Synthesis of (5′S)-5′-C-alkyl-2′-deoxynucleosides

Article abstract of DOI:10.1002/1522-2675(20010131)84:1<87::AID-HLCA87>3.0.CO;2-1

We describe the synthesis of (5′S)-5′-C-butylthymidine (5a), of the (5′S)-5′-C-butyl- and the (5′S)-5′-C-isopentyl derivatives 16a and 16b of 2′-deoxy-5-methylcytidine, as well as of the corresponding cyanoethyl phosphoramidites 9a,b and 14a,b, respective

Full text of DOI:10.1002/1522-2675(20010131)84:1<87::AID-HLCA87>3.0.CO;2-1

Helvetica Chimica Acta ± Vol. 84 (2001)
87
Synthesis of (5'S)-5'-C-Alkyl-2'-deoxynucleosides
by Huldreich Trafelet1), Eugen Stulz, and Christian Leumann*
Department of Chemistry and Biochemistry, University of Berne, Freiestr. 3, CH-3012 Bern
We describe the synthesis of (5'S)-5'-C-butylthymidine (5a), of the (5'S)-5'-C-butyl- and the (5'S)-5'-C-
isopentyl derivatives 16a and 16b of 2'-deoxy-5-methylcytidine, as well as of the corresponding cyanoethyl
phosphoramidites 9a,b and 14a,b, respectively. Starting from thymidin-5'-al 1, the alkyl chain at C(5') is
introduced via Wittig chemistry to selectively yield the (Z)-olefin derivatives 3a and 3b (Scheme 2). The
secondary OH function at C(5') is then introduced by epoxidation followed by regioselective reduction of the
epoxy derivatives 4a and 4b with diisobutylaluminium hydride. In the latter step, a kinetic resolution of the
diastereoisomer mixture 4a and 4b occurs, yielding the alkylated nucleoside 2a and 2b, respectively, with (5'S)-
configuration in high diastereoisomer purity (de ˆ 94%). The corresponding 2'-deoxy-5-methylcytidine
derivatives are obtained from the protected 5'-alkylated thymidine derivatives 7a and 7b via known base
interconversion processes in excellent yields (Scheme 3). Application of the same strategy to the purine
nucleoside 2'-deoxyadenine to obtain 5'-C-butyl-2'-deoxyadenosine 25 proved to be difficult due to the
sensitivity of the purine base to hydride-based reducing agents (Scheme 4).
1. Introduction. ± With the intention to study the effects of minor-groove hydration
on structure and stability of the DNA double helix, we became interested in the
preparation and biophysical investigation of oligodeoxynucleotides containing 5'-C-
butyl- and 5'-C-isopentyl-substituted (5'S)-2'-deoxynucleosides. Since these nucleoside
analogues were unknown, we needed to develop a synthesis for the corresponding
deoxynucleosides as well as for their phosphoramidite building blocks for standard,
solid-phase oligodeoxynucleotide chemistry.
Several approaches to the preparation of 5'-C-alkyl deoxynucleosides are reported
in the literature. The synthesis of the 5'-C-methyl-substituted deoxyribonucleosides, the
simplest members of this class, via deoxygenation of the corresponding hexofuranose
nucleosides thereby pioneered the field [1]. More recent and more general approaches
involve the use of the corresponding nucleosid-5'-al (CH2(5')OH replaced by
CH(5')ˆO) as starting materials, to which the 5'-C-substituents were added either
via organometallic reagents [2][3] or via aldol-type chemistry [4][5]. A radical
approach has been used to prepare 5'-C-allylated nucleosides starting from 5'-
selenonucleosides [6]. Probably the most versatile strategy, however, was developed by
Wang and Middelton [7]. As a key intermediate, they prepared the 5',6'-epoxyhex-
ofuranose nucleosides, which could selectively be substituted at the C(6') position with
various heteronucleophiles and cyanide.
We report here the synthesis of the hitherto unknown 5'-C-butyl and 5'-C-
isopentylthymidines as well as on the 5'-C-butyl- and 5'-C-isopentyl-substituted 2'-
1
)
Present address: Siegfried AG, CH-4800 Zofingen.

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deoxy-5-methylcytidines starting from natural thymidine via Wittig chemistry of the
nucleosid-5'-al, followed by an epoxidation/reduction pathway.
2. Results and Discussion. ± 2.1. (5'S)-5'-C-Butyl- and (5'S)-5'-C-Isopentylthymi-
dines and the Corresponding 2'-(Cyanoethyl Phosphoramidites). In initial experiments,
we investigated scope and limitations of direct alkylation of thymidin-5'-al 1 (Scheme 1)
by organometallic reagents. Compound 1 is accessible in 3 steps from thymidine by oxida-
tion of the 5'-OH group with Dess-Martin periodinane [8]. The results of direct addition
of various butyl-derived organometallic reagents to 1 are summarized in the Table.
Scheme 1. Synthesis of 5'-C-Alkylthymidines via Direct Addition of Organometal Reagents to Thymidin-5'-al 1
TBDMS ˆ tBuMe2Si
The addition of BuLi gave 5'-C-butyl-3'-O-[(tert-butyl)dimethylsilyl]thymidine
(2a) in poor yields and poor diastereoselectivity (Entry 1). Reaction of 1 with BuMgBr
in Et2O in the presence of the Lewis acid MgBr2 led to a small selectivity increase in
favor of the desired (5'S) diastereoisomer of 2a (Entry 3)2).
Neither addition of Bu4NBr nor the workup with ethylenediaminetetraacetic acid
(EDTA) [10] could improve the yield significantly. As the main by-product in all
experiments, the reduced 3'-O-[(tert-butyl)dimethylsilyl]thymidine was obtained, most
likely as a result of a b-hydride transfer [10] of the Grignard reagent to the carbonyl C-
atom. Also the change of the organometallic reagent to BuCeCl2 [11] or BuTi(OiPr)3
did not improve the yield or the diastereoselectivity (Entries 5 and 6). The failure in
this direct approach prompted us to change strategy.
2
)
The assignment of the configuration at the newly formed stereocenter was achieved by comparison of the
1H-NMR difference NOE spectra of the corresponding cyclic silyl ether derivatives (5'S)-6a and (5'R)-6a
[9]. One diastereoisomer showed NOEs between H C(4') and H C(5'), as well as between H C(5') and
3
CH2(7') ), while the other isomer showed NOEs between H C(3') and H C(5'), as well as between
H
C(4') and CH2(6'). This is in agreement with the assignment of the (5'S)-configuration to the former and
(5'R)-configuration to the latter isomer.

Helvetica Chimica Acta ± Vol. 84 (2001)
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Table. Direct Addition of Various Butylmetallic Reagents to 1: Exper. Conditions and Diastereoselectivity Data
Entry
BuMR (equiv.)
Solvent
T [8]
t [h]
Yield [%]
(5'S)-2a/5'(R)-2a
1
2
3
4
5
6
BuLi (2.2)
BuMgBr (5)
BuMgBr (5) ‡ MgBr2 (5)
BuMgBr (4) ‡ Bu4NBr (4)
BuCeCl2 (3)
Et2O
Et2O
Et2O
Et2O
THF
Et2O
76
76
76
76
76
0
2.0
3.0
3.5
2.7
5.0
23
37
30
43
37
5a)
n. d.
50 : 50
62 : 38
50 : 50
64 : 36
52 : 48
BuTi(O-iPr)3 (3)
48.0
a) Besides 28% of 1.
Wittig olefination of 1 with butyl- or isopentyltriphenylphosphonium ylide in THF
at low temperature gave 3a in 65% and 3b in 54% from 3-O-[(tert-butyl)dimethyl-
silyl]thymidine (1) (Scheme 2).
Scheme 2
a) 3 equiv. of alkylphosphonium ylide, THF 788 ! r.t.; 65% (3a), 54% (3b). b) 1.9 equiv. of mCIPBA,
CH2Cl2, 38 ! 78; 74% (4a), 77% (4b). c) 2 ± 4 equiv. of DIBAH, THF, 788, 6.5 h; 40% (2a), 31% (2b).
d) 1 equiv. of Bu4NF, THF, r.t., 12 ± 24 h; 95% (5a), 95% (8a), 74% (8b). e) 1.2 ± 2.4 equiv. of pixyl chloride,
pyridine, r.t., 16 h; 91% (7a), 87% (7b). f) 4 equiv. of iPr2NEt, 1.5 equiv. of PCl(OCH2CH2CN)(iPr2N), THF,
r.t., 2 h; 91% (9a), 73% (9b). TBDMS ˆ tBuMe2Si
For both 3a and 3b, the (E)/(Z) ratio (assignment by 1H-NMR NOE spectroscopy,
see Exper. Part) was ca. 1:9. Epoxidation with 3-chloroperbenzoic acid (mCIPBA) in
CH2Cl2 afforded 4a and 4b, respectively, in yields of 70 ± 80% and in diastereoisomer

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ratios (5'S,6'R)/(5'R,6'S)3) of ca. 1.8 :1. Diastereoselection in this reaction was thus
comparable to the best cases in the direct alkylation approach (Table). As expected,
the reduction of the diastereoisomer mixtures 4a and 4b with the Lewis acid
diisobutylaluminium hydride (DIBAH) in THF at low temperature proceeded with
regiospecificity, yielding, e.g., 40% of 2a along with 33% of recovered starting material.
Unexpectedly, a high diastereoisomer ratio (5'S)/(5'R) of 97:3 was observed in the
product 2a, which is due to the kinetic control of the reaction. Although via this kinetic
resolution, 2a (5'S) and 2b (5'S) were obtained in acceptable diastereoisomer purity, we
generally preferred to separate the diastereomer mixture of 4a and 4b by flash
chromatography (FC) before reduction. Therefore, 2a(5'S)- and 2b (5'S) were usually
prepared from the diastereoisomerically pure (5'S,6'R)-4a and -4b3) in 84 and 68%
yield, respectively.
Desilylation of 2a (5'S) to 5a was achieved in 95% yield with Bu4NF. Attempts to
introduce the routinely used 4,4'-dimethoxytrityl protecting group at the 5'-OH group
in satisfactory yield failed. We, therefore, switched to the sterically less-demanding 9-
phenyl-9H-xanthen-9-yl (ˆ pixyl) protecting group [12]. Reaction of 2a and 2b (both
(5'S)) with pixyl chloride under standard conditions gave 7a and 7b in 91% and 87%
yield, respectively. Subsequent desilylation with Bu4NFat room temperature (! 8a and
8b, resp.) and phosphitylation gave the corresponding 2'-(cyanoethyl phosphorami-
dites) 9a and 9b in good to excellent yields.
2.2. 5'-C-Butyl- and 5'-C-Isopentyl-Substituted (5'S)-2'-Deoxy-5-methylcytidines and
Their Corresponding 2'-Cyanoethyl Phosphoramidites. We planned to obtain the 5'-C-
alkylated 2'-deoxy-5-methylcytidine phosphoramidite building blocks from 7a and 7b
via a known base-interconversion process [13] (Scheme 3).
Thus, 7a and 7b were first transformed into the 1,2,4-1H-triazol-1-yl derivatives 10a
and 10b with POCl3 and 1,2,4-1H-triazole in 87 and 91% yield, respectively. Treatment
of 10a and 10b with conc. NH3 in dioxane gave the 5-methylcytidine derivatives 11a and
11b almost quantitatively. N4-Benzoylation with benzoyl chloride in pyridine at room
temperature furnished 12a and 12b in 87 and 70% yield, respectively. The analogous
reaction sequence as applied in the thymidine series (silyl-ether cleavage (!13a,b) and
phosphitylation) yielded the 2'-(cyanoethyl phosphoramidites) 14a and 14b. The
benzoate 12a could also be directly prepared from 10a via nucleophilic aromatic
substitution with the benzamide anion in 87% yield. The free nucleosides 16a and 16b
were obtained after quantitative desilylation of 11a and 11b with Bu4NF and pixyl-
group removal with a mild acid via 15a and 15b, respectively.
2.3. 5'-C-Butyl-2'-deoxyadenosine. To test whether the alkylation procedure also
applies to purine nucleosides, we prepared the 2'-deoxyadenosin-5'-al 17 from 2'-
deoxyadenosine in 5 steps [14] (Scheme 4). From the reaction of 17 with butyltriphen-
ylphosphonium ylide, the Wittig product 19 was obtained in more than 70% yield and a
(Z)/(E) ratio of 91:9 (1H-NMR). Interestingly, if the reaction was quenched at 788,
the hydroxy phosphonium intermediate 18 of the Wittig reaction could also be isolated
and separately transformed into 19 by treatment with base. The epoxidation of 19 with
mCIPBA gave only small amounts of the desired epoxy derivative 20, mainly because
3
)
For convenience, the alkyl substituents at C(5') are numbered by an extension of the monosaccharide
numbering (C(6'), C(7') etc.).

Helvetica Chimica Acta ± Vol. 84 (2001)
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Scheme 3
a) 14 equiv. of 1,2,4-1H-triazole, 3 equiv. of POCl3, 13 equiv. of Et3N, r.t., 1 h, 87% (10a), 91% (10b). b) 25% aq.
NH3 soln., dioxane, r.t.; 2 h, 92% (11a), quant. (11b). c) 5 equiv. of KH, 4 equiv. of PhCONH2, THF, r.t., 1 h;
87% (12a). d) 3.2 equiv. of PhCOCl, pyridine, 0 ! r.t., 23 h, then 25% aq. NH3 soln., 10 min.; 70% (12b). e) 1.1
i
equiv. of Bu4NF, THF, r.t., 12 ± 24 h; 99% (13a), quant. (13b), 54% (15a), 47% (15b). f) 4 equiv. of Pr2NEt,
1.5 ± 2.2 equiv. of PCl(OCH2CH2CN)(iPr2N), THF, r.t., 2 h; 83% (13a), 84% (13b). g) Cl2CHCOOH, THF/
H2O 9 :1, r.t., 15 min; quant. (16a); 80% AcOH/THF 4 :1, r.t., 48 h; 69% (16b). TBDMS ˆ tBuMe2Si
Scheme 4.
a) 3 equiv. of BuP(Ph)3Br, 3 equiv. of NaHMDS, THF, 788 ! r.t. 4.75 h; 76%. b) 1.2 equiv. of DMDO,
CH2Cl2, 208 ! r.t., 22 h; 71%. c) 1 equiv. of BH3 ´ THF, THF, 788, 30 min, then 8 equiv. of Oxoneꢀ, 47%
(21) from (5'S,6'R)-20; 76% (22) from (Z)-19.
of acid-catalyzed depurination [15]. The alternative use of dimethyldioxirane
(DMDO) [16] improved the yield of 20 to 71%, the by-products arising from known
side reactions [17]. To our surprise, reactions of 20 directed towards epoxide ring

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opening ( ! 25) failed. Instead, on treatment with DlBAH or BH3 ´ THF complex, the
nucleobase- reduced nucleoside 21 was isolated in 47 or 49% yield.
Direct hydroboration of 19 to give 25 also failed. Again the corresponding
nucleobase-reduced compound 22 was obtained, this time in yields as high as 76%.
After these results, we changed to the strategy developed by Wang and Middelton
[7] (Scheme 5). Thus, reaction of 2'-deoxyadenosin-5'-al 17 with methyltriphenylphos-
phonium ylide in THF at 788 gave 23 in 70% yield. The following epoxidation with
DMDO never gave more than a rather poor 30% of 24 as diastereoisomer mixture
(77:23), along with usually 30% of starting material. CuI-catalyzed nucleophilic
epoxide opening at the C(6') position3) with PrMgBr at low temperature finally
furnished 25 in 62% yield. Thus, with this reaction sequence, 5'-alkylated deoxyaden-
osine nucleosides can be obtained. However, yields and selectivity of the reactions
deserve further improvement.
Scheme 5
a) 3 equiv. of CH2ˆP(Ph)3Br, 3 equiv. of NaHMDS, THF, 788 ! r.t., 2 h; 70%; b) 4 equiv. of DMDO,
CH2Cl2, 08 ! r.t., 2 d; 30%. c) 45 equiv. of PrMgBr, 0.5 equiv. of CuI, THF,
TBDMS ˆ tBuMe2Si
78 to
188, 2 h; 62%.
2.4. Confirmation of the Relative Configuration at C(5') by X-Ray Analysis. The
assignment of the configuration at C(5'), which was determined for the 5'-C-alkylated
1
thymidines by H-NMR difference NOE spetroscopy of the cyclic silyl derivative 6a,
was corroborated by the X-ray analysis of 15a (Fig.)4).
In addition, the X-ray structure of 15a shows the furanose ring in the 3'-endo
conformation. This is not surprising considering the large substituent at C(4'). A
second, more important feature is that the torsion angle g lies in the ‡ sc range which
corresponds to that in A- and B-DNA. This was not a priori to be expected after
introduction of a butyl chain at C(5'). Furthermore, refinement of the structure showed
that the butyl chain is flexible. It occurs in two conformations, one having two the other
having only one gauche arrangement within the C-chain. In the crystal, one molecule of
MeOH is packed between the base and sugar part of 15a, bridging them via H-bonds.
This gives rise to two layers in the crystal lattice: a hydrophilic layer containing the
4
)
Crystallographic data (excluding structure factors) for the structure of 15a have been deposited with the
Cambridge Crystallographic Data Centre as deposition No. CCDC-148358. Copies of the data can be
obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
‡44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk.

Helvetica Chimica Acta ± Vol. 84 (2001)
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Fig. 1. ORTEP Plot of crystals of 15a: a) stereoscopic view (25% probability thermal ellipsoids), b) the two
conformations of the butyl chain, and c) view along the crystallographic a-axis

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nucleobase, the sugar moiety, and the MeOH, and a hydrophobic layer containing the
pixyl group and the butyl side chain.
3. Conclusions. ± (5'S)-5'-C-Butyl- and (5'S)-5'-C-isopentylthymidine and 5'-C-
butyl- and 5'-C-isopentyl-substituted (5'S)-2'-deoxy-5-methylcytidine as well as the
corresponding 2'-(cyanoethyl phosphoramidite) building blocks for solid-phase oligo-
nucleotide synthesis are accessible via the Wittig/epoxidation/reduction approach
presented here. It is conceivable that, with this synthesis, a large variety of 5'-C-
alkylnucleosides may be obtained. However, further improvement in the control of
diastereoselectivity at C(5') is desirable. The route described corresponds to a variation
of the known ꢁepoxide routeꢂ [7], and thus complements the palette of synthetic
methodologies towards 5'-C-substituted nucleosides. The synthesis of corresponding
oligodeoxynucleotides as well as a structural and thermochemical analysis of duplexes
containing these 5'-C-alkylated nucleosides by UV-spectroscopic methods and by
isothermal titration calorimetry has recently been completed [9] and will be reported
soon.
We thank the BENEFRI Small Molecule Crystallography Service directed by Prof. Helen Stoeckli-Evans
for measuring the X-ray data set, and Prof. Peter Bigler for measuring the NOE spectra.
Experimental Part
General. All reactions were carried out under Ar starting from thymidine (Fluka, purum). Chemicals and
solvents: Dess-Martin periodane [8], 1.1m Bu4NF soln. in THF, 2-cyanoethyl diisopropylphosphoramidochlor-
idite (Aldrich), THF, distilled over K/benzophenone, pyridine distilled over CaH2, CH2Cl2, distilled over P2O5;
all other reagents: Fluka purum or puriss. TLC: pre-coated glass plates SIL G-25 UV254 (Macherey-Nagel);
visualization: UV (254 nm) and anisaldehyde stain (EtOH (180 ml), AcOH (10 ml), anisaldehyde (10 ml),
conc. H2SO4 (2 ml)). Flash chromatography (FC): silica gel (30 ± 60 mm) Baker. M.p.: uncorrected; Büchi 510.
[a]D: Perkin-Elmer polarimeter; l ˆ 10 cm, c in g/100 ml. UV Spectra: Varian-Cary 3E-UV/VIS photo-
spectrometer connected to a Compaq ProLinea-3/25-zs personal computer. IR: 1600-FT-IR Perkin-Elmer
spectrometer; nÄ in cm 1. 1H- and 13C-NMR: Bruker AC-300 (300 and 75 MHz resp.); if not otherwise stated, all
spectra in CDCl3; d in ppm rel. to CHCl3 (ˆ 7.27 (1H) and 77.00 (13C) ppm, resp.), J in Hz; 13C multiplicities from
DEPT spectra; arbitrary numbering of the 5'-O-alkyl substituent3). 1D-NOE: Bruker DRX-500 (500 MHz);
d(irradiated) ! d(observed). 31P-NMR: Bruker AMX 400 (161.92 MHz); d in ppm rel. to 85% phosphoric acid.
MS (m/z (%)): Varian MAT CH-7A, ionization energy 70 eV; only selected peaks; LSI: AutoSpec Q VG, matrix
or DTT/DTE 2,2',2''-nitrilotris[ethanol] (1,4-dithio-dl-threitol/1,4-dithioerythritol) 4 :1. Elemental analyses:
Mikroanalytisches Laboratorium, ETH-Zürich.
(5'Z)-5'-C-Butylidene-3'-O-[(tert-butyl)dimethylsilyl]-5'-deoxythymidine (3a). To a suspension of butyl-
triphenylphosphonium bromide (2.88 g, 7.2 mmol) in abs. THF (16 ml), 2m sodium hexamethyldisilazide
(NaHMDS) in THF (3.6 ml) was added dropwise and stirred at r.t. for 30 min, and then under reflux for 1 h. To
the cooled ( 788) soln., a soln. of 1 (dried by repeated co-evaporation with abs. toluene; 850 mg, 2.4 mmol) in
THF (4 ml) was added. After 4 h, stirring was continued at r.t. for another 12 h. The suspension was diluted with
tert-butyl methyl ether (tBuOMe) (40 ml) and poured into sat. NH4Cl soln. (25 ml), the aq. phase extracted with
tBuOMe (3 Â 40 ml), the combined org. phase dried (MgSO4) and evaporated, and the residue submitted to FC
(75 g, hexane/AcOEt 7 :3): 3a (619 mg, 65%). White solid. Anal. data from a crystallized (hot hexane) sample.
TLC (hexane/AcOEt 1 :1): Rf 0.42. M.p. 130 ± 1318. [a]2D0 ‡ 93.0 (CHCl3, c ˆ 1.40). IR (KBr): 3166m, 3027m,
2965m, 2857m, 1691s, 1654s, 1473m, 1426m, 1259m, 1117m, 1073m. 1H-NMR: 8.75 (br., s, NH); 7.22 (d, J ˆ 1.1,
H
C(6)); 6.19 (t, J ˆ 6.4, H C(1')); 5.75 (dt, J ˆ 11.0, 7.6, H C(6')); 5.39 (ddd, J ˆ 10.9, 9.3, 4.4, H C(5')); 4.61
(dd, J ˆ 9.3, 4.4, H C(4')); 4.13 (dt, J ˆ 6.4, 4.4, H C(3')); 2.37 (ddd, J ˆ 13.6, 6.4, 4.4, Ha C(2')); 2.24 ± 2.06
(m, Hb C(2')), CH2(7')); 1.94 (d, J ˆ 1.1, Me C(5)); 1.44 (m, CH2(8')); 0.89 (s, tBuSi); 0.07 (s, MeSi)); 0.06 (s,
MeSi)). 13C-NMR: 163.7 (s); 150.1 (s); 136.7 (d); 135.3 (d); 126.3 (d); 110.8 (s); 85.2 (d); 82.4 (d); 76.0 (d); 41.1
(t); 29.9 (t); 25.3 (q); 22.7 (q); 17.9 (s); 12.6 (q); 4.8 (q). NOE: 5.75 (H C(6')) ! 1.44 (CH2(8'), 4.6%),

Helvetica Chimica Acta ± Vol. 84 (2001)
95
2.10 (CH2(7'), 3.0%), 2.18 (Hb C(2'), 2.6%), 5.39 (H C(5'), 13.5%); 5.39 (H C(5')) ! 2.10 (CH2(7'),
1.5%), 2.18 (Hb C(2'), 5.9%), 4.61 (H C(4'), 2.5%), 5.75 (H C(6'), 10.7%), 7.22 (H C(6), 8.2%); 4.61
(H C(4')) ! 2.10 (CH2(7')), 2.18 (Hb C(2'), 2.7%), 4.13 (H C(3'), 2.0%), 5.39 (H C(5'), 3.8%); 4.13
(H C(3')) ! 2.10 (CH2(7'), 5.0%), 4.61 (H C(4'), 3.1%), 5.39 (H C(5'), 5.9%), 7.22 (H C(6), 4.5%); 2.37
(Ha C(2')) ! 1.44 (C H2(8'), 5.8%), 2.18 (Hb C(2'), 8.9%), 4.61 (H C(4'), 8.8%), 5.75 (H C(6'), 3.9%),
7.22 (H C(6), 2.5%); 2.15 (Hb C(2')) ! 1.44 (H2C(8'), 1.7%), 2.37 (Ha C(2'), 14.8%), 4.13 (H C(3'),
7.2%), 4.61 (H C(4'), 1.9%), 5.39 (H C(5'), 1.7%), 5.75 (H C(6'), 1.8%), 7.22 (H C(6), 10.9%). MS: 394
‡
(8, M ), 183 (100). Anal. calc. for C20H34N2O4Si (394.59): C 60.88, H 8.68, N 7.10; found: C 61.02, H 8.45,
N 7.07.
5'(Z)-3'-O-[(tert-Butyl)dimethylsilyl]-2'-deoxy-5'-C-(3-methylbutylidene)thymidine (3b). As described for
3a; from (3-methylbutyl)triphenylphosphonium bromide (3.468 g, 8.39 mmol), 2m NaHMDS in THF (4.20 ml,
8.39 mmol), and 1 (991 mg, 2.80 mmol) in THF (5.50 ml) FC (70 g, hexane/AcOEt 2 :1): 3b (620 mg, 54%).
White solid. Anal. data from a crystallized (hot hexane) sample. M.p.: 1378. TLC (hexane/AcOEt 2 :1): Rf 0.30.
[a]2D2 ˆ ‡2.7 (acetone, c ˆ 0.86). IR (NaCl): 3171s, 3078s, 2953s, 2857s, 1682s, 1471s, 1271s, 1118m, 1076m,
1055m, 838m, 778m. 1H-NMR: 9.32 (br., s, NH); 7.31 (s, H C(6)); 6.20 (t, J ˆ 6.2, H C(1')); 5.70 ± 5.82 (m, 1
H); 5.43 (tt, J ˆ 10.9, 1.7, 1 H); 4.60 (ddd, J ˆ 9.0, 4.2, 1.1, 1 H); 4.13 (m, 1 H); 2.37 (ddd, J ˆ 13.6, 6.6, 4.4,
Ha C(2')); 1.96 ± 2.15 (m, 3 H); 1.93 (s, C(5)); 1.60 ± 1.77 (sept., J ˆ 6.7, 1 H); 0.96 (s, 3 H); 0.92 (s, 3 H); 0.90 (s,
tBu(Si); 0.07 (s, MeSi); 0.06 (s, Si). 13C-NMR: 163.9 (s); 150.2 (s); 135.7 (d); 135.3 (d); 126.8 (d); 110.8 (s); 85.2
(d); 82.3 (d); 76.0 (d); 75.9 (d); 41.1 (t); 36.9 (t); 28.5 (d); 25.6 (q); 22.4 (q); 22.1 (q); 17.9 (s); 12.6 (q); 4.8 (q);
‡
4.9 (q). MS: 408 (6, M ), 283 (100). Anal. calc. for C21H36N2O4Si (408.61): C 61.73, H 8.88, N 6.86; found: C
61.92, H 8.99, N 6.95.
cis-(5'S,6'R)- and cis-(5'R,6'S)-5'-C-Butyl-3'-O-[(tert-butyl)dimethylsilyl]-5'-deoxy-5',6'-epoxythymidine
((5'S,6'R)-4a and (5'R,6'S)-4a, resp.)3). To a soln. of 3a (162 mg, 0.44 mmol) in dry CH2Cl2 (1 ml), mCLPBA
(258 mg, 0.82 mmol) was added at 388 and stirred for 18 h. After stirring for an additional 24 h at 58, the
t
suspension was diluted with BuOMe (10 ml) and quenched with 15% (w/v), aq. Na2S2O3 soln. (5 ml). After
10 min, 1m aq. NaHCO3 (15 ml) was added, the aq. phase extracted with tBuOMe (3 Â 30 ml), the combined org.
phase dried (MgSO4) and evaporated, and the residue submitted to FC (silica gel (20 g), hexane/AcOEt 4 :1 ‡
0.5% MeOH): 126 mg (74%) of (5'S,6'R)-4a/(5'R,6'S)-4a 63 :37. White foam. Separation of the diastereoiso-
mers could be achieved by repeated FC (CH2Cl2/MeCN 12 :1).
Data of (5'S,6'R)-4a: TLC (CH2Cl2/MeCN 5 :1): Rf 0.24. [a]2D1 ˆ ‡79.1 (CHCl3, c ˆ 1.30). IR (KBr): 3186w,
3060w, 2958s, 2931s, 2858m, 1696s, 1466m, 1364m, 1275s, 1260s, 1202m, 1103m, 1057s, 837s, 778m. 1H-NMR: 9.02
(br. s, NH); 7.55(d, J ˆ 1.3, H C(6)); 6.23 (t, J ˆ 6.5, H C(1')); 4.45 (dt, J ˆ 6.1, 4.0, H C(3')); 3.97 (dd, J ˆ 5.1,
4.0, H C(4')); 3.07 (dt, J ˆ 7.5, 4.4, H C(6')); 3.00 (dd, J ˆ 5.2, 4.4, H C(5')); 2.31 (ddd, J ˆ 13.5, 6.3, 4.4, 1
H
C(2')); 2.17 (dt, J ˆ 13.6, 6.6, 1 H C(2')); 1.93 (d, J ˆ 1.3, Me C(5)); 1.43 ± 1.77 (m, 4 H); 0.97 (t, J ˆ 7.2,
Me(9')); 0.90 (s, tBu(Si)); 0.10 (s, 2 MeSi). 13C-NMR: 163.8 (s); 150.2 (s); 136.0 (d); 110.8 (s); 85.9 (d); 84.1 (d);
74.2 (d); 57.5 (d); 56.6 (d); 40.6 (t); 29.8 (t); 26.9 (q); 20.3 (t); 17.9 (s); 13.8 (q); 12.5 (q); 4.6 (q); 4.9 (q).
‡
‡
MS: 410 (2, M ), 201 (100). HR-LSI-MS: 411.2317 (C20H34N2O5Si ; calc. 411.2315).
Data of (5'R,6'S)-4a: TLC (CH2Cl2/MeCN 5 :1): 0.29. [a]2D0 ˆ ‡54.9 (CHCl3, c ˆ 0.80). IR (KBr): 3184m,
3054m, 2958s, 2931s, 2858s, 1694s, 1470s, 1404m, 1363m, 1301m, 1274s, 1192m, 1105m, 1058s, 837m, 779m.
1H-NMR: 9.09 (br., s, NH); 7.15 (d, J ˆ 1.3, H C(6)); 6.26 (dd, J ˆ 8.6, 5.5, H C(1')); 4.56 (dt, J ˆ 5.7, 1.8,
H
C(3')); 3.70 (dd, J ˆ 8.6, 1.8, H C(4')); 3.21 ± 3.06 (m, H C(6')); 2.89 (dd, J ˆ 8.6, 4.0, H C(5')); 2.32 (ddd,
J ˆ 13.4, 5.5, 2.0, 1 H C(2')); 2.14 (ddd, J ˆ 13.6, 8.4, 5.5, 1 H C(2')); 1.94 (d, J ˆ 1.3, Me C(5)); 1.64 ± 1.46 (m,
4 H); 0.99 (t, J ˆ 7.1, Me(9')); 0.90 (s, tBu(Si)); 0.11 (s, 2 MeSi). 13C-NMR: 163.6 (s); 150.2 (s); 135.1 (d); 111.2
(s); 86.2 (d); 84.6 (d); 74.8 (d); 57.2 (d); 55.9 (d); 39.9 (t); 29.6 (t); 25.7 (q); 19.7 (t); 18.0 (s); 13.9 (q); 12.7 (q);
‡
4.9 (q). MS: 411 (1, [M ‡ 1] ), 227 (100). Anal. calc. for C20H34N2O5Si (410.59): C 58.51, H 8.35, N 6.82;
found: C 58.46, H 8.24, N 6.79.
cis-(5'S,6'R)- and cis-(5'R,6'S)-3'-O-[(tert-Butyl)dimethylsilyl]-5'-deoxy-5',6'-epoxy-5'-C-(3-methylbu-
tyl)thymidine and ((5'S,6'R)-4b and (5'R,6'S)-4b, resp.)3). As described above; from 3b (560 mg, 1.37 mmol)
in abs. CH2Cl2 (14.0 ml) and mCLPBA (680 mg, 2.75 mmol) at 78 for 72 h. FC (60 g, hexane/AcOEt 4 :1):
(5'S,6'R)-4b (377 mg, 57%) and ca. 20% of (5'R,6'S)-4b as white foams. The diastereoisomers were purified by
repeated FC (CH2Cl2/MeCN 12 :1).
Data of (5'R,6'S)-4b: TLC (CH2Cl2/MeCN 10 :1): Rf 0.33. [a]2D1 ˆ ‡4.9 (CHCl3, c ˆ 1.04). IR (NaCl): 3424s,
2957m, 2931s, 2858m, 1696s, 1466m, 1364m, 1275s, 1260s, 1202m, 1103m, 1057s, 837s, 778m. 1H-NMR: 9.02 (br. s,
NH); 7.55 (d, J ˆ 1.3, H C(6)); 6.23 (t, J ˆ 6.5, H C(1')); 4.45 (dt, J ˆ 6.1, 4.0, H C(3')); 3.97 (dd, J ˆ 5.1, 4.0,
H
C(4')); 3.07 (dt, J ˆ 7.5, 4.4, H C(6')); 3.00 (dd, J ˆ 5.2, 4.4, H C(5')); 2.31 (ddd, J ˆ 13.5, 6.3, 4.4, 1

96
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Helvetica Chimica Acta ± Vol. 84 (2001)
C(2')); 2.17 (dt, J ˆ 13.6, 6.6, 1 H C(2')); 1.93 (d, J ˆ 1.3, Me C(5)); 1.43 ± 1.77 (m, 4 H); 0.97 (t, J ˆ 7.2, 1
Me(8')); 0.90 (s, tBuSi); 0.10 (s, 2 MeSi).
Data of (5'S,6'R)-4b: TLC (CH2Cl2/MeCN 10 :1): 0.26. [a]2D0 ˆ ‡3.8 (acetone, c ˆ 0.98). IR (NaCl): 3193m,
3057m, 2956s, 2858s, 1696s, 1471m, 1404m, 1366w, 1257w, 1193w, 1117w, 1068w, 836m. 1H-NMR: 8.75 (br. s, NH);
7.54 (s, H C(6)); 6.20 (t, J ˆ 6.4, H C(1')); 4.41 (dd, J ˆ 10.1, 4.2, 1 H); 3.94 (t, J ˆ 4.4, 1 H); 3.09 (q, J ˆ 4.1, 1
H); 2.90 (t, J ˆ 4.6, 1 H); 2.26 (m, 1 H C(2')); 2.13 (m, 1 H C(2')); 1.91 (s, Me C(5)); 1.82 (sept., J ˆ 6.6,
t
H
C(8')); 1.62 (m, 1 H); 1.49 (m, 1 H); 0.96, 0.94 (d, J ˆ 2.1, 2 Me(8')); 0.88 (s, BuSi); 0.08 (s, 2 MeSi).
13C-NMR: 163.51 (s); 150.14 (s); 135.15 (d); 111.20 (s); 86.21 (d); 84.62 (d); 74.80 (d); 56.38 (q); 55.71 (d); 39.96
(t); 36.29 (t); 26.70 (d); 25.71 (q); 22.68 (q); 22.63 (q); 17.98 (s); 12.65 (q); 4.86 (q). MS: 425 (2, M ), 241
‡
(100).
(5'S)-5'-C-Butyl-3'-O-[(tert-butyl)dimethylsilyl]thymidine (2a). To a soln. of 4a (mixture of diastereoiso-
mers; 125 mg, 0.30 mmol) in dry THF (1.20 ml), 1m DIBAH in hexane (1.22 ml, 1.22 mmol) was added dropwise
at 788 and stirred for 6.5 h. The reaction was quenched with AcOEt (0.20 ml), diluted with additional AcOEt
(9 ml), and warmed up to r.t. The soln. was treated with sat. aq. potassium sodium tartrate (4.5 ml) and 5m aq.
NaOH (0.20 ml), ultrasonicated, and stored at 48 overnight to allow phase separation. The aq. phase was treated
with 5m NaOH (1 ml) and extracted with AcOEt (9 Â 9 ml), the combined org. layer dried (MgSO4) and
evaporated, and the resulting oil was applied to FC (12 g, CH2Cl2/MeCN 15 :1): starting 4a (41 mg, 33%;
enriched in (5'R,6'S)-4a) and then 2a (51 mg, 40%, (5'S)/(5'R) 97:3 by 1H-NMR) as white foam. TLC (CH2Cl2/
acetone 8 :1): Rf 0.26. [a]2D2 ˆ ‡36.1 (CHCl3, c ˆ 0.92). IR (KBr): 3448m, 3180m, 3060m, 2956s, 2931s, 2858s,
1684s, 1472s, 1362m, 1277s, 1255s, 1198m, 1131s, 1085s, 1049s, 909m, 835m, 778m, 734s. 1H-NMR: 8.64 (br. s,
NH); 7.39 (d, J ˆ 1.5, H C(6)); 6.12 (t, J ˆ 6.8, H C(1')); 4.47 (dt, J ˆ 6.6, 3.3, H C(3')); 3.78 (t, J ˆ 2.9,
H
C(4')); 3.68 (qd, J ˆ 6.6, 2.2, H C(5')); 2.42 (d, J ˆ 6.6, OH); 2.38 (ddd, J ˆ 13.4, 6.8, 1 H C(2')); 2.16 (ddd,
J ˆ 13.4, 6.3, 3.5, 1 H C(2')); 1.92 (d, J ˆ 1.5, Me C(5)); 1.64 ± 1.55 (m, 2 H); 1.51 ± 1.29 (m, 4 H); 0.96 ± 0.87 (m,
Me(9'), tBu(Si)); 0.08 (s, 2 MeSi). 13C-NMR: 163.70 (s); 150.30 (s); 137.22 (d); 110.97 (s); 89.23 (d); 86.98 (d);
72.75 (d); 71.22 (d); 40.15 (t); 34.23 (t); 27.91 (t); 25.71 (q); 22.60 (t); 17.92 (s); 13.97 (q); 12.51 (q); 4.62 (q);
‡
4.80 (q). MS-EI: 413 (1, [M ‡ 1] ), 85 (100).
(5'S)-3'-O-[(tert-Butyl)dimethylsilyl]-5'-C-(3-methylbutyl)thymidine (2b). As described above, from pure
diastereoisomer (5'S,6'R)-4b (467 mg, 1.10 mmol); THF (4.0 ml), and 1m DIBAH in THF (3.30 ml, 3.30 mmol).
FC (CH2Cl2/AcOEt 7 :1, 3 :1): 2b (5'S) (324 mg, 68%). White foam. TLC (CH2Cl2/AcOEt 5 :1): Rf 0.15. [a]D21
ˆ
‡2.0 (acetone, c ˆ 1.06). IR (NaCl): 3486w, 2955m, 2858w, 1696s, 1473m, 1385w, 1254m, 1088w, 1036w, 972w,
835m, 779w. 1H-NMR: 8.51 (br. s, NH); 7.37 (s, H C(6)); 6.10 (t, J ˆ 7.0, H C(1')); 4.44 (m, 1 H); 3.76 (t, J ˆ
2.8, 1 H); 3.62 (br. s, 1 H); 2.33 (m, OH C(5'); 1 H C(2')); 2.15 (ddd, J ˆ 13.2, 6.2, 3.3, 1 H C(2')); 1.90 (s,
Me C(5)); 1.65 (br. s, 1 H); 1.66 ± 1.51 (m, 4 H); 1.40 ± 1.16 (m, 5 H); 0.87 (s, tBuSi); 0.06 (s, 2 MeSi). 13C-NMR:
164.0 (s); 150.6 (s); 137.8 (d); 111.2 (s); 89.5 (d); 87.3 (d); 73.0 (d); 72.0 (d); 40.4 (t); 35.0 (t); 32.9 (t); 28.2 (q);
‡
26.0 (q); 22.8 (q); 18.1 (s); 12.7 (q); 4.5 (q); 4.7 (q). MS: 427 (2, M ), 201 (100).
(5'S)-5'-C-Butylthymidine (5a). A soln. of 2a ((5'S); 44 mg, 0.11 mmol) in THF (1 ml) was treated with
1.1m Bu4NF in THF (0.12 ml, 0.13 mmol) at r.t. and stirred overnight. The mixture was evaporated and the
residue applied to FC (4 g, tBuOMe ‡ 1% MeOH): 5a ((5'S); 30 mg, 95%). Clear colorless oil. TLC (CH2Cl2/
MeOH 10 :1): Rf 0.20. [a]2D1 ˆ ‡41.0 (MeOH, c ˆ 0.62). UV: 265 (9170 Æ 240). IR (film): 3446s, 3061s, 2932s,
2862s, 1684s, 1472m, 1377m, 1276m, 1200m, 1133m, 1083m. 1H-NMR ((D6)acetone): 7.95 (d, J ˆ 1.1, H C(6));
6.30 (dd, J ˆ 7.5, 6.3, H C(1')); 4.49 (dt, J ˆ 5.9, 2.9, H C(3')); 4.28 (br. s, OH), 3.83 (t, J ˆ 2.6, H C(4')); 3.76
(td, J ˆ 6.6, 2.4, H C(5')); 3.10 (br. s, OH), 2.27 (ddd, J ˆ 13.2, 7.5, 5.9, 1 H C(2')); 2.19 (ddd, J ˆ 13.2, 6.2, 3.3, 1
H
C(2')); 1.79 (d, J ˆ 1.3, Me C(5)); 1.65 ± 1.50 (m, 2 H); 1.50-1.40 (m, 1 H); 1.40 ± 1.24 (m, 3 H); 0.87 (t, J ˆ
7.1, Me(9')). 13C-NMR ((D6)acetone): 164.58(s); 151.48(s); 137.70(d); 110.52(s); 90.21(d); 85.70(d); 73.07(d);
‡
71.61(d); 40.88(t); 34.68(t); 28.74(t); 23.31(t); 14.32(q); 12.57(q). EI-MS: 299 (5, [M ‡ 1) ], 147 (100).
(5'S)-5'-C-Butyl-3'-O-[(tert-butyl)dimethylsilyl]-5'-O-(9-phenyl-9H-xanthen-9-yl)thymidine (7a). To a
soln. of dry (co-evaporated with dry pyridine, 3 Â 8 ml) 2a (359 mg, 0.87 mmol) in dry pyridine (9.5 ml), 9-
chloro-9-phenyl-9H-xanthene (509 mg, 1.74 mmol) was added in one portion at r.t. The initially green soln.
slowly turned yellow, and, after 5 h, additional 9-chloro-9-phenyl-9H-xanthene (125 mg, 0.43 mmol) was added
and stirred overnight. The solvent was evaporated, the residue dissolved in CH2Cl2 (30 ml) and mixed with sat.
NaHCO3 soln. (30 ml), the mixture extracted with CH2Cl2 (3 Â 30 ml), the combined org. layer dried (NaSO4)
and evaporated, and the residue applied to FC (60 g, hexane/AcOEt 4 :1 ‡ 0.5% Et3N): 7a as white foam
(535 mg, 91%) and educt (34 mg, 9%). TLC (hexane/AcOEt 3 :2): Rf 0.39. [a]2D2 ˆ ‡33.2 (CHCl3, c ˆ 1.25). IR
(KBr): 3178m (br.), 3024m, 2955s, 2930s, 1696s (br.), 1602m, 1476s, 1447s, 1364m, 1318m, 1292m, 1276m,
1242m, 1133m, 1101m, 1055m, 756s. 1H-NMR: 8.80 (br. s, NH); 7.87 (d, J ˆ 1.3, H C(6)); 7.47 ± 7.33 (m, 4 H);
7.32 ± 7.23 (m, 6 H); 7.09 ± 6.91 (m, 4 H); 6.24 (dd, J ˆ 9.3, 5.1, H C(1')); 3.75 (d, J ˆ 1.1, 1 H); 3.41 (d, J ˆ 2.0, 1

Helvetica Chimica Acta ± Vol. 84 (2001)
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H); 3.25 ± 3.18 (m, 1 H); 2.08 ± 1.98 (m, 4 H, Me C(5) and 1 H C(2')); 1.81 (ddd, J ˆ 12.7, 9.3, 5.0, 1 H C(2');
1.47 ± 1.33 (m, 1 H); 1.13 ± 0.99 (m, 1 H); 0.98 ± 0.85 (m, 2 H); 0.81 (s, tBuSi); 0.77 ± 0.73 (m, 1 H); 0.69 (t, J ˆ 7.5,
Me(9')); 0.11 (s, tBuSi); 0.18 (s, 2 MeSi). 13C-NMR: 163.90 (s); 151.87 (s); 150.18 (s); 147.18 (s); 136.18 (d);
131.76 (d); 130.78 (d); 129.81 (d); 129.77 (d); 127.73 (d); 127.67 (d); 127.13 (d); 124.22 (s); 123.56 (d); 123.39 (s);
123.28 (d); 116.61 (d); 116.57 (d); 110.43 (s); 88.96 (d); 85.28 (d); 74.37 (d); 74.23 (d); 41.22 (t); 31.83 (t); 27.87
‡
(t); 25.65 (q); 22.41 (t); 17.73 (s); 13.84 (q); 12.65 (q); 4.76 (q); 4.92 (q). LSI-MS: 669.3 (0.2, [M ‡ 1) ], 257
(100).
(5'S)-3'-O-[(tert-Butyl)dimethylsilyl]-5'-C-(3-methylbutyl)-5'-O-(9-phenyl-9H-xanthen-9-yl)thymidine
(7b). As described above, from 2b (308 mg, 0.80 mmol); pyridine (4.3 ml), and 9-chloro-9-phenyl-9H-xanthene
(314 mg, 1.07 mmol). FC (30 g, hexane/AcOEt 3 :1): 7b (319 mg, 87%). White foam. TLC (hexane/AcOEt
7:2): Rf 0.33. [a]2D1 ˆ ‡27 (acetone, c ˆ 0.84). IR (NaCl): 3441s, 2954m, 2930m, 2857w, 1696s, 1575w, 1473m,
1445m, 1365w, 1317w, 1274w, 1242w, 1132w, 1088w, 1061w, 1040w, 964w, 944w, 833w, 757m. 1H-NMR: 8.20 (br. s,
NH); 7.80 (s, 1 H); 7.40 ± 7.15 (m, 8 H); 7.04 ± 6.85 (m, 5 H); 6.20 (t, J ˆ 5.1, H C(1')); 3.71 (s, 1 H); 3.37 (m, 1
H); 3.19 (m, 1 H); 2.11 ± 1.95 (m, 1 H); 1.88 ± 1.72 (m, 1 H); 1.17 (s, 3 H); 1.12 ± 1.02 (m, 1 H); 1.00 ± 0.72 (m, 3
H); 0.68 (s, tBuSi); 0.64, 0.58 (2 d, J ˆ 6.6, 2 Me C(8')); 0.14 (s, MeSi); 0.20 (s, MeSi). 13C-NMR: 151.95
(s); 151.86 (s); 147.27 (s); 136.19 (d); 131.75 (d); 130.79 (d); 129.86 (d); 129.81 (d); 127.74 (d); 127.70 (d); 127.16
(d); 124.20 (s); 123.60 (d); 123.47 (s); 123.37 (d); 116.68 (d); 116.65 (d) 110.41 (s); 89.02 (d); 85.30 (d); 77.20 (d);
74.91 (d); 74.64 (d); 74.39 (d); 41.27 (s); 34.93 (t); 30.13 (t); 27.99 (t); 26.98 (q); 25.67 (q); 22.55 (q); 22.26 (q);
17.76 (s); 12.66 (q); 4.74 (q); 4.86 (q).
(5'S)-5'-C-Butyl-5'-O-(9-phenyl-9H-xanthen-9-yl)thymidine (8a). As described for 5a, from 7a (510 mg,
0.76 mmol), 1.1m Bu4NF in THF (0.76 ml, 0.84 mmol), and THF (11 ml). FC (20 g, CH2Cl2 ‡ 1% Et3N) and
crystallization (CHCl3) yielded 8a (400 mg, 95%). White needles. M.p.: 142 ± 1448. TLC (AcOEt/hexane 2 :1):
Rf 0.18. [a]2D2 ˆ ‡26.2 (CHCl3, c ˆ 1.17). IR (KBr): 3448m, 3180m, 3060m, 2956s, 2931s, 2858s, 1684s, 1472s,
1362m, 1277s, 1255s, 1198m, 1131s, 1085s, 1049s, 836s, 734s. 1H-NMR: 8.85 (br. s, NH); 7.63 (d, J ˆ 1.1, H C(6));
7.51 ± 7.43 (m, 2 H); 7.42 ± 7.22 (m, 7 H); 7.11 ± 6.98 (m, 4 H); 6.15 (t, J ˆ 6.4, H C(1')); 3.67 ± 3.57 (m, H C(3'),
H
C(4')); 3.30 (m, H C(5')); 2.19 (ddd, J ˆ 4.7, 6.3, 13.6, 1 H C(2')); 2.05 ± 1.95 (m, 1 H C(2'), Me C(5));
1.50 ± 1.33 (m, 2 H, OH); 1.11 ± 0.98 (m, 1 H); 0.92 (q, J ˆ 6.9, 2 H); 0.85 ± 0.72 (m, 2 H); 0.67 (t, J ˆ 7.2 ) .
13C-NMR: 163.73 (s); 152.16 (s); 151.74 (s); 150.17 (s); 147.08 (s); 135.63 (d); 131.79 (d); 130.76 (d); 129.80 (d);
127.77 (d); 127.73 (d); 127.16 (d); 124.06 (s); 123.35 (d); 123.21 (s); 116.76 (d); 116.52 (d); 110.75 (s); 86.47 (d);
83.93 (d); 72.37 (d); 70.67 (d); 40.42 (t); 31.70 (t); 27.78 (t); 22.44 (t); 13.82 (q); 12.74 (q). MS: 467 (7), 257 (100).
Anal. calc. for C33H34N2O6: C 71.46, H 6.18, N 5.05; found: C 71.51, H 6.26, N 5.20%.
(5'S)-5'-C-(3-Methylbutyl)-5'-O-(9-phenyl-9H-xanthen-9-yl)thymidine (8b). As described for 5a, from 7b
(231 mg, 0.34 mmol), 1m Bu4NF in THF (0.4 ml, 0.40 mmol), and THF (4.6 ml). FC (20 g, hexane/AcOEt 1:2,
gradient): 8b (142 mg, 74%). White crystals. TLC (hexane/AcOEt 1:2): Rf 0.48. [a]2D1 ˆ ‡4.4 (acetone, c ˆ
1.04). IR (NaCl): 3443w, 3166w, 3052w, 2950w, 1696m, 1681s, 1666s, 1599m, 1574w, 1473m, 1442m, 1366w,
1313m, 1288w, 1266m, 1236w, 1199w, 1126w, 1088w, 1050w, 1018w, 949w, 907w, 871w, 814w, 756m. 1H-NMR: 8.67
(br. s, NH); 8.44 (s, 1 H); 7.50 ± 6.91 (m, 13 H); 6.17 (dd, J ˆ 6.3, 2.2, H C(1')); 3.93 (dd, 1 H); 3.83 (dd, 1 H);
3.69 (dd, 1 H); 2.71 (d, 1 H); 2.53 (br. s, OH C(3')); 2.38 (m, 1 H C(2')); 2.24 (m, 1 H C(2')); 1.82 (s,
Me C(5)); 1.69 ± 1.52 (m, 3 H); 1.45 ± 1.12 (m, 1 H); 1.08 ± 0.93 (m, 2 H); 0.89 ± 0.78 (m, 6 H). 13C-NMR: 152.20
(s); 151.70 (s); 150.03 (s); 147.09 (s); 135.60 (d); 131.78 (d); 130.76 (d); 129.83 (d); 129.81 (d); 127.78 (d); 127.79
(d); 127.17 (d); 124.02 (s); 123.43 (d); 123.34 (d); 123.20 (s); 116.79 (d); 116.56 (d); 110.74 (s); 86.27 (d); 83.80
(d); 77.20 (d); 72.70 (d); 70.39 (d); 40.35 (t); 34.88 (t); 29.92 (t); 27.98 (d); 22.52 (q); 22.19 (q); 21.04 (d); 14.18
(d); 13.67 (d); 12.74 (q).
(5'S)-5'-C-Butyl-5'-O-(9-phenyl-9H-xanthen-9-yl)thymidine 3'-(2-Cyanoethyl Diisopropylphosphorami-
dite) (9a). To a soln. of 8a (352 mg, 0.64 mmol) and iPr2NEt (0.44 ml, 2.60 mmol) in dry THF (7 ml),
PCl(OCH2CH2CN)(NiPr2) (0.22 ml, 0.97 mmol) was added at r.t. After 2 h, the soln. was diluted with CH2Cl2
(30 ml) and poured into ice-cold sat. aq. NaHCO3 soln. (20 ml). The mixture was extracted with CH2Cl2 (3 Â
30 ml), the combined org. layer dried (Na2SO4) and evaporated, and the residue applied to FC (30 g, hexane/
AcOEt 1 :1 ‡ 1% Et3N): 9a (431 mg, 91%). Colorless foam. TLC (hexane/AcOEt 1:2 ‡ 1% Et3N): Rf 0.58,
0.42. 1H-NMR: 8.67 (br. s, NH); 7.78, 7.72 (2 d, J ˆ 1.1, H C(6)); 7.47 ± 7.21 (m, 10 H); 7.10 ± 6.97 (m, 4 H); 6.21
(dt, J ˆ 4.7, 4.7, H C(1')); 3.91 (s, 1 H); 3.84 (s, 1 H); 3.78 ± 3.46 (m, 5 H); 3.27 (dt, J ˆ 2.6, 9.2, 1 H); 2.62 (t, J ˆ
6.3, 1 H); 2.49 (t, J ˆ 6.5, 1 H); 2.27 (td, J ˆ 6.1, 12.5, 1 H C(2')); 2.02 (d, J ˆ 1.1, Me C(5)); 1.98 ± 1.86 (m, 1
H
C(2')); 1.45 ± 1.20 (m, 2 H); 1.16, 1.06 (d, J ˆ 6.8, 12 H, 2 Me2CHN); 0.98 ± 0.89 (m, 2 H); 0.88 ± 0.73 (m, 2 H);
0.69 (t, J ˆ 7.2, Me(9')). 13C-NMR: 163.74 (s); 151.83 (s); 151.72 (s); 151.87 (s); 147.39 (s); 135.83 (d); 131.69 (d);
130.96 (d); 130.86 (d); 129.80 (d); 129.71 (d); 127.70 (d); 127.65 (d); 127.10 (d); 127.06 (d); 123.87 (s); 123.81(s);
123.60 (d); 123.53 (d); 123.32 (d); 123.22 (d); 116.56 (d); 116.50 (d); 110.76 (s); 110.64 (s); 87.46 (d); 87.39 (d);

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Helvetica Chimica Acta ± Vol. 84 (2001)
87.11 (d); 87.02 (d); 84.84 (d); 84.67 (d); 77.20 (d); 75.88 (d); 75.66 (d); 75.61 (d); 75.41 (d); 74.00 (d); 73.94 (d);
58.15 (t); 58.10 (t); 57.92 (t); 57.85 (t); 43.41 (d); 43.25 (d); 40.17 (t); 40.09 (t); 40.00 (t); 31.74 (t); 31.69 (t); 27.78
(t); 24.62 (q); 24.53 (q); 24.48 (q); 24.37 (q); 22.48 (t); 22.43 (t); 20.36 (t); 20.26 (t); 20.15 (t); 20.05 (t); 13.80 (q);
‡
12.63 (q). 31P-NMR: 155.96; 155.44. MALDI-TOF-MS (pos.-ion mode, matrix salicylamide): 755.4 (M ‡ H) ;
calc. 755.8).
(5'S)-5'-C-Butyl-3'-O-[(tert-butyl)dimethylsilyl]-4-dehydroxy-5'-O-(9-phenyl-9H-xanthen-9-yl)-4-(1H-
1,2,4-triazol-1-yl)thymidine (10a). To an ice-cold soln. of 1,2,4-1H-triazole (469 mg, 6.78 mmol) and POCl3
(0.13 ml, 1.43 mmol) in abs. MeCN (3.90 ml), Et3N (0.90 ml, 6.47 mmol) was added and stirred for 15 min. Then
a soln. of 7a (325 mg, 0.49 mmol) in abs. MeCN (2.00 ml) was added during 5 min, and after 20 min, stirring was
continued at r.t. After 1 h, the reaction was quenched with Et3N (0.54 ml) and H2O (0.20 ml), and the solvent
was removed. The solid was redissolved in CH2Cl2 (15 ml) and washed with 0.5m aq. NaHCO3. The aq. layer was
extracted with CH2Cl2 (3 Â 10 ml) and the combined org. layer dried (NaSO4) and evaporated. FC (25 g,
CH2Cl2/MeOH 100 :1 ! 100 :3): 10a (306 mg, 87%) as white foam and 7a (25 mg, 7%). TLC (MeCl2/MeOH
20 :1): Rf 0.51. [a]2D6 ˆ ‡100.0 (acetone, c ˆ 0.89). IR (KBr): 3060w, 2955s, 2930s, 1684s, 1602m, 1521s, 1502s,
1
1476s, 1446s, 1430s, 1379m, 1319m, 1293m, 1241m, 1123m, 1100m, 1056m, 972s, 949m, 834m, 757m. H-NMR:
9.36 (s, 1 H); 8.59 (s, 1 H); 8.17 (s, 1 H); 7.41 ± 7.34 (m, 2 H); 7.32 ± 7.21 (m, 4 H); 7.21 ± 7.06 (m, 3 H); 7.06 ± 6.95
(m, 3 H); 6.87 (dd, J ˆ 7.9, 1.7, 1 H); 6.24 (dd, J ˆ 8.6, 5.2, H C(1')); 3.90 (s, H C(3')); 3.35 (d, J ˆ 4.8,
H
C(4')); 3.29 ± 3.22 (m, H C(5')); 2.57 (s, Me C(5)); 2.52 (dd, J ˆ 13.2, 5.3, 1 H C(2')): 1.90 (ddd, J ˆ 13.1,
8.5, 4.8, 1 H C(2')); 1.50 ± 1.44 (m, 1 H); 1.19 ± 1.03 (m, 1 H); 1.02 ± 0.88 (m, 2 H); 0.80 (s, tBuSi, 1 H of Bu); 0.70
(t, J ˆ 7.1, Me(9')). 13C-NMR: 158.06 (s); 153.93 (s); 153.44 (d); 152.08 (s); 151.86 (s); 147.39 (d); 147.07 (s);
145.10 (d); 131.69 (d); 130.84 (d); 129.94 (d); 129.86 (d); 127.55 (d); 127.50 (d); 127.14 (d); 123.67 (d); 123.37 (d);
116.64 (d); 104.95 (s); 90.46 (d); 88.69 (d); 74.75 (d); 74.01 (d); 42.57 (t); 32.14 (t); 28.04 (t); 25.70 (q); 22.42 (s);
‡
17.80 (s); 17.34 (d); 13.84 (q); 4.72 (q); 4.96 (q). LSI-MS: 720.5 (0.4, [M ‡ H] ), 257 (100).
(5'S)-3'-O-[(tert-Butyl)dimethylsilyl]-4-dehydroxy-5'-C-(3-methylbutyl)-5'-O-(9-phenyl-9H-xanthen-9-yl)-
4-(1H-1,2,4-triazol-1-yl)thymidine (10b). As described for 10a, from 1,2,4-1H-triazole (580 mg, 8.52 mmol),
POCl3 (0.16 ml, 1.83 mmol), Et3N (1.15 ml, 8.27 mmol), MeCN (5.00 ml), 7b (430 mg, 0.63 mmol), and MeCN
(2.00 ml). FC (30 g, hexane/AcOEt 2 :1, gradient to AcOEt): 10b (421 mg, 91%). White foam. TLC (hexane/
AcOEt 3 :2): Rf 0.31. [a]2D1 ˆ ‡113.7 (acetone, c ˆ 1.00). IR (KBr): 3144w, 3059w, 2954s, 2930s, 2857m, 1684s,
1602m, 1572w, 1522s, 1502s, 1477s, 1459s, 1446s, 1430s, 1380m, 1320s, 1293m, 1242s, 1205m, 1188m, 1117m,
1090m, 1063m, 1042m, 1004(w), 973s, 949m, 872w, 834m, 779m, 758s, 734m, 701m, 670m. 1H-NMR: 9.36 (s, 1 H);
8.61 (s, 1 H); 8.17 (s, 1 H); 7.42 ± 7.33 (m, 2 H); 7.31 ± 7.22 (m, 4 H); 7.21 ± 7.11 (m, 3 H); 7.09 ± 6.97 (m, 3 H); 6.86
(dd, J ˆ 7.9, 1.7, 1 H); 6.24 (dd, J ˆ 8.6, 5.2, H C(1')); 3.89 (s, 1 H); 3.35 (d, J ˆ 4.6, 1 H); 3.27 ± 3.20 (m,
H
H
C(5')); 2.57 (d, J ˆ 0.4, Me C(5)); 2.52 (dd, J ˆ 13.1, 5.3, 1 H C(2')); 1.91 (ddd, J ˆ 13.0, 8.6, 4.8, 1
C(2')); 1.49 ± 1.32 (m, 1 H); 1.21 ± 1.07 (m, 1 H); 1.07 ± 0.85 (m, 2 H); 0.80 (s, tBuSi); 0.81 ± 0.75 (m, 1 H); 0.68
(d, J ˆ 6.4, 1 Me(8')); 0.62 (d, J ˆ 6.4, 1 Me(8')); 0.11 (s, MeSi); 0.18 (s, MeSi). 13C-NMR: 158.04 (s); 153.93
(s); 153.43 (d); 152.09 (s); 151.81 (s); 147.39 (d); 147.11 (s); 145.08 (d); 131.65 (d); 130.83 (d); 129.95 (d); 129.89
(d); 127.55 (d); 127.47 (d); 127.13 (d); 123.67 (d); 123.63 (s); 123.58 (s); 123.43 (d); 116.68 (d); 104.95 (s); 90.45
(d); 88.70 (d); 77.31 (s); 74.74 (d); 74.35 (d); 42.57 (t); 35.04 (t); 30.43 (t); 28.00 (d); 25.70 (q); 22.55 (q); 22.25
‡
(q); 17.80 (s); 17.36 (q); 4.72 (q); 4.94 (q). LSI-MS: 734.1 (0.1, [M ‡ H] ), 257 (100).
(5'S)-5'-C-Butyl-3'-O-[(tert-butyldimethylsilyl]-2'-deoxy-5-methyl-5'-O-(9-phenyl-9H-xanthen-9-yl)cyti-
dine (11a). To a soln. of 10a (100 mg, 0.14 mmol) in dioxane (0.56 ml) 25% aq. NH3 soln (0.14 ml) was added
and stirred at r.t. After 2 h, the solvent was removed and the residue applied to FC (10 g, AcOEt, AcOEt/MeOH
19 :1): 11a (85 mg, 92%). White foam. TLC (AcOEt): Rf 0.15. [a]2D6 ˆ ‡48.6 (acetone, c ˆ 0.94). IR (KBr):
3342m, 3073m, 2955s, 2929s, 2857s, 1668s, 1603s, 1573m, 1515s, 1478s, 1446s, 1352m, 1318s, 1293s, 1259m, 1240m,
1128m, 1101m, 1087s, 1054s, 1002m, 959m, 834m, 778m, 757s, 700m. 1H-NMR: 8.20 (s, NH); 7.96 (d, J ˆ 0.7,
H
C(6)); 7.42 ± 7.31 (m, 4 H); 7.30 ± 7.21 (m, 6 H); 7.09 ± 6.98 (m, 3 H); 6.91 (dd, J ˆ 7.9, 1.7, 1 H); 6.26 (dd, J ˆ
8.9, 5.1, H C(1')); 3.79 (br. s, 1 H); 3.38 (d, J ˆ 4.6, 1 H); 3.28 ± 3.20 (m, H C(5')); 2.27 (dd, J ˆ 12.9, 5.3, 1
H
C(2')); 2.05 (s, Me C(5)); 1.82 (ddd, J ˆ 12.9, 8.6, 4.7, 1 H C(2')); 1.50 ± 1.34 (m, 1 H); 1.16 ± 1.01 (m,1 H);
t
1.01 ± 0.85 (m, 2 H); 0.85 ± 0.65 (m, 2 H); 0.79 (s, BuSi); 0.68 (t, J ˆ 7.1, Me(9'));
0.12 (s, MeSi);
0.19
(s, MeSi). 13C-NMR: 165.67 (s); 156.14 (s); 151.98 (s); 151.83 (s); 147.51 (s); 138.93 (d); 131.75 (d); 130.97 (d);
129.76 (d); 129.68 (s); 127.70 (d); 127.57 (d); 126.97 (d); 123.89 (d); 123.81 (s); 123.58 (d); 123.22 (d); 116.53 (d);
101.12 (s); 89.16 (d); 86.74 (d); 77.19 (s); 74.61 (d); 74.19 (d); 42.25 (t); 31.93 (t); 27.96 (t); 25.68 (q); 22.45 (t);
‡
‡
17.77 (s); 13.85 (q); 13.42(q); 4.69 (q); 4.93 (q). LSI-MS: 1334.4 (8, [2M 2 H] ), 690.3 (2.6, [M ‡ Na] ),
‡
668.3 (1.3, [M ‡ H] ), 257 (100).
(5'S)-3'-O-[(tert-Butyl)dimethylsilyl]-2'-deoxy-5-methyl-5'-C-(3-methylbutyl)-5'-O-(9-phenyl-9H-xanthen-
9-yl)cytidine (11b). As described for 11a, from dioxane/25% aq. NH3 soln. 4 :1 (2.86 ml) and 10b (420 mg,

Helvetica Chimica Acta ± Vol. 84 (2001)
99
0.57 mmol). FC (21 g, AcOEt/MeOH 20 :1, gradient): 11b (415 mg, quant.). White foam. TLC (AcOEt): Rf
0.13. [a]2D3 ˆ ‡56.4 (acetone, c ˆ 0.92). IR (KBr): 3342m, 3131m, 2954s, 2929s, 2858m, 1670s, 1657s, 1604s,
1511m, 1478s, 1447s, 1317m, 1293m, 1241m, 1133m, 1087m, 1061m, 1040m, 834m, 757m. 1H-NMR: 8.19 (s,
NH2 C(4)); 7.99 (s, H C(6)); 7.43 ± 7.31 (m, 4 H); 7.31 ± 7.20 (m, 5 H); 7.08 ± 6.98 (m, 3 H); 6.91 (dd, J ˆ 7.9, 1.7,
1 H); 6.28 (dd, J ˆ 9.0, 5.0, H C(1')); 3.79 (s, 1 H); 3.38 (d, J ˆ 4.6, 1 H); 3.5 ± 3.18 (m, H C(5')); 2.27 (dd, J ˆ
12.6, 5.1, 1 H C(2')); 2.09 (s, Me C(5)); 1.84 (ddd, J ˆ 12.8, 8.7, 4.6, 1 H C(2')); 1.14 (sept., J ˆ 6.6, 1 H); 1.06 ±
0.92 (m, 1 H); 0.92 ± 0.83 (m, 1 H); 0.82 ± 0.58 (m, 2 H); 0.80 (s, tBuSi); 0.67 (d, J ˆ 6.4, 1 Me C(8')); 0.60 (d, J ˆ
6.6, Me C(8')); 0.11 (s, MeSi); 0.18 (s, MeSi). 13C-NMR: 165.81 (s); 156.31 (s); 152.01 (s); 151.80 (s);
147.50 (s); 138.78 (d); 131.72 (d); 130.94 (d); 129.78 (d); 129.74 (d); 127.68 (d); 127.59 (d); 127.00 (d); 123.85 (s);
123.80 (s); 123.59 (d); 123.30 (d); 116.58 (d); 101.61 (s); 89.19 (d); 86.70 (d); 74.60 (d); 74.53 (d); 42.23 (t); 34.99
(t); 30.23 (t); 28.00 (d); 25.67 (q); 22.57 (q); 22.24 (q); 17.77 (s); 13.47 (q); 4.68 (q); 4.89 (q). LSI-MS: 682.2
‡
(0.2, [M ‡ H] ), 257 (100).
(5'S)-N4-Benzoyl-5'-C-butyl-3'-O-[(tert-butyl)dimethylsilyl]-2'-deoxy-5-methyl-5'-O-(9-phenyl-9H-xan-
then-9-yl)cytidine (12a). To a suspension of oil-free KH (75 mg, 1.87 mmol) in dry THF (3.50 ml), PhCONH2
(170 mg, 1.39 mmol) was added. After the gas evolution had ceased, this suspension was quickly added to a soln.
of 10a (250 mg, 0.35 mmol) in dry THF (3.50 ml) and stirred at r.t. After 1 h, the reaction was quenched with
AcOH (0.12 ml, 1.50 mmol) and 0.5m aq. NaHCO3 (10 ml). The mixture was extracted with CH2Cl2 (3 Â 10 ml)
and the combined org. layer dried (NaSO4) and evaporated. FC (25 g, hexane/AcOEt 4 :1) gave 12a (232 mg,
87%). White foam. TLC (hexane/AcOEt 3 :1): Rf 0.67. [a]2D3 ˆ ‡72.9 (CHCl3, c ˆ 1.03). IR (KBr): 3068w,
2955m, 2929m, 2857w, 1712s, 1652m, 1601s, 1568s, 1478s, 1447s, 1362m, 1328s, 1275s, 1261s, 1238s, 1207m, 1124m,
1092m, 1055m, 959m, 834m, 756m, 712m. 1H-NMR: 13.36 (br. s, NH); 8.40 ± 8.36 (m, 2 H, Ph); 8.08 (d, J ˆ 1.1,
H
C(6)); 7.62 ± 7.32 (m, 7 H); 7.31 ± 7.22 (m, 5 H); 7.11 ± 7.01 (m, 3 H); 6.94 (dd, J ˆ 7.9, 1.7, 1 H); 6.25 (dd, J ˆ
9.1, 5.1, H C(1')); 3.80 (br. s, H C(4')); 3.40 (d, J ˆ 4.6, H C(3')); 3.28 ± 3.19 (m, H C(5')); 2.24 (d, J ˆ 0.9,
Me C(5)); 2.14 (dd, J ˆ 12.9, 5.2, 1 H C(2')); 1.84 (ddd, J ˆ 12.7, 9.2, 4.9, 1 H C(2')); 1.49 ± 1.38 (m, 1 H);
1.16 ± 1.06 (m, 1 H); 1.06 ± 0.88 (m, 2 H); 0.87 ± 0.67 (m, 2 H); 0.80 (s, tBuSi); 0.70 (t, J ˆ 7.2, Me(9')); 0.11 (s,
MeSi); 0.18 (s, MeSi). 13C-NMR: 179.56 (s); 160.02 (s); 151.95 (s); 151.89 (s); 147.87 (s); 147.19 (s); 137.56 (d);
137.36 (s); 132.23 (d); 131.78 (d); 130.82 (t); 129.90 (d); 129.85 (d); 128.11 (d); 127.74 (d); 127.70 (d); 127.15 (d);
124.13 (s); 123.62 (d); 123.45 (d); 123.32 (s); 116.65 (d); 116.62 (d); 111.32 (s); 89.36 (d); 86.07 (d); 77.20 (s);
74.49 (d); 74.20 (d); 41.60 (t); 31.93 (t); 27.92 (t); 25.67 (q); 22.43 (t); 17.76 (s); 13.86 (q); 13.79 (q); 4.76 (q);
‡
4.93 (q). LSI-MS: 772.5 (4, [M ‡ H] ), 257 (100).
(5'S)-N4-Benzoyl-3'-O-[(tert-butyl)dimethylsilyl]-2'-deoxy-5-methyl-5'-C-(3-methylbutyl)-5'-O-(9-phenyl-
9H-xanthen-9-yl)cytidine (12b). Dried (co-evaporation with pyridine) 11b (300 mg, 0.44 mmol) was dissolved in
dry pyridine (5.0 ml), cooled to 08, and treated with PhCOCl (65 ml, 0.53 mmol). The mixture was warmed to r.t.
overnight, and after 12 h, additional PhCOCl (0.100 ml, 0.87 mmol) was added. After 23 h, the mixture was
quenched with H2O (1.0 ml), stirred for 5 min, treated with cold conc. aq. NH3 soln. (1.0 ml), and stirred for
another 10 min. The solvent was evaporated, the solid redissolved in 0.5m aq. NaHCO3 soln. (10 ml), the soln.
extracted with CH2Cl2 (4 Â 10 ml), the combined org. layer dried (NaSO4) and evaporated, and residual
pyridine co-evaporated with toluene. FC (28 g, hexane/AcOEt 3 :1) gave 12b (243 mg, 70%). White foam. TLC
(hexane/AcOEt 3 :1): Rf 0.69. [a]2D2 ˆ ‡86.7 (acetone, c ˆ 1.15). IR (KBr): 3068m, 3029m, 2954s, 2929s, 2900m,
2857m, 1709s, 1654s, 1600s, 1568s, 1477s, 1447s, 1364s, 1318s, 1275s, 1261s, 1238s, 1207m, 1093m, 1062m, 1041m,
962m, 834m, 778m, 757s, 712m, 681m. 1H-NMR: 13.68 (br. s, NH); 8.41 ± 8.35 (m, 2 H, Ph); 8.10 (d, J ˆ 0.9,
H
C(6)); 7.60 ± 7.52 (m, 1 H); 7.52 ± 7.36 (m, 6 H); 7.36 ± 7.23 (m; 5 H); 7.10 ± 7.01 (m, 3 H); 6.94 (dd, J ˆ 8.0, 1.6,
1 H); 6.25 (dd, J ˆ 9.2, 5.0, H C(1')); 3.78 (br. s, 1 H); 3.40 (d, J ˆ 4.8, 1 H); 3.25 ± 3.18 (m, H C(5')); 2.24 (d,
J ˆ 0.7, Me C(5)); 2.14 (dd, J ˆ 12.7, 5.5, 1 H C(2')); 1.86 (ddd, J ˆ 12.7, 8.8, 4.8, 1 H C(2')); 1.49 ± 1.34 (m, 1
H); 1.22 ± 1.11 (m, 1 H); 1.06 ± 0.90 (m, 1 H); 0.89 ± 0.73 (m, 1 H); 0.80 (s, tBuSi); 0.72 ± 0.55 (m, 1 H); 0.68 (d,
J ˆ 6.6, 1 Me C(8')); 0.62 (d, J ˆ 6.6, 1 Me C(8')); 0.11 (s, MeSi); 0.18 (s, MeSi). 13C-NMR: 160.02 (s);
151.98 (s); 151.85 (s); 147.87 (s); 147.25 (s); 137.56 (d); 137.35 (s); 132.24 (d); 131.75 (d); 130.82 (d); 129.90 (d);
129.88 (s); 128.11 (d); 127.70 (d); 127.14 (d); 124.06 (s); 123.64 (d); 123.50 (s); 123.38 (d); 116.67 (d); 111.32 (s);
89.49 (d); 86.07 (d); 77.20 (s); 74.57 (d); 74.49 (d); 41.63 (t); 34.94 (t); 30.20 (t); 28.00 (d); 25.67 (q); 22.56 (q);
‡
22.26 (q); 17.76 (s); 13.79 (q); 4.74 (q); 4.90 (q). LSI-MS: 786.4 (1, [M ‡ H] ), 150 (100).
(5'S)-N4-Benzoyl-5'-C-butyl-2'-deoxy-5-methyl-5'-O-(9-phenyl-9H-xanthen-9-yl)cytidine (13a). As de-
scribed for 5a, from 12a (230 mg, 0.30 mmol), 1.0m Bu4NF in THF (0.33 ml, 0.33 mmol), and THF (4.30 ml).
FC (hexane/AcOEt 1 :1, gradient): 13a (193 mg, 99%). TLC (hexane/AcOEt 1:1): Rf 0.48. [a]2D4 ˆ ‡91.5
(acetone, c ˆ 0.93). IR (KBr): 3448m, 3068w, 2956m, 2929m, 2870m, 1706s, 1654s, 1600s, 1571s, 1477s, 1447s,
1364m, 1317s, 1276s, 1243s, 1210m, 1024m, 955m, 757m, 713m. 1H-NMR: 13.37 (br. s, NH); 8.39 ± 8.33 (m, 2 H,
Ph); 7.85 (d, J ˆ 1.1, H C(6)); 7.61 ± 7.42 (m, 5 H); 7.32 ± 7.23 (m, 5 H); 7.14 ± 7.01 (m, 4 H); 6.14 (t, J ˆ 6.1,

100
H
Helvetica Chimica Acta ± Vol. 84 (2001)
C(1')); 3.68 (q, J ˆ 5.4, H C(3')); 3.62 (dd, J ˆ 4.6, 2.2, H C(4')); 3.35 ± 3.29 (m, H C(5')); 2.25 (ddd, J ˆ
13.6, 6.5, 5.1, 1 H C(2')); 2.20 (d, J ˆ 0.9, Me C(5)); 2.05 (dt, J ˆ 13.6, 6.5, 1 H C(2')); 1.52 ± 1.38 (m, 1 H);
1.13 ± 1.02 (m, 1 H); 0.95 (m, 2 H); 0.89 ± 0.76 (m, 2 H); 0.69 (t, J ˆ 7.1, Me(9')). 13C-NMR: 159.86 (s); 152.21 (s);
151.76 (s); 147.83 (s); 147.02 (s); 137.24 (s); 136.93 (d); 132.39 (d); 131.80 (d); 130.77 (d); 129.90 (d); 129.85 (d);
128.11 (d); 127.80 (d); 127.76 (d); 127.18 (d); 124.04 (s); 123.38 (d); 123.17 (s); 116.79 (d); 116.56 (d); 111.53 (s);
86.62 (d); 84.59(d); 72.19 (d); 70.40 (d); 40.71 (t); 31.82 (t); 27.78 (t); 22.45 (t); 13.87 (q); 13.83 (q). LSI-MS:
‡
658.2 (8, [M ‡ H] ), 257 (100).
(5'S)-N4-Benzoyl-2'-deoxy-5-methyl-5'-C-(3-methylbutyl)-5'-O-(9-phenyl-9H-xanthen-9-yl)cytidine (13b).
As for 5a, from 12b (238 mg, 0.30 mmol), and 1.0m Bu4NF in THF (0.33 ml, 0.33 mmol), and THF (4.40 ml).
FC (20 g, AcOEt/hexane 1 :1, AcOEt): 13b (203 mg, quant.). White foam. TLC (hexane/AcOEt 2 :1): Rf 0.17.
[a]2D3 ˆ ‡100.4 (acetone, c ˆ 0.99). IR (KBr): 3447m, 3069m, 3030w, 2955s, 2928s, 2869m, 1701s, 1652s, 1600s,
1570s, 1477s, 1447s, 1365s, 1317s, 1275s, 1244s, 1209m, 1171m, 1124m, 1100m, 1066m, 1024m, 964m, 909m, 757m,
733m, 713m, 680m. 1H-NMR: 13.36 (br. s, NH); 8.41 ± 8.34 (m, 2 H, Ph); 7.86 (d, J ˆ 0.9, H C(6)); 7.61 ± 7.44 (m,
5 H); 7.44 ± 7.31 (m, 5 H); 7.31 ± 7.23 (m, 2 H); 7.12 ± 7.01 (m, 4 H); 6.14 (t, J ˆ 6.2, H C(1')); 3.70 (q, J ˆ 5.5,
H
H
C(3')); 3.61 (dd, J ˆ 4.6, 2.2, H C(4')); 3.30 (ddd, J ˆ 9.6, 3.6, 2.2, H C(5')); 2.26 (ddd, J ˆ 13.6, 6.5, 5.2, 1
C(2')); 2.20 (d, J ˆ 0.9, Me C(5)); 2.09 (dt, J ˆ 13.8, 6.3, 1 H C(2')); 1.50 ± 1.35 (m, 1 H); 1.16 (m, 2 H);
1.15 ± 0.76 (m, 2 H); 0.67 (d, J ˆ 6.6, 1 Me C(8')); 0.61 (d, J ˆ 6.6, 1 Me C(8')). 13C-NMR: 159.86 (s); 152.25
(s); 151.74 (s); 147.83 (s); 147.08 (s); 137.26 (s); 136.92 (d); 132.39 (d); 131.80 (t); 130.78 (d); 129.91 (d); 129.86
(d); 128.11 (d); 127.82 (d); 127.75 (d); 127.19 (d); 124.00 (s); 123.45 (d); 123.38 (d); 123.22 (s); 116.81 (d); 116.60
(t); 111.53 (s); 86.54 (d); 84.54 (d); 77.20 (s); 72.59 (d); 70.33 (d); 40.72 (s); 34.88 (d); 30.06 (t); 28.01 (d); 22.54
‡
(q); 22.21 (q); 13.87 (q). HR-LSIMS: 672.3074 (C41H42N3O6 ; calc. 672.3089).
(5'S)-N4-Benzoyl-5'-C-butyl-2'-deoxy-5-methyl-5'-O-(9-phenyl-9H-xanthen-9-yl)cytidine 3'-(2-Cyanoethyl
i
Diisopropylphosphoramidite) (14a). As described for 9a, from 13a (188 mg, 0.29 mmol), Pr2NEt (0.20 ml,
1.15 mmol), dry THF (3.20 ml), PCl(OCH2CH2CN)(NiPr2) (150 ml, 0.64 mmol). FC (18 g, hexane/AcOEt 3 :1,
gradient): 14a (204 mg, 83%) as a diastereoisomeric mixture. TLC (hexane/AcOEt 2 :1): Rf 0.62, 0.37. 1H-NMR:
13.35 (br. s, NH); 8.40 ± 8.33 (m, 2 H, Ph); 7.99, 7.92 (2 d, J ˆ 1.1, H C(6)); 7.61 ± 7.22 (m, 12 H); 7.14 ± 6.97 (m, 4
H); 6.23 (m, H C(1')); 3.97, 3.88 (2 br. s, 1 H); 3.80 ± 3.45 (m, 5 H); 3.30 (dt, J ˆ 9.0, 2.5, 1 H); 2.62, 2.49 (2 t, J ˆ
6.5, 2 H); 2.43 ± 2.30 (m, 1 H C(2')); 2.22 ± 2.20 (m, Me C(5)); 1.94 (ddd, J ˆ 13.4, 8.6, 5.3, 1 H C(2')); 1.48 ±
1.31 (m, 1 H); 1.24 ± 1.19 (m, 1 H); 1.15, 1.06 (2 d, J ˆ 6.8, 2 Me2CH); 1.02 ± 0.74 (m, 4 H); 0.74 ± 0.63 (m, Me(9')).
13C-NMR: 159.91 (s); 151.91 (s); 151.86 (s); 151.69 (s); 147.82 (s); 147.39 (s); 137.29 (s); 137.16 (d); 132.36 (d);
131.69 (d); 130.98 (d); 130.86 (d); 129.91 (d); 129.86 (s); 129.82 (d); 129.73 (d); 128.10 (d); 127.72 (d); 127.65 (d);
127.11 (d); 127.06 (d); 123.81 (s); 123.75 (s); 123.64 (d); 123.58 (d); 123.34 (d); 123.24 (d); 116.58 (d); 116.53 (d);
111.51 (s); 87.86 (d); 87.80 (d); 87.47 (d); 87.39 (d); 85.69 (d); 85.39 (d); 77.23 (s); 75.93 (d); 75.71 (d); 75.46 (d);
73.98 (d); 73.93 (d); 58.17 (t); 58.08 (t); 57.93 (t); 57.83 (t); 43.43 (d); 43.39 (d); 43.26 (d); 43.22 (d); 40.56 (t);
40.48 (t); 40.34 (t); 31.82 (t); 31.77 (t); 27.80 (t); 24.63 (q); 24.54 (q); 24.50 (q); 24.40 (q); 22.50 (t); 22.45 (t);
20.36 (t); 20.26 (t); 20.16 (t); 20.06 (t); 13.80 (q); 13.75 (q); 8.34 (t); 8.09 (t). 31P-NMR (CDCl3): 151.23, 150.59.
‡
LSI-MS 858 (1.4, [M ‡ H] ), 150 (100).
(5'S)-N4-Benzoyl-2'-deoxy-5-methyl-5'-C-(3-methylbutyl)-5'-O-(9-phenyl-9H-xanthen-9-yl)cytidine 3'-(2-
Cyanoethyl Diisopropylphosphoramidite) (14b). As described for 9a, from 13b (185 mg, 0.27 mmol), THF
(3.0 ml) iPr2NEt (0.19 ml, 1.10 mmol), and PCl(OCH2CH2CN)(NiPr2) (0.09 ml, 0.41 mmol). FC (23 g, hexane/
AcOEt 3 :1, gradient): 14b (203 mg, 84%) as diastereoisomer mixture. Light yellow foam. TLC (hexane/AcOEt
2 :1): Rf 0.58, 0.50. IR (KBr): 3068w, 2964m, 2930m, 2879m, 1708s, 1654m, 1600s, 1570s, 1477m, 1447s, 1365m,
1
1318m, 1275s, 1239s, 1205m, 1123m, 1099m, 1080m, 1053m, 1024m, 976m, 757m, 713m. H-NMR: 13.35 (br. s,
NH); 8.41 ± 8.33 (m, 2 H, Ph); 8.01, 7.96 (2 d, J ˆ 1.1, H C(6)); 7.58 ± 7.52 (m, 1 H); 7.51 ± 7.34 (m, 6 H); 7.34 ±
7.22 (m, 5 H); 7.11 ± 6.96 (m, 4 H); 6.23 (dt, J ˆ 4.7, H C(1')); 3.96, 3.88 (br. s, 1 H); 3.80 ± 3.46 (m, 5 H); 3.32 ±
3.24 (m, 1 H); 2.62, 2.49 (2 t, J ˆ 6.5, 2 H); 2.37 (td, J ˆ 12.4, 5.2, 1 H C(2')); 2.22 (2 d, J ˆ 1.0, Me C(5)); 1.97
(ddd, J ˆ 13.2, 8.4, 5.2, 1 H C(2')); 1.47 ± 1.33 (m, 1 H); 1.30 ± 1.10 (m, 2 H); 1.16, 1.07 (2 d, J ˆ 6.8, Me2CH);
1.04 ± 0.79 (m, 3 H); 0.70 ± 0.59 (m, 2 Me C(8')). 13C-NMR: 157.74 (s); 149.76 (s); 149.70 (s); 149.52 (s); 149.48
(s); 145.79 (s); 145.27 (s); 135.12 (d); 134.97 (d); 130.19 (d); 129.49 (d); 128.79 (d); 128.66 (d); 127.73 (d); 127.67
(d); 127.59 (d); 125.93 (d); 125.55 (d); 125.45 (d); 124.93 (d); 121.57 (d); 121.48 (s); 121.42 (s); 121.24 (d); 121.14
(d); 114.45 (d); 114.40 (d); 109.43 (s); 109.34 (s); 85.66 (d); 85.60 (d); 85.33 (d); 85.25 (d); 83.41 (d); 83.22 (d);
75.04 (s); 73.77 (d); 73.49 (d); 73.28 (d); 72.14 (d); 56.01 (t); 55.91 (t); 55.77 (t); 55.66 (t); 41.25 (d); 41.09 (d);
41.05 (d); 38.41 (d); 38.33 (t); 38.22 (t); 32.74 (t); 32.66 (t); 27.90 (t); 25.85 (d); 25.78 (d); 22.46 (q); 22.37 (q);
22.33 (q); 22.22 (q); 20.34 (q); 20.01 (q); 18.19 (t); 18.09 (t); 17.98 (t); 17.88 (t); 11.57 (q). 31P-NMR: 167.72,
‡
167.04. LSI-MS: 872 (0.8, [M ‡ H] ), 150 (100).

Helvetica Chimica Acta ± Vol. 84 (2001)
101
(5'S)-5'-C-Butyl-2'-deoxy-5-methyl-5'-O-(9-phenyl-9H-xanthen-9-yl)cytidine (ˆ4-Amino-5-methyl-1-
[2',6',7'8',9'-pentadeoxy-5'-O-(9-phenyl-9H-xanthen-9-yl)-a-l-lyxo-nonafuranosyl]pyrimidin-2(1H)-one; 15a).
As described for 5a, from 11a (81 mg, 0.12 mmol), 1.0m Bu4NF in THF (0.14 ml, 0.14 mmol), and THF
(1.75 ml). Crystallization from hot acetone (10 ml) and recrystallization from hot MeOH (5 ml) gave 15a
(36 mg, 54%). Colorless blocks. M.p. 2128 (dec.). TLC (AcOEt/MeOH 20 :1): Rf 0.33. [a]2D3 ˆ ‡76.0 (MeOH,
c ˆ 0.55). IR (KBr): 3492m, 3311m, 3209m, 3059w, 2957m, 2929m, 2867w, 1659s, 1602s, 1514s, 1477s, 1447s,
1318s, 1292s, 1238m, 1128m, 1102m, 1065s, 1025m, 965m, 758s, 702m. 1H-NMR ((D6)DMSO): 7.54 (br. s,
H
C(6)); 7.44 ± 7.20 (m, 1 NH, 9 H (pixyl)); 7.12 ± 7.01 (m, 2 H (pixyl)); 6.97 (dd, J ˆ 8.0, 1.6, 1 H (pixyl)); 6.92
(dd, J ˆ 7.9, 1.7, 1 H (pixyl)); 6.85 (br. s, NH); 6.04 (dd, J ˆ 7.9, 5.7, H C(1')); 4.91 (d, J ˆ 4.1, OH C(3')); 3.58
(t, J ˆ 2.5, 1 H); 3.56 ± 3.50 (m, 1 H); 3.24 ± 3.18 (m, H C(5')); 2.00 (ddd, J ˆ 12.9, 5.7, 2.2, 1 H C(2')); 1.85 (s,
Me C(5)); 1.88 ± 1.76 (m, 1 H C(2')); 1.25 ± 1.11 (m, 1 H); 1.02 ± 0.88 (m, 1 H); 0.88 ± 0.65 (m, 4 H); 0.59 (t, J ˆ
7.0, Me(9')). 13C-NMR ((D6)DMSO): 165.49 (s); 155.15 (s); 151.28 (s); 150.98 (s); 148.35 (s); 137.66 (d); 131.36
(d); 131.09 (d); 130.03 (d); 127.89 (d); 127.27 (d); 127.02 (d); 124.24 (s); 123.71 (d); 123.54 (d); 122.89 (s); 116.45
(d); 116.36 (d); 101.33 (s); 87.15 (d); 84.51 (d); 76.11 (s); 73.63 (d); 71.10 (d); 41.00 (t); 31.09 (t); 27.30 (t); 22.12
‡
(t); 13.84 (q); 13.72 (q). LSI-MS: 554.0 (1.1, [M ‡ H] ), 118 (100).
X-Ray Analysis of 15a: Colorless transparent block (0.55 Â 0.35 Â 0.10 mm); monoclinic space group P2(1).
Intensities were collected at 223 K with a Stoe Image Plate diffractometer (MoKa, l 0.71073 Š). Of the 5908
independent reflections (q ˆ 2.09 ± 25.968), 4720 with F > 4s(I) were used in the refinement. The structure was
solved by direct methods with SHELX-86 [18] and refined by full-matrix least-square procedures SHELX-97.
Non-H-atoms were refined anisotropically. The refinement converged at R ˆ 0.0736, Rw ˆ 0.1781.
(5'S)-2'-Deoxy-5-methyl-5'-C-(3-methylbutyl)-5'-O-(9-phenyl-9H-xanthen-9-yl)cytidine (15b). As de-
scribed for 5a, from 11b (96 mg, 0.14 mmol), 1.0m Bu4NF in THF (0.15 ml, 0.15 mmol), and THF (2.0 ml).
Crystallization from hot MeOH (4 ml) gave 15b (38 mg, 47%). Colorless plates. M.p. 211 ± 2148 (dec.). TLC
(AcOEt/MeOH 20 :1): Rf 0.12. [a]2D2 ˆ ‡98.4 (MeOH, c ˆ 0.56). IR (KBr): 3396m, 3337m, 3214m, 3064w,
2952m, 2925m, 2867w, 1661s, 1600s, 1573m, 1514m, 1477s, 1445s, 1317m, 1292m, 1239m, 1101m, 1080m, 1038m,
1
1019m, 968m, 950m, 787m, 755m. H-NMR ((D6)DMSO): 7.56 (s, H C(6)); 7.43 ± 7.18 (m, 10 H, including 1
NH); 7.13 ± 7.01 (m, 2 H); 6.97 (dd, J ˆ 12.5, 1.7, 1 H); 6.94 (dd, J ˆ 12.7, 1.7, 1 H); 6.86 (br. s, 1 NH); 6.05 (dd, J ˆ
7.9, 5.7, H C(1')); 4.92 (d, J ˆ 3.9, OH C(3')); 3.58 (br. s, H C(3'), H C(4')); 3.24 ± 3.16 (m, H C(5')); 2.07 ±
1.96 (m, 1 H C(2')); 1.90 ± 1.79 (m, 1 H C(2')); 1.84 (s, Me C(5)); 1.23 ± 1.09 (m, 1 H); 1.01 (d, J ˆ 6.5, 1 H);
0.97 ± 0.71 (m, 2 H); 0.57 ± 0.51 (m, 1 H); 0.56 (d, J ˆ 6.4, 1 Me C(8')); 0.53 (d, J ˆ 6.4, 1 Me C(8')). 13C-NMR
((D6)DMSO): 165.50 (s); 155.15 (s); 151.28 (s); 150.93 (s); 148.44 (s); 137.64 (d); 131.32 (d); 131.08 (d); 130.07
(d); 127.89 (d); 127.24 (d); 127.01 (d); 124.27 (s); 123.71 (d); 123.57 (d); 122.81 (s); 116.47 (d); 116.39 (d); 101.33
(s); 87.12 (d); 84.49 (d); 76.08 (s); 73.98 (d); 71.02 (d); 41.03 (t); 34.46 (t); 29.33 (t); 27.60 (d); 22.50 (q); 22.26
‡
(q); 13.70 (q). LSI-MS: 568.2 (0.2, [M ‡ H] ), 257 (100).
(5'S)-5'-C-Butyl-2'-deoxy-5-methylcytidine (16a). At r.t., 15a (80 mg, 0.14 mmol) was dissolved in THF/
H2O 9:1 (4.0 ml) and then Cl2CHCOOH (0.12 ml) was added. After 15 min, the solvent was removed and the
yellow residue adsorbed on silica gel and purified by FC (3 g, CH2Cl2/MeOH 7:1, gradient): 16a (43 mg,
quant.). White solid. TLC (CH2Cl2/MeOH 5 :1): Rf 0.16. [a]2D1 ˆ ‡64.8 (MeOH, c ˆ 0.42). UV (H2O): 208
(10850), 277 (7050). IR (KBr): 3359s, 3212s, 2956m, 2931m, 2870m, 1664s, 1603s, 1522m, 1485s, 1358m, 1297m,
1
1135m, 1082m, 1050m, 1025m, 1006m, 786m. H-NMR ((D6)DMSO): 7.83 (d, J ˆ 0.9, H C(6)); 7.59 (br. s, 1
NH); 6.99 (br. s, 1 NH); 6.13 (t, J ˆ 6.7, H C(1')); 4.93 (br. s, OH C(3'), OH C(5')); 4.21 (dt, J ˆ 5.7, 3.0,
H
C(3')); 3.62 (t, J ˆ 2.8, H C(4')); 3.58 ± 3.51 (m, H C(5')); 2.08 ± 1.91 (m, 2 H C(2')); 1.81 (d, J ˆ 0.7,
Me C(5)); 1.51 ± 1.36 (m, 3 H); 1.36 ± 1.19 (m, 3 H); 0.86 (t, J ˆ 7.0, Me(9')). 13C-NMR ((D6)DMSO): 164.95
(C(2)); 154.64 (C(4)); 139.23 (C(6)); 101.34 (C(5)); 89.09; 84.98 (C(1'), C(2')); 71.35, 69.90 (C(4'), C(5')); 40.71
(C(2')); 33.77 (C(6')); 27.92 (C(7')); 22.43 (C(8')); 14.21, 13.54 (C(9'), Me C(5)). HR-MS: 298.17668
‡
(C14H24N3O4 ; calc. 298.17667).
(5'S)-2'-Deoxy-5-methyl-5'-C-(3-methylbutyl)cytidine (16b). To a soln. of 80% AcOH/THF 4 :1 (4.0 ml),
15b (42 mg, 0.074 mmol) was added and the mixture stirred at r.t. for 48 h. The solvent was removed and the
solid partitioned between H2O (3 ml) and tBuOMe (3 ml). The aq. layer extracted with tBuOMe (2 Â 3 ml), the
combined org. phase evaporated, and the residue dissolved in 1m aq. NH3 (1 ml), adsorbed on silica gel and
submitted to FC (MeCl2/MeOH 7:1): 16b (16 mg, 69%). TLC (MeCl2/MeOH 5 :1): Rf 0.27. [a]2D0 ˆ ‡59.2
(MeOH, c ˆ 0.47). UV (H2O): 210 (10980), 276 (7460). IR (KBr): 3456m, 3100m, 2954s, 2932s, 2868m, 1674s,
1610s, 1516m, 1489s, 1453m, 1411m, 1345m, 1319m, 1298m, 1261m, 1191m, 1139m, 1096s, 1076m, 786m.
1H-NMR ((D6)DMSO): 7.80 (d, J ˆ 0.9, H C(6)); 7.25 (br. s, 1 NH); 6.78 (br. s, 1 NH); 6.13 (t, J ˆ 6.7,
H
C(1')); 5.03 (very br. s, OH C(5'), OH C(3')); 4.22 (dt, J ˆ 5.7, 3.0, H C(3')); 3.62 (t, J ˆ 2.8, H C(4'));
3.52 (td, J ˆ 6.5, 2.2, H C(5')); 2.08 ± 1.89 (m, 2 H C(2')); 1.80 (d, J ˆ 0.7, Me C(5)); 1.62 ± 1.38 (m, 3 H);

102
Helvetica Chimica Acta ± Vol. 84 (2001)
1.38 ± 1.00 (m, 3 H); 0.85 (d, J ˆ 6.4, 1 Me C(8')); 0.84 (d, J ˆ 6.6, 1 Me C(8')). 13C-NMR ((D6)DMSO): 165.48
(s); 155.37 (s); 138.99 (d); 101.29 (s); 89.02 (d); 84.93 (d); 71.31 (d); 70.21 (d); 40.72 (t); 34.99 (t); 31.86 (t); 27.74
‡
(d); 22.81 (q); 22.69 (q); 13.61 (q). HR-LSI-MS: 312.12233 (C15H26N3O4 ; calc. 312.12296).
N6-Benzoyl-5'-C-butylidene-3'-O-[(tert-butyl)dimethylsilyl]-2,5'-dideoxyadenosine (19). To a suspension of
butyltriphenylphosphonium bromide (1.005 g, 2.52 mmol) in dry THF (3.80 ml), 1.8m NaHMDS in THF
(1.40 ml, 2.52 mmol) was added, and after 0.5 h at r.t., the mixture was refluxed for 1 h. To the cooled ( 788)
orange suspension, a soln. of 17 (392 mg, 0.84 mmol) was added within 15 min. The mixture was slowly warmed,
and after 2.25 h (08), additional NaHMDS (0.20 ml, 0.36 mmol) was added and stirred for another 2.5 h. The
mixture was diluted with CH2Cl2 (10 ml) and subsequently washed with 1m aq. NH4Cl (7 ml) and sat. aq.
NaHCO3 soln. (10 ml). The aq. layer was extracted with CH2Cl2 (3 Â 10 ml), the combined org. phase dried
(MgSO4) and evaporated, and the brown residue submitted to FC (40 g, CH2Cl2/AcOEt 4 :1, gradient): 19
(324 mg, 76%), (Z)/(E) 9 :1 (by 1H-NMR). White foam. TLC (AcOEt): 0.73. IR (KBr): 3313m, 3148s, 3014w,
2956m, 2929m, 2856m, 1664s, 1601s, 1565m, 1474m, 1438m, 1417m, 1347m, 1324m, 1309m, 1248s, 1193s, 1129m,
857m, 842m, 782m. 1H-NMR: 9.12 (br. s, NH); 8.80 (s, 1 H); 8.16 (s, 1 H); 8.05 ± 8.00 (m, 2 H, Ph); 7.65 ± 7.57 (m,
1 H, Ph); 7.57 ± 7.48 (m, 2 H, benzoyl); 6.42 (t, J ˆ 6.2, H C(1')); 5.72 (dt, J ˆ 10.8, 7.7, 1 H); 5.55 ± 5.46 (m, 1 H);
4.76 (ddd, J ˆ 9.3, 4.3, 0.9, H C(4')); 4.45 (dd, J ˆ 10.5, 4.6, H C(3')); 2.85 (dt, J ˆ 13.4, 5.9, 1 H C(2')); 2.54
(ddd, J ˆ 13.3, 6.6, 5.1, 1 H C(2')); 2.24 ± 2.08 (m, 2 H C(7')); 1.50 ± 1.37 (m, 2 H C(8')); 0.96 ± 0.90 (m,
Me(9')); 0.92 (s, tBuSi); 0.11 (s, MeSi); 0.10 (s, MeSi). 13C-NMR: 152.46 (d); 151.31 (d); 149.46 (s); 141.63 (d);
136.02 (d); 135.89 (s); 133.66 (s); 132.72 (d); 128.83 (d); 127.84 (d); 127.13 (s); 126.75 (d); 123.99 (s); 123.76 (s);
88.39 (d); 84.77 (d); 84.59 (d); 83.00 (d); 76.21 (d); 40.80 (t); 29.88 (t); 25.70 (q); 22.72 (t); 17.98 (s); 13.71 (q);
‡
4.77 (q); 4.80 (q). HR-LSI-MS: 507.2649 (C27H38N5O3Si , calc. 507.2666).
N6-Benzoyl-5'-C-butyl-3'-O-[(tert-butyl)dimethylsilyl]-2',5'-dideoxy-5',6'-epoxyadenosine3) (20). To a cold
(
208) soln. of 19 (191 mg, 0.38 mmol) in CH2Cl2 (4.50 ml), 0.10m DMDO in acetone (4.50 ml, 0.45 mmol) [16]
was added and stirred at 08 for 4 h. Then additional DMDO (3.80 ml, 0.38 mmol) was added and the mixture
warmed to r.t. After 22 h, evaporation and FC (15 g, CH2Cl2/MeOH 75 :1, 50 :1) gave (5'R,6'S)/(5'S,6'R)-20
(141 mg, 71%). A further FC (14 g, AcOEt/hexane 1:1, gradient) provided first (5'R,6'S)-20 (26 mg, 13%), and
after mixed fractions, (5'S,6'R)-20 (70 mg, 35%).
Data of (5'R,6'S)-20: TLC (AcOEt/hexane 2 :1): Rf 0.28. [a]2D0 ˆ ‡18.1 (CHCl3, c ˆ 0.99). IR (KBr): 3244w,
3186w, 3088w, 3064w, 2956s, 2929s, 2857m, 1696s, 1608s, 1577s, 1508m, 1458s, 1252s, 1102m, 1057s, 836m, 778m.
1H-NMR: 8.79 (s, 1 H); 8.16 (s, 1 H); 8.06 ± 8-01 (m, 2 H, Ph); 7.65 ± 7.59 (m, 1 H, Ph); 7.59 ± 7.50 (m, 2 H, Ph);
6.47 (dd, J ˆ 8.6, 5.7, H C(1')); 4.83 ± 4.79 (m, H C(3')); 3.83 (dd, J ˆ 8.9, 1.4, H C(4')); 3.24 ± 3.13 (m, 1
H
C(2')); 3.19 (dd, J ˆ 8.5, 3.7, H C(5')); 3.10 ± 3.03 (m, H C(6')); 2.49 (ddd, J ˆ 13.2, 5.7, 1.8, 1 H C(2'));
t
1.62 ± 1.44 (m, 2 H C(7'), 2 H C(8')); 1.03 ± 0.92 (m, Me(9')); 0.95 (s, BuSi); 0.16 (s, MeSi); 0.15 (s, MeSi).
13C-NMR: 164.68 (s); 152.42 (d); 151.64 (s); 149.63 (s); 141.98 (d); 133.60 (s); 132.76 (d); 128.83 (d); 127.86 (d);
123.97 (s); 86.17 (d); 85.35 (d); 75.28 (d); 57.29 (d); 55.62 (d); 39.33 (t); 29.64 (t); 25.74 (q); 19.65 (t); 18.01 (s);
‡
13.92 (q); 4.80 (q); 4.88 (q). HR-LSI-MS: 524.2693 (C27H38N5O4Si ; calc. 524.2671).
Data for (5'S,6'R)-20. TLC (AcOEt/hexane 2 :1): Rf 0.22. [a]1D9 ˆ ‡16.3 (CHCl3, c ˆ 0.99). IR (KBr):
3254w, 3184w, 3094w, 3065w, 2958s, 2930s, 2858m, 1700s, 1611s, 1582s, 1512m, 1457s, 1253s, 1223m, 1112m,
1061m, 838m. 1H-NMR: 8.80 (s, 1 H); 8.36 (s, 1 H); 8.07 ± 8.00 (m, 2 H, Ph); 7.65 ± 7.57 (m, 1 H, Ph); 7.57 ± 7.49
(m, 2 H, Ph); 6.47 (t, J ˆ 6.3, H C(1')); 4.79 (q, J ˆ 5.0, H C(3')); 4.03 (dd, J ˆ 6.2, 4.3, H C(4')); 3.15 ± 3.04
(m, H C(5'), H C(6')); 2.93 (dt, J ˆ 13.2, 6.0, 1 H C(2')); 2.52 (ddd, J ˆ 13.2, 6.7, 5.0, 1 H C(2')); 1.78 ± 1.65
(m, 1 H); 1.62 ± 1.45 (m, 3 H); 0.99 ± 0.91 (m, Me(9')); 0.15 (s, MeSi); 0.14 (s, MeSi). 13C-NMR: 164.65 (s);
152.43 (d); 151.24 (s); 149.51 (s); 142.16 (d); 133.64 (s); 132.71 (d); 128.80 (d); 127.83 (d); 123.63 (s); 85.10 (d);
85.05 (d); 73.98 (d); 57.10 (d); 56.64 (d); 40.61 (t); 30.21 (t); 25.67 (q); 20.23 (q); 17.90 (s); 13.85 (q); 4.64 (q);
‡
4.86 (q). HR-LSI-MS: 524.2693 (C27H38N5O4Si ; calc. 524.2671).
N6-Benzoyl-5'-C-butyl-3'-O-[(tert-butyl)dimethylsilyl]-2',5'-dideoxy-5',6'-epoxy-7,8-dihydroadenosine3)
(21). To a soln. of (5'S,6'R)-20 (63 mg, 0.12 mmol) in dry THF (1.15 ml), 1m BH3 ´ THF complex in THF (0.12 ml,
0.12 mmol) was added at 788 and stirred for 30 min. The reaction was quenched with sat. aq. NaHCO3 soln.
(0.57 ml), and the resulting yellow soln. treated with Oxoneꢀ (560 mg, 0.96 mmol) in sat. aq. NaHCO3 soln.
(2.9 ml), warmed to r.t., and stirred for 40 min. The mixture was diluted with CH2Cl2 (4 ml), the org. phase
separated, and the aq. layer extracted with CH2Cl2 (3 Â 3 ml). The combined org. layer was dried (MgSO4) and
the crude product was submitted to FC (6 g, AcOEt/hexane 1:2): 21 (29 mg, 47%) and 20 (22 mg, 35%). TLC
(AcOEt/hexane 2 :1): Rf 0.28. [a]1D9 ˆ ‡55.8 (CHCl3, c ˆ 1.16). IR: 3309m, 3210m, 3126w, 2957s, 2926s, 2858s,
1664s, 1629m, 1578s, 1518s, 1491s, 1405s, 1345m, 1314s, 1260s, 1116s, 1045s, 1005m, 894m, 836m, 777m, 757m.
1H-NMR: 9.16 (br. s, NH); 7.91 ± 7.88 (m, 2 H); 7.82 (s, H C(2)); 7.58 ± 7.53 (m, 1 H); 7.49 ± 7.43 (m, 2 H); 6.15 (t,
J ˆ 6.9, H C(1')); 5.31 (br. s, H N(7), H C(8)); 5.15 (m, H C(8)); 4.38 (dt, J ˆ 6.2, 4.1, H C(3')); 3.78 (dd,

Helvetica Chimica Acta ± Vol. 84 (2001)
103
J ˆ 7.0, 4.1, H C(4')); 3.01 (dt, J ˆ 7.5, 3.9, H C(6')); 2.88 (dd, J ˆ 7.0, 4.2, H C(5')); 2.35 (dt, J ˆ 13.2, 6.7, 1
H
C(2')); 2.10 (ddd, J ˆ 13.2, 6.6, 4.2, 1 H C(2')); 1.80 ± 1.62 (m, 1 H); 1.61 ± 1.43 (m, 3 H); 0.97 (t, J ˆ 7.3,
Me(9')); 0.92 (s, tBuSi); 0.12 (s, MeSi); 0.10 (s, MeSi). 13C-NMR: 165.35 (s); 160.96 (s); 148.91 (d); 133.55 (d);
133.18 (s); 132.46 (d); 128.79 (d); 127.60 (d); 122.26 (s); 83.34 (d); 82.94 (d); 74.05 (d); 63.45 (t); 57.09 (d); 56.85
(d); 37.38 (t); 30.49 (t); 25.71 (q); 20.29 (t); 17.94 (s); 13.89 (q); 4.56 (q); 4.87 (q). HR-LSI-MS 526.2850
‡
(C27H40N5O4Si ; calc. 526.2791).
N6-Benzoyl-3'-O-[(tert-butyl)dimethylsilyl]-5'-butylidene-2',5'-deoxyadenosine (22). To a soln. of 19
(40 mg, 0.08 mmol) in dry THF (0.80 ml), 1m BH3 ´ THF complex soln. in THF (80 ml, 0.08 mmol) was slowly
added at 408. After 40 min, additional BH3 ´ THF complex soln. (8 ml, 0.008 mmol) was added and warmed to
208. After 1.5 h, the reaction was quenched with sat. aq. NaHCO3 soln. (0.40 ml), and a soln. of Oxone ꢀ
(338 mg, 0.64 mmol) in sat. aq. NaHCO3 soln. (2.0 ml) was added and stirred at r.t. for 30 min. The mixture was
diluted with CH2Cl2 (3 ml), the aq. phase extracted with CH2Cl2 (3 Â 3 ml), the combined org. phase dried
(MgSO4) and evaporated, and the residue submitted to FC (5 g, AcOEt/hexane 1:2, gradient): 22 (31 mg, 76%)
and 19 (4 mg, 10%). TLC (AcOEt/hexane 1:1): Rf 0.48. [a]1D9 ˆ ‡91.3 (CHCl3, c ˆ 0.38). UV: 241, 274, 336. IR
(film): 3300w, 3219w, 3137w, 2956s, 2929s, 2891m, 2857s, 1665s, 1636m, 1581s, 1514s, 1490s, 1402s, 1343m, 1310m,
1259s, 1112s, 1064s, 1027s, 889m, 837s, 777m, 708m. 1H-NMR: 9.42 (br. s, NH C(6)); 7.94 ± 7.83 (m, 3 H); 7.62 ±
7.54 (m, 1 H, Ph); 7.54 ± 7.44 (m, 2 H, Ph); 6.19 (t, J ˆ 6.8, H C(1')); 5.62 (dt, J ˆ 10.9, 7.4, H C(6')); 5.38 ± 5.29
(m, H N(7), H C(5')); 5.29 ± 5.25 (m, 1 H C(8)); 5.12 (t, J ˆ 4.0, 1 H C(8)); 4.54 (dd, J ˆ 9.2, 4.0, H C(4'));
4.07 (dt, J ˆ 6.1, 4.1, H C(3')); 2.30 ± 2.17 (m, 1 H C(2')): 2.17 ± 1.99 (m, 2 H C(7'), 1 H C(2')); 1.39 (sext.,
J ˆ 7.4, 2 H C(8')); 0.95 ± 0.87 (m, Me(9')); 0.90 (s, tBuSi); 0.07 (s, MeSi); 0.06 (s, MeSi). 13C-NMR: 165.43 (s);
161.15 (s); 148.97 (d); 134.87 (d); 133.51 (s); 133.18 (s) 132.43 (d); 128.75 (d); 127.62 (d); 127.40 (d); 122.29 (s);
86.35 (d); 82.05 (d); 76.47 (d); 63.06 (t); 37.26 (t); 29.91 (t); 25.72 (q); 22.78 (t); 17.99 (s); 13.71 (q); 4.77 (q);
‡
4.84 (q). HR-LSI-MS: 509.2822 (C27H39N5O3Si ; calc. 509.2808).
N6-Benzoyl-3'-O-[(tert-butyl)dimethylsilyl]-2',5'-dideoxy-5'-methylideneadenosine (23). As described for
3a, from methyltriphenylphosphonium bromide (688 mg, 1.92 mmol), 2m NaHMDS in THF (0.96 ml,
1.92 mmol) in THF (4.80 ml), and 17 (300 mg, 0.64 mmol) in THF (3.50 ml). FC (40 g, CH2Cl2/AcOEt 4 :1,
gradient): 23 (209 mg, 70%). White foam. TLC (AcOEt): Rf 0.82. [a]2D4 ˆ ‡21.7 (CHCl3, c ˆ 1.07). IR (KBr):
3261w, 3066w, 2955s, 2929s, 2886m, 2857s, 1701s, 1611s, 1578s, 1508m, 1458s, 1329m, 1297m, 1255s, 1096m,
1053m, 837s, 779m, 708m. 1H-NMR: 9.20 (br. s, NH); 8.79 (s, 1 H); 8.16 (s, 1 H); 8.06 ± 7.99 (m, 2 H, Ph); 7.63 ±
7.57 (m, 1 H, Ph); 7.55 ± 7.47 (m, 2 H, Ph); 6.47 (t, J ˆ 6.3, H C(1')); 5.97 (ddd, J ˆ 17.2, 10.4, 6.7, H C(5')); 5.36
(dt, J ˆ 17.1, 1.3, 1 H C(6')); 5.27 (dt, J ˆ 10.5, 1.3, H C(6')); 4.49 (dt, J ˆ 5.7, 4.2, 1 H); 4.43 ± 4.38 (m, 1 H); 2.84
(dt, J ˆ 13.2, 6.1, 1 H C(2')); 2.50 (ddd, J ˆ 13.2, 6.4, 4.5, 1 H C(2')); 0.92 (s, tBuSi); 0.11 (s, 2 MeSi). 13C-NMR:
164.70 (s); 152.52 (d); 149.54 (s); 141.53 (d); 135.37 (d); 133.65 (s); 132.71 (d); 128.79 (d); 128.53 (s); 128.37 (s);
127.86 (d); 123.69 (s); 117.99 (t); 88.35 (d); 84.74 (d); 75.63 (d); 40.10 (t); 25.70 (q); 17.99 (s); 4.73 (q). HR-
‡
LSI-MS: 466.2274 (C24H32N5O3Si ; calc. 466.2275).
N6-Benzoyl-3'-O-[(tert-butyl)dimethylsilyl]-2',5'-dideoxy-5',6'-epoxy-5'-methyladenosine3) (24). To an ice-
cold soln. of 23 (142 mg, 0.31 mmol) in dry CH2Cl2 (4.00 ml), was added 0.14m DMDO in acetone (4.35 ml,
0.61 mmol) and stirred overnight at r.t. After evaporation, CH2Cl2 (1.00 ml) and DMDO soln. (4.35 ml,
0.61 mmol) were added and stirred for 2 d at r.t. Then 1 g of deactivated silica gel (MeOH) was added, the
solvent evaporated, and the residue submitted to FC (AcOEt/hexane 1:1, gradient): 24 (45 mg, 30%; dr. 77 :23
by 1H-NMR) as white foam and 23 (45 mg, 31%). 24 TLC (AcOEt/hexane 2 :1): Rf 0.32. IR (KBr): 3385m,
3058m, 2955s, 2929s, 2856s, 1717s, 1608s, 1583s, 1516s, 1489m, 1456s, 1352m, 1330m, 1299m, 1255s, 1223m, 1184m,
1120m, 1084m, 1027m, 837m, 780m, 721m, 695m. 1H-NMR: 9.12 (br. s, NH); 8.80 (s, 1 H); 8.46, 8.23 (2 s, 1 H);
8.07 ± 8.00 (m, 2 H, Ph); 7.71 ± 7.43 (m, 3 H, Ph); 6.62 (dd, J ˆ 7.5, 6.0, H C(1')); 6.49 (dd, J ˆ 7.4, 6.3, H C(1'));
4.74 (dt, J ˆ 5.2, 2.8, H C(3')); 4.59 (dt, J ˆ 5.3, 2.8, H C(3')); 4.20 (t, J ˆ 2.3, H C(4')); 3.97 (dd, J ˆ 5.1, 2.5,
H
C(4')); 3.29 (ddd, J ˆ 5.0, 4.0, 2.6, 1 H); 3.22 ± 3.18 (m, 1 H); 3.08 ± 2.98 (m, 1 H); 2.89 (t, J ˆ 4.4, 1 H); 2.82 ±
2.75 (m, 2 H); 2.72 ± 2.61 (m, 1 H); 2.53 ± 2.40 (m, 1 H C(2')); 0.95, 0.93 (2 s, tBuSi); 0.15, 0.13 (2 s, 2 MeSi).
13C-NMR: 164.55 (s); 152.66 (d); 151.80 (s); 149.38 (s); 141.76 (d); 141.47 (d); 133.65 (s); 132.71 (d); 132.13 (d);
132.01 (d); 131.90 (d); 131.86 (d); 128.83 (d); 128.54 (d); 128.37 (d); 127.83 (d); 123.13 (s); 87.66 (d); 85.24 (d);
84.52 (d); 84.11 (d); 74.25 (d); 72.61 (d); 51.79 (d); 51.18 (d); 45.75 (t); 43.75 (t); 41.03 (t); 40.12 (t); 25.71 (q);
‡
17.99 (s); 4.69 (q); 4.88 (q). HR-MS: 482.2224 (C24H32N5O4Si ; calc. 482.2212).
N6-Benzoyl-5'-butyl-3'-O-[(tert-butyl)dimethylsilyl]-2'-deoxydenosine (25). A soln. of 0.61m PrMgBr
(1.20 ml, 7.29 mmol) in THF was added dropwise to a suspension of anh. CuI (15.8 mg, 0.08 mmol) in dry
THF (7.50 ml). Then, the mixture was cooled to 788, reheated to 408, and slowly treated with a soln. of 24
(78 mg, 0.16 mmol) in dry THF (1.80 ml). The suspension turned immediately yellow, and after 30 min, the
mixture was slowly warmed to 188. After 2 h, the reaction was quenched with sat. aq. NH4Cl soln. (4.50 ml),

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Helvetica Chimica Acta ± Vol. 84 (2001)
warmed to r.t., and diluted with CH2Cl2 (6 ml). The aq. phase was extracted with CH2Cl2 (2 Â 4 ml), the
combined org. phase concentrated and washed with 0.5m EDTA soln. (3 ml), dried (MgSO4), and evaporated,
and the residue submitted to FC (8 g, AcOEt/hexane 1 :1): 25 (53 mg, 62%; d.r. 84 :16 by 1H-NMR). Light green
foam. TLC (AcOEt/hexane 2 :1): Rf 0.47. IR (KBr): 3284m, 2955s, 2928s, 2857s, 1700s, 1611s, 1582s, 1517m,
1459s, 1331m, 1255s, 1105m, 1086m, 1051m, 835m, 777m. 1H-NMR: 9.11 (br. s, NH); 8.79, 8.77 (2 s, 1 H); 8.10,
8.09 (2 s, 1 H); 8.07 ± 7.98 (m, 2 H, Ph); 7.72 ± 7.58 (m, 1 H, Ph); 7.56 ± 7.42 (m, 2 H, Ph); 6.36 (dd, J ˆ 9.6, 5.3,
H
C(1')); 6.32 (dd, J ˆ 9.8, 5.2, H C(1')); 6.07 (br. s, OH); 5.39 (d, J ˆ 11.2, OH); 4.68 (d, J ˆ 5.0, 1 H); 4.06
(br. s, 1 H); 3.94 ± 3.88 (m, H C(5')); 3.74 ± 3.64 (m, H C(5')); 3.11 ± 2.99 (m, 1 H C(2')); 2.21 (ddd, J ˆ 12.9,
8.0, 5.4, 1 H C(2')); 1.68 ± 1.23 (m, 2 H C(6'), 2 H C(7'), 2 H C(8')); 1.00 ± 0.86 (m, Me(9')); 0.94 (s, tBuSi);
0.13 (s, MeSi); 0.12 (s, MeSi). 13C-NMR: 164.42 (s); 152.10 (d); 151.95 (d); 150.73 (s); 150.22 (s); 142.62 (d);
133.49 (s); 132.88 (d); 132.14 (s); 132.01 (d); 131.87 (s); 128.88 (d); 128.54 (d); 128.38 (d); 127.86 (d); 124.65 (s);
93.37 (d); 91.65 (d); 87.77 (d); 87.44 (d); 74.98 (d); 72.13 (d); 71.83 (d); 71.77 (d); 41.50 (t); 40.77 (t); 34.05 (t);
32.74 (t); 28.44 (t); 28.08 (t); 25.78 (q); 25.70 (q); 22.72 (t); 22.64 (t); 17.98 (s); 17.85 (s); 13.98 (q); 13.95 (q);
‡
2
4.56 (q); 4.71 (q); 4.80 (q). HR-MS: 526.2850 (C27H40N5O4Si ; calc. 526.2831).
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Received August 16, 2000