6 ϭ 8.1, 1 H, H-6), 7.47Ϫ7.26 and 6.90 (14 H, MMT),
5.62 (br. s, 1 H, 1 H, H-1Ј), 5.17 (d, 1 H, H-5), 4.44 (d, J2Ј,3Ј
ϭ
4.6 Hz, 1 H, H-2Ј), 4.08 (m, 1 H, H-4Ј), 3.78 (s, 3 H, OCH3), 3.57
(dd, J5Јa,5Јb ϭ 11.5 Hz, J5Јa,4Ј ϭ 1.8 Hz, 1 H, H-5Јa), 3.52 (dd, 3J ϭ
7.9, 2J ϭ 12.4 Hz, 1 H, CH2N3), 3.37 (dd, J5Јb,4Ј ϭ 3.4 Hz, H-5Јb),
[1]
A. De Mesmaeker, R. Häner, P. Martin, H. E. Moser, Acc.
3
2
3.22 (dd, J ϭ 6.2, J ϭ 12.4 Hz, 1 H, CH2N3), 2.52 (m, 1 H, H-
3Ј), 0.90 [s, 9 H, SiC(CH3)3], 0.19 (s, 3 H, SiCH3), 0.14 (s, 3 H,
SiCH3). Ϫ 13C NMR (CD3CN, 20 °C, δ ϭ 118.41 and 1.40): δ ϭ
164.3, 160.0, 151.5, 145.4, 145.2, 141.4 (C-6), 135.9, 131.6, 129.5,
129.4, 129.1, 128.3, 114.3, 102.0 (C-5), 92.4 (C-1Ј), 88.1, 83.1 (C-
4Ј), 78.2 (C-2Ј), 63.4 (C-5Ј), 56.1 (OCH3), 48.6 (CH2N3), 42.5 (C-
3Ј), 26.3 [SiC(CH3)3], 18.8 [SiC(CH3)3], Ϫ4.09 (SiCH3), Ϫ5.16
(SiCH3).
Chem. Res. 1995, 40, 366Ϫ374.
[2]
S. M. Freier, K-H. Altmann, Nucleic Acids Res. 1997, 25,
4429Ϫ4443.
[3]
E. Uhlmann, A. Peyman, Chem. Rev. 1990, 90, 543Ϫ584.
[4]
W. Stec, G. Zon, W. Egan, B. Stec, J. Am. Chem. Soc. 1984,
106, 6077Ϫ6079.
[5]
W. J. Stec, G. Zon, J. Chromat. 1985, 326, 236Ϫ280.
C. J. Markus-Sekura, A. M. Woerner, K. Shinozuka, G. Zon,
[6]
G. V. Quinnan, Nucleic Acids Res. 1987, 15, 5749Ϫ5763.
[7]
C. A. Stein, J. L. Tonkinson, L. Yakubov, Pharmac. Ther. 1991,
1-[3-C-Aminomethyl-2-O-(tert-butyldimethylsilyl)-3-deoxy-5-O-(4-
methoxytrityl)-β-D-ribo-pentofuranosyl]uracil (8): Compound 7
52, 365Ϫ384.
[8]
W. K. Olson, J. Am. Chem. Soc. 1982, 104, 278Ϫ286.
[9]
(21.5 mg, 0.032 mmol) was dissolved in dioxane (0.3 mL). Triphen-
ylphosphane (18 mg, 0.069 mmol, 2 equiv.) and 32% aqueous
ammonia (0.24 mL) were added, and the mixture was stirred for
10 hours. The reaction mixture was concentrated, and traces of
water were removed by lyophilization. The residue was purified by
silica gel column chromatography (stepwise gradient of 0Ϫ10%
v/v methanol in CHCl3 containing 0.5% v/v triethylamine) to give
8 (19 mg, 94%): Rf ϭ 0.47 (CHCl3/methanol, 9:1, v/v, containing
W. Guschlbauer, K. Jankowski, Nucleic Acids Res. 1980, 8,
1421Ϫ1433.
[10]
A. M. Kawasaki, M. D. Casper, S. M. Freier, E. A. Lesnik, M.
C. Zounes, L. L. Cummins, C. Gonzalez, P. D. Cook, J. Med.
Chem. 1993, 36, 831Ϫ841.
H. Inoue, Y. Hayase, A. Imura, S. Iwai, K. Miura, E. Ohtsuka,
Nucleic Acids Res. 1987, 15, 6131Ϫ6148.
J. K. Chen, R. G. Schultz, D. H. Lloyd, S. M. Gryaznov, Nuc-
leic Acids Res. 1995, 23, 2661Ϫ2668.
S. M. Gryaznov, D. H. Lloyd, J. K. Chen, R. G. Schultz, L. A.
[11]
[12]
1
0.5% v/v Et3N). Ϫ H NMR (CD3CN, 20 °C, δ ϭ 1.94): δ ϭ 7.98
[13]
(d, J5,6 ϭ 8.1, 1 H, H-6), 7.48Ϫ7.27 and 6.90 (14 H, MMT), 5.60
(br. s, 1 H, H-1Ј), 5.14 (d, 1 H, H-5), 4.44 (d, J2Ј,3Ј ϭ 4.4 Hz, 1 H,
H-2Ј), 4.05 (m, 1 H, H-4Ј), 3.77 (s, 3 H, OCH3), 3.51 (dd, J5Јa,5Јb ϭ
11.3 Hz, J5Јa,4Ј ϭ 2.0 Hz, 1 H, H-5Јa), 3.37 (dd, J5Јb,4Ј ϭ 3.5 Hz,
1 H, H-5Јb), 2.79 (dd, 3J ϭ 8.5, 2J ϭ 12.5 Hz, 1 H, CH2NH2), 2.55
DeDionisio, L. Ratmeyer, W. D. Wilson, PNAS 1995, 92,
5798Ϫ5802.
[14]
J. Lebreton, A. Waldner, V. Fritsch, R. M. Wolf, A. De Mes-
maeker, Tetrahedron Lett. 1994, 35, 5225Ϫ5228.
I. Idziak, G. Just, M. J. Damha, P. A. Giannaris, Tetrahedron
Lett. 1993, 34, 5417Ϫ5420.
E. Rozners, D. Katkevica, E. Bizdena, R. Strömberg (unpub-
lished results).
A. De Mesmaeker, C. Lesueur, M-O. Bevierre, A. Waldner, V.
Fritsch, R. Wolf, Angew. Chem. Int. Ed. Engl. 1996, 35,
2790Ϫ2794.
A. De Mesmaeker, J. Lebreton, C. Jouanno, V. Fritsch, R. M.
Wolf, S. Wendeborn, Synlett 1997, 1287Ϫ1290.
[15]
3
2
(dd, J ϭ 5.1, J ϭ 12.5 Hz, 1 H, CH2NH2), 2.30 (m, 1 H, H-3Ј),
[16]
0.89 [s, 9 H, SiC(CH3)3], 0.20 (s, 3 H, SiCH3), 0.15 (s, 3 H, SiCH3).
Ϫ
13C NMR (CD3CN, 20 °C, δ ϭ 118.41 and 1.40): δ ϭ 164.4,
[17]
159.9, 151.5, 145.5, 145.3, 141.4 (C-6), 136.0, 131.6, 129.5, 129.4,
129.1, 129.0, 128.2, 114.2, 101.7 (C-5), 92.2 (C-1Ј), 88.0, 83.4 (C-
4Ј), 78.2 (C-2Ј), 63.7 (C-5Ј), 56.0 (OCH3), 45.8 (C-3Ј), 38.4
(CH2NH2), 26.2 [SiC(CH3)3], 18.8 [SiC(CH3)3], Ϫ4.00 (SiCH3),
[18]
4310
Eur. J. Org. Chem. 2001, 4305Ϫ4311

Synthesis of 3Ј-Deoxy-3Ј-C-(hydroxymethyl)uridines
FULL PAPER
M. M. Faul, B. E. Huff, S. E. Dunlap, S. A. Frank, J. E. Fritz,
S. W. Kaldor, M. E. LeTourneau, M. A. Staszak, J. A. Ward,
J. A. Werner, L. L. Winneroski, Tetrahedron 1997, 53,
8085Ϫ8104.
[19]
[27]
[28]
E. Rozners, R. Strömberg, Nucleosides & Nucleotides 1997,
16, 967Ϫ970.
[20]
J-J. Vasseur, F. Debart, Y. S. Sanghvi, P. D. Cook, J. Am. Chem.
Soc. 1992, 114, 4006Ϫ4007.
D. PeocЈh, E. E. Swayze, B. Bhat, S. Dimock, R. Griffey, Y. S.
[21]
T-S. Lin, J-L. Zhu, G. E. Dutschman, Y-C. Cheng, W. H. Pru-
soff, J. Med. Chem. 1993, 36, 353Ϫ362.
Sanghvi, Nucleosides & Nucleotides 1997, 16, 959Ϫ962.
[22]
[29]
[30]
V. Mohan, R. H. Griffey, D. R. Davis, Tetrahedron 1995 51,
V. Samano, M. J. Robins, Synthesis 1991, 283Ϫ288.
A. Matsuda, H. Okajima, A. Masuda, A. Kakefuda, Y. Yoshi-
mura, T. Ueda, Nucleosides & Nucleotides 1992, 11, 197Ϫ226.
K. K. Ogilvie, S. Beaucage, A. L. Schifman, N. Y. Theriault,
K. L. Sadana, Can. J. Chem. 1978, 56, 2768Ϫ2780.
G. H. Hakimelahi, Z. A. Proba, K. K. Ogilvie, Can. J. Chem.
1982, 60, 1106Ϫ1113.
6855Ϫ6868.
[23]
A. De Mesmaeker, A. Waldner, J. Lebreton, P. Hoffmann, V.
[31]
[32]
[33]
Fritsch, R. M. Wolf, S. M. Freier, Angew. Chem. Int. Ed. Engl.
1994, 33, 226Ϫ229.
[24]
T. Kofoed, M. H. Caruthers, Tetrahedron Lett. 1996, 37,
6457Ϫ6460.
[25]
M. G. B. Drew, S. Gorsuch, J. H. M. Gould, J. Mann, J. Chem.
F. Hansske, D. Madej, M. J. Robins, Tetrahedron 1984, 40,
125Ϫ135.
Soc., Perkin Trans. 1 1999, 969Ϫ978.
Y. S. Sanghvi, R. Bharadwaj, F. Debart, A. De Mesmaeker,
[26]
Received April 25, 2001
Synthesis 1994, 1163Ϫ1166.
[O01204]
Eur. J. Org. Chem. 2001, 4305Ϫ4311
4311