Oligonucleosides with a nucleobase-including backbone. Part 1. Concept, force-field calculations, and synthesis of uridine-derived monomers and dimers

Article abstract of DOI:10.1002/1522-2675(20000705)83:7<1311::AID-HLCA1311>3.0.CO;2-2

A new type of oligonucleosides has been devised to investigate the potential of oligonucleosides with a nucleobase-including backbone to form homo- and/or heteroduplexes (cf. Fig. 2). It is characterised by ethynyl- linkages between C(5') and C(6) of uridine, and between C(5') and C(8) of adenosine. Force-field calculations and Maruzen model studies suggest that such oligonucleosides form autonomous pairing systems and hybridize with RNA. We describe the syntheses of uridine-derived monomers, suitable for the construction of oligomers, and of a dimer. Treatment of uridine-5'- carbaldehyde (2) with triethylsilyl acetylide gave the diastereoisomeric propargylic alcohols 6 and 7 (1:2, 80%; Scheme 1). Their configuration at C(5') was determined on the basis of NOE experiments and X-ray crystal- structure analysis. Iodination at C(6) of the (R)-configured alcohol 7 by treatment with lithium diisopropylamide (LDA) and N-iodosuccinimide (NIS) gave the iodide 17 (62%), which was silylated at O-C(5') to yield 18 (89%; Scheme 2). C-Desilylation of 7 with NaOH in MeOH/H₂O led to the alkyne 10 (98%); O-silylation of 10 at O-C(5') gave 16 (84%). Cross-coupling of 18 and 16 yielded 63% of the dimer 19, which was C-desilylated to 20 in 63% yield. Cross-coupling of 10 and the 6-iodouridine 13 (70%), followed by treatment of the resulting dimer 14 with HF and HCl in MeCN/H₂O, gave the deprotected dimer 15 (73%).

Full text of DOI:10.1002/1522-2675(20000705)83:7<1311::AID-HLCA1311>3.0.CO;2-2

Helvetica Chimica Acta ± Vol. 83 (2000)
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Oligonucleosides with a Nucleobase-Including Backbone
Part 1
Concept, Force-Field Calculations, and Synthesis of Uridine-Derived Monomers
and Dimers
by Simon Eppacher, Nathalie SolladieÂ, Bruno Bernet, and Andrea Vasella*
Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich
A new type of oligonucleosides has been devised to investigate the potential of oligonucleosides with a
nucleobase-including backbone to form homo- and/or heteroduplexes (cf. Fig. 2). It is characterised by ethynyl-
linkages between C(5') and C(6) of uridine, and between C(5') and C(8) of adenosine. Force-field calculations
and Maruzen model studies suggest that such oligonucleosides form autonomous pairing systems and hybridize
with RNA. We describe the syntheses of uridine-derived monomers, suitable for the construction of oligomers,
and of a dimer. Treatment of uridine-5'-carbaldehyde (2) with triethylsilyl acetylide gave the diastereoisomeric
propargylic alcohols 6 and 7 (1:2, 80%; Scheme 1). Their configuration at C(5') was determined on the basis of
NOE experiments and X-ray crystal-structure analysis. Iodination at C(6) of the (R)-configured alcohol 7 by
treatment with lithium diisopropylamide (LDA) and N-iodosuccinimide (NIS) gave the iodide 17 (62%), which
was silylated at OÀC(5') to yield 18 (89%; Scheme 2). C-Desilylation of 7 with NaOH in MeOH/H2O led to the
alkyne 10 (98%); O-silylation of 10 at OÀC(5') gave 16 (84%). Cross-coupling of 18 and 16 yielded 63% of the
dimer 19, which was C-desilylated to 20 in 63% yield. Cross-coupling of 10 and the 6-iodouridine 13 (70%),
followed by treatment of the resulting dimer 14 with HF and HCl in MeCN/H2O, gave the deprotected dimer 15
(73%).
Introduction and Concept. ± Pairing studies of DNA/RNA-analogues1) [6 ± 10] with
modified carbohydrate, nucleobase, and backbone moieties form the basis of current
insight into the structural requirements for the formation of stable duplexes. All
backbone-modified analogues that have so far been investigated maintain a separation
between nucleobase and backbone, irrespective of whether the backbone is derived
from a carbohydrate or a peptide (PNA [11][12]). This leads to the question of whether
this structural invariant, which implies a functional differentiation of nucleobases and
backbone is indeed required for the formation of homo- and/or heteroduplexes. To
answer this question, we have conceived a new type of oligonucleoside analogues that
possess a nucleobase-including backbone (Fig. 1). In these analogues, the 3',5'-
phosphodiester linkage of RNA is replaced by a link L between C(5') and C(6) or C(5)
of uridine, and between C(5') and C(8) or C(2) of adenosine, respectively (structures
I ± IV in Fig. 2). From among the conceivable charged or uncharged links L, we have
chosen the ethynediyl group as the sterically least demanding with the potential for a
convergent, ideally binomial, synthesis of oligomers [13] and a reactivity that should
1
)
Most DNA and RNA analogues have been prepared in search of antisense compounds [1][2], to investigate
autonomous pairing systems, protein/DNA interactions [3], electron transfer in DNA [4], and DNA
damage [5].

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Fig. 1. Conventional oligonucleotides with structural separation of the nucleobases and the backbone (A) and
oligonucleosides with a nucelobase-including backbone (B)
allow for facile derivatisations. The 5'-OH groups should be retained to favour
water-solubility, to allow for derivatisations, and to simplify the synthesis. Before
undertaking the synthesis, we decided to evaluate the potential of the 5',6-linked
pyrimidine analogues I-A, the 5',8-linked purine analogues III-A, and their 5',5- and
5',2-linked regioisomers corresponding to II and IV (Fig. 2) to form homo- and/or
heteroduplexes, using both force-field calculations and Maruzen models. We report the
results of the calculation and model-studies, the syntheses of uridine-derived
monomers, suitable for the construction of oligomers, and the synthesis of a
deprotected dimer.
Results and Discussion. ± 1. Nomenclature. The names for the nucleosides bearing
ethynyl groups are abbreviated by a combination of a single letter for the base (U and
A), three letters for the carbohydrate chain (Hep for 6,7-dideoxyhex-6-ynofuranosyl),
and a single letter for the configurational prefix (r for d-ribo, a for d-allo, and t for l-
talo). The linking mode in oligomers is indicated by two numerals in parenthesis. A
dash, as in (3'-5'), indicates a phosphinato group between O(3') and O(5') (natural
nucleotides) and determines the (3 ! 5') direction of the linkage. The en dash, as in
(5À7'), indicates a single bond between the two specified centers (acetyleno analogues)
and the (5 ! 7') direction of the linkage. The chain direction in heteroduplexes is
assigned by correlating the connecting site at the base and the 3' connecting site, and the
connecting site at the terminal acetylenic atom and the 5' connecting site. Thus, in the
heteroduplex (7'À5)rHepU6 ´ (5'-3')A6, the strands are parallel. As proposed in the

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Fig. 2. Oligonucleosides I ± IV varying in the connecting points of the link L on the sugar and the nucleobase
moiety and proposed uridine and adenosine oligomers I-A and III-A
1996 recommendations for the nomenclature of carbohydrates [14], ꢀdownstream and
upstream endꢁ are the expressions used to name the ends at the start (opposite to the
arrow direction) and at the end of the strand. Starting from the downstream end, the
nucleosides are numbered by roman numerals (e.g., HÀC(6/II) ˆ HÀC(6) of the
second nucleobase, HÀC(1'/III) ˆ HÀC(1') of the third furanosyl unit).
2. Force-Field Calculations of Acetyleno Analogues of RNA Oligonucleotides.
Force-field calculations were performed to evaluate the potential of oligonucleosides
possessing acetyleno bridges between the carbohydrate moiety and the nucleobase to
form homo- and heteroduplexes similar to the homoduplexes of natural RNA, and to
evaluate the appropriate chain length of the carbohydrate unit and the appropriate
attachment points between the carbohydrate unit and the nucleobase. Force-field
calculations were, however, not intended to find other possible helical or non-helical
tertiary structures of such hetero- and homoduplexes possessing a modified backbone.
Calculations were performed with Macromodel V. 4.5 (Amber* force field, gas
phase) [15]. To obtain hetero- and homoduplexes possessing a modified backbone, the
A helix of a RNA oligomer was built with the grow tool of Macromodel, energy-
minimised, and modified. First, evaluation of the chain length of the link showed that

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an acetyleno group between C(5') and the base is better than a buta-1,3-diyne group
between C(5') and the base, and much better than an acetyleno group between C(4')
and the base. A C(5')ÀOH group has a negligible influence upon the tertiary structure,
independent of the configuration at C(5'); modified strands containing rHepU, aHepU,
tHepU, rHepA, aHepA, and tHepA residues lead to similar RNA hetero- and homo-
duplexes. Next, the attachment point at the base was evaluated. For uridine, C(6) is
superior to C(5), whereas both C(2) and C(8) of adenosine are appropriate attachment
points. Fig. 3 shows the calculated helical structures of the homoduplex (7'À6)aHep-
Fig. 3. Amber*-calculated structures of the fully- and the semi-modified duplex (7'-6)aHepU14 ´ (8À7')aHepA14
and (7'À6)aHepU14 ´ (5'-3')A14
U14 ´ (8À7')aHepA14 and the heteroduplex (7'À6)aHepU14 ´ (5'-3')A14. There are A
helices (11 residues per turn), showing slightly enhanced axial rises (ca. 2.9 Š instead of
2.74 Š), but similar propeller- and buckle-twist angles as the unmodified (3'-5')U14 ´ (5'-
3')A14. The ring pucker is changed from 3E for (3'-5')U14 and 3T2 for (5'-3')A14 to 4E for
both (7'À6)aHepU14 and (8À7')aHepA14. Finally, the compatibility of these acetyleno
nucleosides with natural nucleotides in the same strand was evaluated. Replacing a (3'-
5')U unit by a (7'À5)-linked aHepU or a (7'À6)-linked aHepU unit and replacing a (5'-
3')A unit by a (8À7')-linked aHepA led to severely propeller- and buckle-twisted base
pairs. However, a (7'À2)-linked aHepA is tolerated in a strand of natural nucleotides.
The question of whether such acetyleno-oligonucleosides may form other helical or
non-helical tertiary structures was investigated with the help of Maruzen models.

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3. Maruzen Model Studies. Maruzen-model studies have been performed on the
homoduplex (7'À6)aHepU ´ (8À7')aHepA and the heteroduplexes (7'À6)aHepU ´ (5'-
3')A and (3'-5')U ´ (8À7')aHepA. Since Maruzen models fix the bond angles of sp2 and
sp centers at 1208 and 1808, respectively, the repeating unit of a HepU and aHepA in all
structures is characterised by three torsion angles c, n, m, and the sugar-pucker. Based
4
on the results of the force-field calculations, a E sugar pucker of these acetyleno-
oligonucleosides was used. For heteroduplexes, all torsion angles of the RNA strands
with the exception of c were chosen as described for RNA strands in RNA duplexes
[16]. Table 1 shows all so far constructed types of helix or ladder structures of homo-
Table 1. Tertiary Structure, Orientation of Strands, and Torsion-Angle Ranges for c, n, and ma) of Homo- and
Heteroduplexes Containing Acetyleno-Nucleoside Strands Derived from Maruzen Models
Duplex
Tertiary structure, c(aHepU) n(aHepU) m(aHepU) c(aHepA) n(aHepA) m(aHepA)
orientation of
strands
or c(U)
or c(A)
aHepUn ´ aHepAn right-handed helix,
antiparallel
aHepUn ´ aHepAn left-handed helix,
antiparallel
ac, ap
À sc
ac, ap
ac
sc
ac
sc
sc
ac
sc
À sc
sc
ac
À sc
sc
À sc
ac
sc
aHepUn ´ An
aHepUn ´ An
aHepUn ´ An
aHepUn ´ An
Un ´ aHepAn
Un ´ aHepAn
Un ´ aHepAn
Un ´ aHepAn
right-handed helix,
parallel
ladder structure,
antiparallel
ladder structure,
antiparallel
left-handed helix,
parallel
À sc
À sc
sc
À ac, À ap
sc
À sc
À sc
À sc
sc
ac
right-handed helix, À ac, À ap
sc, ac
sc, ac
À sc
sc
sc, À sc
ap
À sc
parallel
ladder structure,
antiparallel
ladder structure,
antiparallel
left-handed helix,
parallel
sc
À sc
sc
sc
ac, ap
À sc
ac
a) c(aHepU) and c(U): torsion angle O(4')ÀC(1')ÀN(1)ÀC(2), c(aHepA) and c(A): torsion angle
O(4')ÀC(1')ÀN(9)ÀC(4), n(aHepU) and n(aHepA): torsion angle C(3')ÀC(4')ÀC(5')ÀC(6'), m(aHepU):
torsion angle C(4')ÀC(5')ÀC(6)ÀN(1), m(aHepA): torsion angle C(4')ÀC(5')ÀC(8)ÀN(9).
and heteroduplexes of acetyleno-oligonucleosides. All these models maintain a parallel
orientation of Watson-Crick base pairs at a distance of ca. 3 Š, comparable to the
distance between base pairs in RNA duplexes (2.6 ± 3.3 Š [17]). The homoduplex of
(7'À6)aHepU ´ (8À7')aHepA can form a right- and a left-handed helix with antipar-
allel strand orientation. For heteroduplexes, we find a left- and a right-handed helix and
two ladder structures. Rotation of all c angles in the RNA strand by 1808 or the rotation
of all c angles and m angles in the modified strand by 1808 causes a change from a helix
to a ladder structure, while rotation of all c angles by 1808 in both single strands causes a
change from a right-handed helix to a left-handed helix.

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4. Synthesis of Uridine-Derived Monomers and Dimers. A binomial synthesis of the
desired uridine-derived oligomers based on the Sonogashira coupling [18] requires a
regioselective cross coupling of two doubly functionalised and selectively protected
monomers. One kind of these monomers is represented by the iodo-uridines 17 and 18
that possess a protected alkynyl group, while C(6) is activated by the I substituent (cf.
Scheme 2). The alkynes 10 and 16 possessing a monosubstituted alkynyl group
correspond to the second kind of monomers if one implies activation of HÀC(6)
subsequent to the cross coupling, e.g., by regioselective iodination. These monomers 10,
16, and 17 were prepared from the (5'R) (ˆd-allo) configured propargylic alcohol 7,
which was synthesized from uridine in three steps (Scheme 1). Repetition of the
oxidation of 2',3'-O-isopropylideneuridine (1) with CrO3 [19], or DCC/DMSO [20] on
a scale of 0.3 to 1 g gave the carbaldehyde 2 in high yields. Unfortunately, these
methods proved unsatisfactory when the scale was increased to 10 g. Oxidation with
CrO3 and pyridine in a mixture of CH2Cl2 and DMF yielded only 40% of 2, while
oxidation with pyridinium chlorochromate (PCC) was difficult to reproduce. Pfitzner-
Scheme 1
a) Periodinane, CH2Cl2; 81% (2); 93% (5). b) BrMgCꢀCÀSiMe3, THF; 80% of 3/4 1 :2. c) NaBH4, EtOH;
99% of 3/4 1:1. d) BrMgCꢀCÀSiEt3, THF; 80% of 6/7 1:2. e) DEAD, Ph3P, THF; 94% (8); 94% (9). f)
NaOH, MeOH/H2O 1 :1; 98% from 7; 95% from 9. g) H2O/MeCN/37% HCl/40% HF 100 :50 :2 :2; quant.

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Moffatt oxidation followed by treatment of the crude aldehyde with N,N'-diphenyl-
ethylenediamine [21] gave the N,N'-diphenylimidazolidine in high yield, but its cleavage
‡
with Dowex 50WX8 (H form) in aqueous THF led to the highly water-soluble hydrate
of 2, which was degraded during attempted alkynylation. However, oxidation of 1 with
periodinane [22] on a 50-g scale gave 2 in 95% yield as ca. 85% pure material.
Treatment of crude 2 with 2.5 equiv. of Me3SiCꢀCMgBr led in 80% to a 1:2 mixture of
the diastereoisomeric propargylic alcohols 3 and 4, which were, at best, partially
separated by flash chromatography (FC) and crystallization2). Substitution of
Me3SiCꢀCMgBr by bis[(trimethylsilyl)ethinyl]zinc or addition of CeCl3 [23] had no
significant influence on yield and ratio of the products. Oxidation of 3/4 (1:1) with
periodinane yielded 93% of a single ketone 5, establishing that 3 and 4 are
diastereoisomers. This ketone could not be reduced with a sufficiently high degree of
diastereoselectivity (<2 :1) by either NaBH4, Alpine Borane [24], or BH3 in the
presence of Coreyꢁs oxazaborolidine [25]. Addition of Et3SiCꢀCMgBr to 2 yielded
80% of a 1:2 mixture 6/7. In contradistinction to the trimethylsilyl derivatives 3 and 4,
the triethylsilyl derivatives 6 and 7 were easily separated by a combination of FC and
crystallization. Treatment of 2',3'-O-isopropylidene-uridines with PPh3 and diethyl
azodicarboxylate (DEAD) yields the corresponding 2,5'-anhydro-uridines [26] which
are hydrolysed under basic conditions [27]. This sequence should allow inversion of the
configuration at C(5') of 6 and 7. Indeed, treatment of the d-allo-isomer 7 with PPh3
and DEAD gave 94% of the l-talo 2,5'-anhydride 8; similarly, the l-talo 6 gave 94% of
the d-allo anhydride 93). The rigid skeleton of 8 and 9 allowed assignment of the
1
absolute configuration at C(5') by H-NMR spectroscopy (see below). C-Desilylation
of the major isomer 7 with NaOH in MeOH/H2O proceeded quantitatively to the
crystalline alcohol 10. This alcohol was also prepared in an overall yield of 89% by
hydrolysis with NaOH in MeOH/H2O4) of the anhydride 9 obtained from the minor
isomer 6. Hydrolysis of 9 gave 10. Deisopropylidenation of 10 in a mixture of 0.16n
HCl and 0.3n HF in MeCN/H2O 1:2 [28] at 238 gave quantitatively the crystalline triol
11.
MM3* Molecular modelling showed that the anhydrides 8 and 9 possess a rigid
skeleton. The furanose ring adopts a EO conformation, as evidenced by J(1',2') ˆ
J(3',4') ˆ 0 Hz. The 1,5,3-dioxazepane ring adopts a chair-like conformation. As
expected, the pseudoequatorial HÀC(5') of 8 resonates at lower field (5.15 ppm) than
the pseudoaxial HÀC(5') of 9 (4.86 ppm); both HÀC(5') show a small J(4',5') value (8:
1.6, 9: 1.2 Hz), demonstrating the gauche orientation of HÀC(4') and HÀC(5'). The
configuration at C(5') was determined by NOE experiments. Irradiation of HÀC(5') of
8 led to a NOE of 8% for HÀC(3') at 4.95 ppm, and of 12% for HÀC(4') at 4.63 ppm,
evidencing the (5'S)-configuration of 8. Irradiation of HÀC(5') of 9 led only to a NOE
2
)
)
)
Protection of HOÀC(5') of 3/4 1:2 by an Ac, (substituted) benzoyl, 1-naphthoyl, 2-naphthoyl
(allyloxy)carbonyl, (benzyloxy)carbonyl, imidazolylcarbonyl, or imidazolylthiocarbonyl group gave, in
each case, an inseparable mixture of diastereoisomers.
Treatment of 6 with PPh3, DEAD, and 4-nitrobenzoic acid gave a 1:3 mixture of 9 and the 5'-O-(4-
nitrobenzoyl) derivative of 7. Similarly, 7 led to a 1 :3 mixture of 8 and the 5'-O-(4-nitrobenzoyl) derivative
of 6.
3
4
Treatment of 9 with TsOH ´ H2O in MeOH/H2O yielded 90 ± 95% of 7 besides 5 ± 10% of 6.

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(19%) for HÀC(4') at 4.68 ppm, in keeping with the (5'R)-configuration of 9 and,
hence, also of 10 and 7.
The (5'R)-configuration of 9, 10, and 11 was also established by X-ray analyses5)
(Fig. 4). Similarly to force-field calculations and the solid-state structure of 2',3'-O-
isopropylidene-2,5'-anhydrouridine [29], the 1,5,3-dioxazepane ring of crystalline 9
adopts a chair-like conformation, the furanose ring a EO conformation (pseudorota-
tional phase angle [30] P ˆ 2708). The propargylic alcohol 10, in the solid state,
possesses an intramolecular O(5')ÀH ´´´ O(2) H-bond characterized by a H ´´´ O
distance of 1.74 Š, and a O(5')ÀH ´´´ O(2) bond angle of 156.98. This is the first
example of an O(5')ÀH ´´´ O(2') intramolecular H-bond of a 6-unsubstituted uridine in
the solid state (for intramolecular H-bonds in 6-substituted uridines, see [31 ± 33]). The
furanose ring of 10 adopts a E1 conformation, which belongs to the southern puckering
family (P ˆ 1658). The crystalline triol 11 possesses the 2E conformation and forms only
intermolecular H-bonds: O(5')H to O(4'), O(3')H to HO(2'), O(2')H to HO(3'), and
N(3)H to OˆC(4). The anhydro bond of 9 (O(4')ÀC(1')ÀN(1)ÀC(2) c angle ˆ 67.08)
and the H-bond of 10 (c ˆ 63.18) lead to a similar syn-conformation. In the absence of
an intramolecular H-bond, 11 adopts an anti-conformation (c ˆ À124.38).
Fig. 4. X-Ray crystal structures of 9, 10, and 11
We considered it advantageous to use the easily accessible iodide 13 to investigate
the conditions of cross-coupling and deprotection of the resulting dimer (Scheme 2).
2',3'-O-Isopropylideneuridine (1) was silylated and iodinated by treatment with LDA
5
)
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as
deposition No CCDC-142232 (9), No. CCDC-142233 (10), and No. CCDC-142234 (11). Copies of the data
can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB21EZ (fax:
‡44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta ± Vol. 83 (2000)
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Scheme 2
a) TIPSOTf, pyridine, CH2Cl2; 94% (12); 84% (16); 89% (18). b) LDA, THF, then NIS, then AcOH; 78% (13);
62% (17). c) [Pd2(dba)3], CuI, P(fur)3, toluene/NEt3 1:1; 70% (14); 63% (19). d) H2O/MeCN/37% HCl/40%
HF 100 :50 :2 :2; 73%. e) NaOH, MeOH/H2O 1 :1; 98%. f) AgNO3, MeOH/AcOEt, then KCN; 63%.

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and NIS [34] to give 73% of the iodide 13. Cross-coupling of 10 and 13 in the presence
of 5% [Pd2(dba)3], 7% CuI, and 7% P(fur)3 in toluene/NEt3 1:1 at 238 [35] resulted in
70% of the dimer 14, which was purified by FC6). Treatment of 14 with dilute aqueous
CF3COOH at room temperature led to partial decomposition. However, applying the
same conditions as used for the deisopropylidenation of the monomer 10 (0.16n HCl
and 0.3n HF) gave 15 (73%) which is soluble in H2O and in MeOH and was purified by
RP-HPLC.
Iodination of 7 by treatment with LDA and NIS [34] gave 62% of the iodide 17
besides 24% of starting material7), which were separated by FC (Scheme 2). Silylation
of 17 with TIPSOTf yielded 89% of the silyl ether 18; similarly, 10 yielded 84% of 16.
Cross-coupling of 16 and 18 under the same conditions as used for 10 and 13 gave 63%
of the dimer 19, which was selectively C-desilylated with AgNO3 and KCN in MeOH to
afford the dimer 20, a potential partner for a further Sonogashira reaction. Coupling
constants J(1',2') ˆ 2.6 ± 3.7 and J(3',4') ˆ 2.5 ± 3.7 Hz show a ca. 1:1 equilibrium
between the 3T2 and 2T3 conformers for the d-ribo- and d-allo-configured alcohols 1, 4,
7, 10, and 17, the d-ribo silyl ether 12, and the d-allo silyl ether 16 (Table 2). The small
J(1',2') < 1.0 Hz and J(3',4') ꢁ 2.2 Hz of the 5-ulofuranosyluridines 2 and 5, and the l-
talo alcohols 3 and 6, however, indicate a preference for the EO conformer that has
already been observed for the 2,5'-anhydrides 8 and 9. Whereas the 6-iodo-propargylic
2
alcohol 17 still adopts a ca. 1:1 equilibrium of 3T2 and T3 conformers (J(1',2') ˆ
3
J(3',4') ˆ 3.7 Hz), the 6-iodo silyl ethers 13 and 18 prefer the T2 conformation, as
evidenced by J(1',2') ˆ 1.2 and J(3',4') ˆ 3.6 ± 4.6 Hz.
The observation of an intramolecular O(5')ÀH ´´´ O(2) H-bond in the solid state of
10 raises the question of whether such H-bonds are also present in CDCl3 solution. The
chemical shift of the OH groups of 3, 4, 6, 7, and 17 in CDCl3 (3.0 ± 3.8 ppm) does not
allow unambigous assignment of an intramolecular H-bond (see [38]). However, a
small J(4',5') value may evidence an intramolecular H-bond, as the HÀC(4')ÀC(5')ÀH
dihedral angle of À 67.48 for the solid-state conformation of 10 corresponds to a
J(4',5') ˆ 1.6 Hz [39]. The propargylic alcohols 3, 4, 6, 7, and 10 show J(4',5') ˆ 3.1 ±
4.7 Hz, indicating a weak preference for the conformers exhibiting synclinal HÀC(4')
and HÀC(5') bonds, which is also observed for the silyl ether 16 (J(4',5') ˆ 3.7 Hz).
Thus, the similar J(4',5') values of the alcohols and the silyl ether 16 agree with the
absence of an intramolecular H-bond. This is corroborated by similar d(HÀC(2'))
values of 3, 4, 6, and 7 (4.87 ± 4.91 ppm) and the silyl ether 16 (4.72 ppm), evidencing a
preference for an anti-conformation (as already found for uridines; see [40] and refs.
cit. there). The downfield shift of HÀC(2') of the iodides 13, 17, and 18 (5.20 ±
5.30 ppm, Dd ˆ 0.3 ± 0.5 ppm) evidences a preferred syn-conformation. The large
J(4',5') values of the silyl ethers 13 (6.7 Hz for both HÀC(5)) and 18 (8.4 Hz) indicate a
steric interaction between the nucleobase and the side chain at C(4'); the conformer
possessing antiperiplanar HÀC(4') and HÀC(5') bonds is favoured. The smaller J(4',5')
6
)
Preliminary experiments with several acetylenes showed that these conditions were superior to using, e.g.,
[Pd(PPh3)4], CuI, and PPh3 in NEt3; PdCl2(PPh3)2, CuI, and PPh3 in NEt3; [Pd2(dba)3], CuI, and P(fur)3, in
TMEDA; Pd2(dba)3, CuI, and P(fur)3 in NEt3/DMSO; [Pd2(dba)3], CuI, and P(fur)3 in NEt3/DMF;
Pd2(dba)3, CuI, and P(fur)3 in pyridine; Pd2(dba)3, CuI, and AsPh3 in NEt3/toluene [36][37].
Surprisingly, the TIPSÀO(5') protected derivative of 7 decomposed under these conditions.
7
)

Helvetica Chimica Acta ± Vol. 83 (2000)
1321
value of the iodo alcohol 17 (4.2 Hz) is due to a partial intramolecular H-bond favoured
by the syn-conformation. The 13C-NMR spectra of 1 ± 10, 12, 13, and 16 ± 18 show the
expected shifts for C(2') (81.4 ± 86.1 ppm), C(3') (80.0 ± 84.7 ppm), C(4') (86.9 ±
91.6 ppm, ulofuranosyl derivatives 2 and 5: 99.5 and 100.3 ppm), and C(5') (61.6 ±
66.1 ppm, ulofuranosyl derivatives 2 and 5: 199.6 and 184.4 ppm; Table 3). The signals
for the CꢀCSiR3 groups of 3, 4, 6, 7, 17, and 18 appear at characteristic positions (2s) at
88.2 ± 92.3 and 101.7 ± 106.5 ppm; cf. [35][37], whereas the corresponding CꢀCSiR3
groups of the 2,5'-anhydrides 8 and 9 resonate in the narrow range of 95.2 ± 97.4 ppm.
The CꢀCH groups of 10 and 16 give rise to a doublet at 74.7 and 75.8 ppm, and a singlet
at 81.3 and 81.7 ppm. The introduction of the I substituent at C(6) of 13, 17, and 18 leads
to an upfield shift of C(6) at 113 ± 114.2 ppm (Dd ꢂ 28 ppm) and to a downfield shift of
C(1') at 101.6 ± 102.8 ppm (Dd ꢂ 8 ppm)8).
1
The H-NMR assignments of the dimers 14, 19, and 20 were corroborated by
selective homodecoupling experiments. The values for HÀC(2'/II), HÀC(3'/II),
HÀC(4'/II), and HÀC(5'/II) of the silyl ethers 14, 19, and 20 differ only slightly (Dd ꢁ
0.08 ppm) from the corresponding values of the silylated iodinated precursors 13 and
18. Similarly, the J(1',2'/II), J(2',3'/II), J(3',4'/II), and J(4',5'/II) values of 14, 19, and 20
differ only slightly (DJ ꢁ 0.3 Hz) from the corresponding values of 13 and 18. This
evidences the preferred syn-conformation for unit II of 14, 19, and 20. The d values of
HÀC(2'/I), HÀC(3'/I), HÀC(4'/I), HÀC(5'/I), J(1',2'/I), J(2',3'/I), J(3',4'/I), and the
J(4',5'/I) value of 14, 19, and 20 differ more strongly (Dd ˆ 0.05 ± 0.38 ppm, DJ ˆ 0.5 ±
1.8 Hz) from the corresponding values of the precursors 10 and 16. Especially the
downfield shift of HÀC(2'/I) (ca. 0.2 ppm) suggests a ca. 1:1 equilibrium of the syn-
and anti-conformer for the unit I of the dimers 14, 19, and 20. The 13C-NMR
1
assignments of 14, 19, and 20 are based on the H,13C-COSY spectrum of 19 (cf.
Table 5). The d values for the signals of C(1') to C(5') of unit II differ only slightly from
the corresponding signals of unit I (Dd ꢁ 2.7 ppm). In contrast to the I substituent, the
acetyleno groups attached at C(6/II) have a negligible influence upon the chemical shift
of C(1'/II). The acetylenic C(6'/I) and C(7'/I) of 14, 19, and 20 resonate at 100.0 ±
101.0 ppm and 76.6 ± 76.7 ppm [42], respectively, whereas C(6'/II) and C(7'/II) of 19,
and 20 appear at expected positions (Et3SiÀCꢀC of 19 at 87.8 and 106.3 ppm, HCꢀC
of 20 at 73.7 and 83.8 ppm). The bridging acetyleno group of 14, 19, and 20 leads to a
downfield shift of C(5/II) by ca. 6 ppm. Deprotection of 14 leads to the expected
upfield shifts for C(2'/I), C(3'/I), C(2'/II), and C(3'/II) (Dd ˆ 8.2 ± 9.7 ppm) and to
smaller shifts of the other C-atoms (Dd ˆ 0.1 ± 3.8 ppm).
We thank F. Hoffmann-La Roche AG, Basel, for generous support.
Experimental Part
General. Solvents were distilled before use: THF from K/benzophenone, CH2Cl2 from CaH2. Reactions
were run under Ar. Qual. TLC: precoated silica-gel plates (Merck silica gel 60 F254); detection by spraying with
ꢀmostainꢁ (400 ml of 10% aq. H2SO4, 20 g of (NH4)6Mo7O24 ´ H2O, 0.4 g of Ce(SO4)2) and heating. Flash
chromatography (FC): silica gel Merck60 (0.04 ± 0.063 mm). Optical rotations: 1-dm cell at 258 and 589 nm. FT-
The downfield shift of C(1') is surprising. No 13C-NMR data of 6-iodinated uridines are available, but
iodination of toluene in ortho-position leads to a downfield shift of 7 ppm for the Me group (2-iodotoluene:
28.1 ppm [41], toluene: 21.4 ppm [41]).
8
)

1322
Helvetica Chimica Acta ± Vol. 83 (2000)
1
IR: 1 ± 2% soln. in the indicated solvent. H- and 13C-NMR: at 200, 300, 400, or 500 MHz, and 50, 75, 100, or
125 MHz, resp. MS: Fast-atom-bombardment (FAB; NOBA: 3-nitrobenzyl alcohol), or electron spray
ionisation (ESI).
1-(2,3-O-Isopropylidene-b-d-ribo-pentodialdo-1,4-furanosyl)uracil (2). At 238, a soln. of periodinane
(89.1 g, 0.21 mol) in CH2Cl2 (1 l) was treated with 1 (57 g, 0.2 mol) in 3 portions during 30 min, stirred for 8 h at
238, and evaporated. The residue was dissolved in AcOEt (500 ml), and filtered. Evaporation gave ca. 85% pure
2 (54 g, 81%), which was used without further purification for the next step. 1H-NMR (200 MHz, CDCl3): see
Table 2; additionally, 9.60 (br. s, NH); 1.55, 1.38 (2s, Me2C). 13C-NMR (75 MHz, CDCl3): see Table 3,
additionally, 27.3, 25.1 (2q, Me2C).
Table 2. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of 1 ± 10, 12, 13, 16, 17, and 18 in
CDCl3 Solution
1a)
2
3
4
5
6
7
8
9
10a) 12
13
6.46 5.69 6.51 6.44
7.53
6.10 5.96 6.04 6.05
5.20 4.72 5.30 5.27
16
17
18
HÀC(5) 5.68
HÀC(6) 7.82
HÀC(1') 5.86
HÀC(2') 4.91
HÀC(3') 4.82
HÀC(4') 4.21
5.79 5.72 5.74 5.80 5.71 5.72 6.07 6.12 5.78 5.67
7.30 7.55 7.53 7.33 7.48 7.55 7.30 7.31 7.87 7.68
5.52 5.72 5.73 5.57 5.70 5.78 5.37 5.37 5.95 5.99
5.25 4.91 4.90 5.43 4.94 4.87 4.88 4.91 4.84 4.69
5.13 4.91 4.98 5.25 4.91 5.00 4.95 5.17 4.98 4.85
4.57 4.28 4.35 4.66 4.30 4.33 4.63 4.68 4.24 4.27
±
±
±
4.85 4.94 5.16 5.03
4.22 4.27 4.28 4.07
HÀC(5') 3.79, 3.70 9.42 4.62 4.64
±
±
4.63 4.64 5.15 4.86 4.54 4.00, 3.88 3.87 4.76 4.63 4.62
±
HÀC(7')
±
8.1
±
±
±
±
±
±
2.97
±
±
±
2.54
8.1
±
±
±
±
J(5,6)
7.9 8.1 8.1 8.1 8.1 8.1 7.5 7.5 7.9 8.1
J(1',2')
J(2',3')
J(3',4')
J(4',5')
J(5',7')
2.6
6.2
3.4
0
6.2
< 1 3.7 < 1 1.3 3.7
0
0
3.3 2.8
1.2 3.4 3.7 1.2
6.6 6.5 6.3 6.5
4.6 3.7 3.7 3.4
b
)
6.2 6.2 6.7 6.2 5.3 5.6 6.3 6.2
1.3 < 1 2.5 < 1 2.2 2.8
0
±
0
0
2.5 3.4
3.7, 4.7c)
±
4.0 3.3
±
±
4.7 3.1 1.6 1.2 3.7 2.5, 3.4d) 6.7 3.7 4.2 8.4
±
±
±
±
±
±
2.1
±
±
2.2
±
±
a) In CD3OD. b) Not assigned. c) Jgem ˆ 12.0 Hz. d) Jgem ˆ 11.2 Hz.
Table 3. Selected 13C-NMR Chemical Shifts [ppm] of 1 ± 13, 16, 17, and 18 in CDCl3 Solution
1a) 10a) 11b) 12
2
3
4
5
6
7
8
9
13
16
17
18
C(2) 166.6 163.6 163.1 164.0 163.2 164.1 164.0 171.0 171.2 164.9 169.1 163.7 160.9 163.4 160.5 161.8
C(4) 152.5 150.8 150.1 150.5 150.9 150.3 150.6 155.0 155.6 151.0 155.7 150.4 146.6 150.4 147.8 147.4
C(5) 102.9 103.0 102.3 103.2 103.0 101.8 102.9 110.8 111.2 101.3 106.2 102.5 116.3 102.7 117.6 117.0
C(6) 144.2 144.4 141.7 142.8 144.5 142.6 143.1 141.4 141.5 142.1 145.6 140.9 113.3 141.2 113.6 114.0
C(1') 94.4 94.2 93.9 95.1 94.9 94.9 96.2 99.0 99.1 92.7 92.4 91.7 101.6 92.0 102.8 102.4
C(2') 86.1 85.0 82.8 84.1 84.8 84.1 84.4 85.3 85.3 84.2 78.5 85.4 83.4 84.5 81.4 84.2
C(3') 82.4 83.9 80.0 81.0 84.7 81.1 82.1 82.1 81.5 80.7 74.8 80.0 81.8 80.3 80.4 83.1
C(4') 88.6 100.3 87.2 88.5 99.5 89.1 88.6 87.3 88.6 88.3 92.1 86.9 89.5 88.6 88.5 91.6
C(5') 63.3 199.6 62.7 63.1 184.4 63.0 66.1 74.4 75.7 61.6 66.2 63.5 63.7 63.5 63.0 63.9
C(6') ±
C(7') ±
±
±
101.7 102.4 128.6 104.1 102.9 97.4 96.4 81.3 85.7 ±
±
±
81.7 103.2 106.5
75.8 89.3 88.2
c
92.1 91.9
)
89.1 92.3 95.2 96.0 74.7 79.1 ±
a) In CD3OD. b) In D2O. c) Not assigned.
1-[6,7-Dideoxy-2,3-O-isopropylidene-7-C-(trimethylsilyl)-a-l-talo-hept-6-ynofuranosyl]uracil and 1-[6,7-
Dideoxy-2,3-O-isopropylidene-7-C-(trimethylsilyl)-b-d-allo-hept-6-ynofuranosyl]uracil (3 and 4, resp.). At 08,
a soln. of (trimethylsilyl)acetylene (36.8 ml, 0.27 mol) in THF (900 ml) was treated dropwise with 3.0m EtMgBr
in Et2O (89 ml, 0.27 mol), stirred at 08 for 15 min and at 238 for 45 min, cooled to À158, treated dropwise with a
soln. of crude 2 (31.6 g, 0.110 mol) in THF (900 ml), stirred at À158 for 1.5 h, treated with sat. aq. NH4Cl soln.
(400 ml), and allowed to warm to 238. After evaporation, the residue was diluted with AcOEt, washed with sat.

Helvetica Chimica Acta ± Vol. 83 (2000)
1323
aq. NH4Cl soln. and brine, dried (Na2SO4), and evaporated. FC (AcOEt/hexane 1:1) and crystallization gave 4
(9.3 g, 21% from 1) and 3/4 1:1 (18.7 g, 42% from 1).
Data of 3: Colorless solid. Rf(AcOEt/hexane 1:1) 0.25. 1H-NMR (300 MHz, CDCl3 3/4 1:1): see Table 2;
additionally, 9.55 (br. s, NH); 3.60 (br. s, OH); 1.56, 1.34 (2s, Me2C); 0.16 (s, Me3Si). 13C-NMR (50 MHz, CDCl3,
3/4 1:1): see Table 3; additionally, 114.7 (s, Me2C); 27.2, 25.3 (2q, Me2C); À0.3 (q, Me3Si).
Data of 4: Colourless crystals. Rf(AcOEt/hexane 1:1) 0.26. M.p. 162.5 ± 165.08. [a]2D5 ˆ À66.9 (c ˆ 0.8,
CHCl3). IR (CHCl3): 3390w (br.), 3008w, 2876w, 2176w, 1697s, 1456m, 1385m, 1088m, 848w. 1H-NMR
(200 MHz, CDCl3): see Table 2; additionally, 9.55 (br. s, NH); 3.21 (br. s, OH); 1.60, 1.38 (2s, Me2C); 0.19
(s, Me3Si). 13C-NMR (50 MHz, CDCl3): see Table 3; additionally, 114.0 (s, Me2C); 26.9, 24.9 (2q, Me2C); À0.7
‡
‡
‡
(q, Me3Si). FAB-MS (NOBA): 761 (19, [2M ‡ H] ), 403 (20, [M ‡ Na] ), 381 (100, [M ‡ H] ), 365 (41, [M À
‡
Me] ). Anal. calc. for C17H24N2O6Si (380.47): C 53.67, H 6.36, N 7.36; found: C 53.63, H 6.13, N 7.39.
1-[6,7-Dideoxy-2,3-O-isopropylidene-7-C-(trimethylsilyl)-b-d-ribo-hept-6-yno-5-ulofuranosyl]uracil (5).
At 238, a soln. of periodinane (0.34 g, 0.8 mmol) in CH2Cl2 (10 ml) was treated with 3/4 1 :1 (0.26 g, 0.68 mmol),
stirred for 30 min at 238, washed with sat. aq. NaHCO3 (2 Â 20 ml), dried (Na2SO4), and evaporated. FC
(AcOEt/hexane 1:1) and crystallization from AcOEt/hexane gave 5 (0.24 g, 93%). Colourless crystals.
Rf(AcOEt/hexane 2 :1) 0.52. M.p. 204.5 ± 210.08 (dec.). [a]2D5 ˆ 55.3 (c ˆ 1.0, CHCl3). IR (CHCl3): 3384w, 2960w,
2929w, 2154w, 1716m, 1695s, 1455m, 1377m, 1257m, 1083m, 909m, 850w. 1H-NMR (200 MHz, CDCl3): see
Table 2; additionally, 8.85 (br. s, NH); 1.54, 1.35 (2s, Me2C); 0.25 (s,Me3Si). 13C-NMR (75 MHz, CDCl3): see
Table 3; additionally, 113.8 (s, Me2C); 26.6, 25.0 (2q, Me2C); À0.62 (q, Me3Si). FAB-MS (NOBA): 757 (36,
‡
‡
[2M ‡ H] ), 379 (100, [M ‡ H] ). Anal. calc. for C17H22N2O6Si (378.46): C 53.95, H 5.86, N 7.40; found: C 53.78,
H5.82, N 7.37.
Reduction of 5. At 238, a soln. of 5 (30 mg, 0.079 mmol) in EtOH (2 ml) was treated dropwise with a soln.
of NaBH4 (3 mg, 0.079 mmol) in EtOH (0.2 ml), stirred for 5 min, treated with sat. aq. NH4Cl soln. (1 ml),
diluted with AcOEt, washed with sat. aq. NH4Cl soln., sat. aq. NaHCO3 soln., and brine, dried (Na2SO4), and
evaporated. FC (AcOEt/hexane 1:1) gave 3/4 1:1 (1H-NMR; 30 mg, 99%).
1-[6,7-Dideoxy-2,3-O-isopropylidene-7-C-(triethylsilyl)-a-l-talo-hept-6-ynofuranosyl]uracil and 1-[6,7-Di-
deoxy-2,3-O-isopropylidene-7-C-(triethylsilyl)-b-d-allo-hept-6-ynofuranosyl]uracil (6 and 7, resp.). At 08, a soln.
of (triethylsilyl)acetylene (58.0 g, 0.44 mol) in THF (900 ml) was treated dropwise with 3.0m EtMgBr in Et2O
(143 ml, 0.44 mol), stirred at 08 for 15 min and at 238 for 45 min, cooled to À158, treated dropwise with a soln. of
crude 2 (50.0 g, 0.187 mol) in THF (900 ml), stirred at À158 for 1.5 h, treated with sat. aq. NH4Cl soln. (400 ml),
and allowed to warm to 238. After evaporation, the residue was diluted with AcOEt, washed with sat. aq. NH4Cl
soln. and brine, dried (Na2SO4), and evaporated. FC (AcOEt/hexane 1:1) and crystallization gave 6 (15.9 g,
20% from 1) and 7 (31.9 g, 41% from 1).
Data of 6: Colourless crystals. Rf(AcOEt/hexane 1:1) 0.32. M.p. 142.5 ± 144.08. [a]2D5 ˆ ‡18.1 (c ˆ 6.1,
CHCl3). IR (CHCl3): 3390w (br.), 2994m, 2913w, 2160w, 1694s, 1457m, 1384m, 1271m, 1087m, 909w. 1H-NMR
(300 MHz, CDCl3): see Table 2; additionally, 8.9 (br. s, NH); 3.0 (br. s, OH); 1.60, 1.26 (2s, Me2C); 1.00 (t, J ˆ
7.5, (MeCH2)3Si); 0.61 (q, J ˆ 7.5, (MeCH2)3Si). 13C-NMR (50 MHz, CDCl3): see Table 3; additionally, 114.2
(s, Me2C); 26.9, 24.9 (2q, Me2C); 6.1 (q, (MeCH2)3Si); 3.9 (t, (MeCH2)3Si). FAB-MS (NOBA): 867 (12, [2M ‡
‡
‡
‡
‡
‡
Na] ), 845 (36, [2M ‡ H] ), 445 (89, [M ‡ Na] ), 423 (100, [M ‡ H] ), 407 (43, [M À Me] ). Anal. calc. for
C20H30N2O6Si (422.55): C 56.85, H 7.16, N 6.63; found: C 56.97, H 7.15, N 6.60.
Data of 7: Colourless crystals. Rf(AcOEt/hexane 1 :1) 0.38. M.p. 167.5 ± 169.08. [a]2D5 ˆ À67.6 (c ˆ 1.1,
1
CHCl3). IR (CHCl3): 3390w (br.), 2958w, 2876w, 2150w, 1697s, 1457m, 1385m, 1272w, 1088m, 909w. H-NMR
(500 MHz, CDCl3): see Table 2; additionally, 9.26 (br. s, NH); 3.52 (br. s, OH); 1.50, 1.36 (2s, Me2C); 0.99 (t, J ˆ
7.5, (MeCH2)3Si); 0.61 (q, J ˆ 7.5, (MeCH2)3Si). 13C-NMR (125 MHz, CDCl3): see Table 3; additionally, 114.4
(s, Me2C); 27.3, 25.1 (2q, Me2C); 7.3 (q, (MeCH2)3Si); 4.2 (t, (MeCH2)3Si). FAB-MS (NOBA): 868 (7, [2M ‡
‡
‡
‡
‡
‡
Na] ), 845 (13, [2M ‡ H] ), 445 (100, [M ‡ Na] ), 423 (57, [M ‡ H] ), 407 (65, [M À Me] ). Anal. calc. for
C20H30N2O6Si (422.55): C 56.85, H 7.16, N 6.63; found: C 57.02, H 7.16, N 6.61.
2,5'-Anhydro-1-[6,7-dideoxy-2,3-O-isopropylidene-7-C-(triethylsilyl)-a-l-talo-hept-6-ynofuranosyl]uracil (8).
A refluxing soln. of 7 (100 mg, 0.24 mmol) and Ph3P (68 mg, 0.24 mmol) in THF (5 ml) was treated dropwise
with diethyl azodicarboxylate (DEAD; 0.045 ml, 0.24 mmol), and stirred for 1 min. After evaporation, FC
(AcOEt/hexane 3 :1) and crystallisation from AcOEt/hexane gave 8 (90 mg, 94%). Colourless crystals.
Rf(AcOEt) 0.31. [a]2D5 ˆ ‡130 (c ˆ 1.3, CHCl3). IR (CHCl3): 2957s, 2927s, 2875m, 2857w, 1644s, 1533s, 1444m,
1378w, 1304w, 1177w, 1076w, 1053m, 944w. 1H-NMR (300 MHz, CDCl3): see Table 2; additionally, 1.50, 1.36
(2s, Me2C); 0.99 (t, J ˆ 7.5, (MeCH2)3Si); 0.61 (q, J ˆ 7.5, (MeCH2)3Si). 13C-NMR (75 MHz, CDCl3): see
Table 3; additionally, 113.8 (s, Me2C); 26.1, 24.6 (2q, Me2C), 7.3 (q, (MeCH2)3Si); 3.9 (t, (MeCH2)3Si). FAB-MS

1324
Helvetica Chimica Acta ± Vol. 83 (2000)
‡
‡
(NOBA): 809 (37 [2M ‡ H] ), 405 (100, M ). Anal. calc. for C20H28N2O5Si (404.54): C 59.38, H 6.98, N 6.92;
found: C 59.43, H 7.12, N 6.82.
2,5'-Anhydro-1-[6,7-dideoxy-2,3-O-isopropylidene-7-C-(triethylsilyl)-b-d-allo-hept-6-ynofuranosyl]uracil (9).
A refluxing soln. of 6 (5.1 g, 12.1 mmol) and Ph3P (3.3 g, 12.7 mmol) in THF (100 ml) was treated dropwise with
DEAD (2 ml, 12.7 mmol) and stirred for 1 min. After evaporation, FC (AcOEt/hexane 3 :1) and crystallization
from AcOEt/hexane gave 9 (4.6 g, 94%). Colourless crystals. Rf(AcOEt) 0.31. M.p. 219 ± 2228. [a]2D5 ˆ À88.7
1
(c ˆ 0.4, CHCl3). IR (CHCl3): 2999m, 2857w, 1644s, 1531s, 1445m, 1378w, 1061m, 867m. H-NMR (300 MHz,
CDCl3): see Table 2; additionally, 1.50, 1.36 (2s, Me2C); 0.99 (t, J ˆ 7.5, (MeCH2)3Si); 0.61 (q, J ˆ 7.5,
(MeCH2)3Si). 13C-NMR (125 MHz, CDCl3): see Table 3; additionally, 113.4 (s, Me2C); 26.0, 24.5 (2q, Me2C);
‡
6.8 (q, (MeCH2)3Si); 4.2 (t, (MeCH2)3Si). FAB-MS (NOBA): 405 (100, [M ‡ H] ). Anal. calc. for C20H28N2O5Si
(404.54): C 59.38, H 6.98, N 6.92; found: C 59.51, H 6.82, N 6.89.
1-(6,7-Dideoxy-2,3-O-isopropylidene-b-d-allo-hept-6-ynofuranosyl)uracil (10). a) From 7: A soln. of 7
(6.0 g, 14.2 mmol) in MeOH (100 ml) was treated dropwise with a soln. of NaOH (2.84 g, 71.1 mmol) in H2O
(50 ml), stirred at 238 for 2 h, and diluted with sat. aq. NH4Cl soln. (50 ml). After evaporation, the residue was
diluted with AcOEt, washed with sat. aq. NH4Cl soln. and brine, dried (Na2SO4), and evaporated. The residue
was crystallized from AcOEt/hexane 1:2 (300 ml) affording 10 (4.3 g, 98%).
b) From 9: A soln. of 9 (4.0 g, 10.0 mmol) in CH3OH (50 ml) was treated dropwise with a soln. of NaOH
(1.60 g, 50.0 mmol) in H2O (50 ml), stirred at 238 for 2 h, and diluted with sat. aq. NH4Cl soln. (50 ml). After
evaporation, the residue was diluted with AcOEt, washed with sat. aq. NH4Cl soln. and brine, dried (Na2SO4),
and evaporated. The residue was crystallized from AcOEt/hexane 1:2 (300 ml) affording 10 (2.9 g, 95%).
Colourless crystals. Rf(AcOEt/hexane 3 :1) 0.37. M.p. 212.5 ± 213.08. [a]2D5 ˆ À51.3 (c ˆ 0.6, MeOH). IR (KBr):
3333m (br.), 3266m, 3000m, 2811m, 2123w, 1690s, 1467w, 1419m, 1387m, 1301w, 1217w, 1089s, 860m. 1H-NMR
(300 MHz, CD3OD): see Table 2; additionally, 1.55, 1.35 (2s, Me2C). 13C-NMR (75 MHz, CD3OD): see Table 3;
‡
additionally, 113.8 (s, Me2C); 26.1, 24.1 (2q, Me2C). FAB-MS (NOBA): 617 (23, [2M ‡ H] ), 309 (100, [M ‡
‡
‡
H] ), 293 (15, [M À Me] ). Anal. calc. for C14H16N2O6 (308.29): C 54.54, H 5.23, N 9.09; found: C 54.54, H 5.27,
N 9.11.
1-(6,7-Dideoxy-b-d-allo-hept-6-ynofuranosyl)uracil (11). A soln. of 10 (150 mg) in MeCN/H2O/40% HF/
37% HCl 100 :50 :2 :2 (10 ml) was stirred at 238 for 65 h. Evaporation and RP-HPLC (H2O/MeOH 10 :0 !
5 :5 ! 1:9) gave 11 (130 mg, 99.5%). Colourless crystals. [a]2D5 ˆ À25.4 (c ˆ 0.8, H2O). IR (KBr): 3433s (br.),
1
3280s, 3182m, 2125w, 1682s, 1465m, 1386m, 1285m, 1133m, 1110m, 1050m, 937m, 835m. H-NMR (300 MHz,
D2O): 7.99 (d, J ˆ 8.1, HÀC(6)); 6.03 (d, J ˆ 6.9, HÀC(1')); 5.71 (d, J ˆ 8.1, HÀC(5)); 4.52 (dd, J ˆ 2.8, 2.2,
HÀC(5')); 4.33 (dd, J ˆ 5.4, 2.2, HÀC(3')); 4.22 (dd, J ˆ 6.9, 5.4, HÀC(2')); 4.07 (dd, J ˆ 2.8, 2.2, HÀC(4')); 2.98
‡
(d, J ˆ 2.2, HÀC(7')). 13C-NMR (75 MHz, CDCl3): see Table 3. FAB-MS (NOBA): 269 (13, [M ‡ H] ); ESI-
‡
‡
‡
MS (pos.-ion mode): 559 (20, [2M ‡ Na] ), 307 (20, [M ‡ K] ), 291 (100, [M ‡ Na] ). ESI-MS (neg.-ion mode):
267 (100, [M À H]À).
2',3'-O-Isopropylidene-5'-O-(triisopropylsilyl)uridine (12). A soln. of pyridine (30 ml, 370 mmol, distilled
from CaH2) and 1 (20 g, 74 mmol) in CH2Cl2 (500 ml) was treated dropwise with TIPSOTf (21 ml, 77 mmol),
stirred at 238 for 20 min, washed with brine (3 Â 300 ml), dried (Na2SO4), and evaporated. FC (AcOEt/hexane
1:1) gave 12 (29.1 g, 94%). Colourless crystals. Rf(AcOEt/hexane 1:1) 0.36. M.p. 119 ± 1208. [a]2D5 ˆ À6.6 (c ˆ 9.8,
CHCl3). IR (CHCl3): 3390w, 3008w, 2945m, 2868m, 1693s, 1458m, 1385m, 1130m, 1086m, 969w, 883w. 1H-NMR
(300 MHz, CDCl3): see Table 2; additionally, 9.33 (br. s, NH); 1.57, 1.34 (2s, Me2C); 1.10 ± 1.05 (m, (Me2CH)3-
Si). 13C-NMR (50 MHz, CDCl3): see Table 3; additionally, 114.5 (s, Me2C); 27.3, 25.4 (2q, Me2C); 18.0 (q,
‡
‡
(Me2CH)3Si), 11.9 (d, (Me2CH)3Si). FAB-MS (NOBA): 441 (54, [M ‡ H] ), 425 (18, [M À Me] ), 397 (100,
‡
[M À Me2CH] ). Anal. calc. for C21H36N2O6Si (440.61): C 57.25, H 8.24, N 6.36; found: C 57.42, H 8.41, N 6.35.
6-Iodo-2',3'-O-isopropylidene-5'-O-(triisopropylsilyl)uridine (13). At À788, a soln. of (i-Pr)2NH (7.7 ml,
0.054 mol, distilled from CaH2) in THF (250 ml) was treated dropwise with 1.65m BuLi in hexane (33 ml,
0.054 mol), stirred at À788 for 15 min and at 08 for 15 min, cooled to À788, treated dropwise with a soln. of 12
(8.0 g, 0.018 mol) in THF (250 ml), stirred for 2.5 h, treated with NIS (12.2 g, 0.159 mol) in THF (250 ml),
stirred for 1.5 h, treated with AcOH (6 ml), and allowed to warm to 238. After evaporation, the residue was
diluted with AcOEt, washed with sat. aq. NaHCO3 soln. and brine, dried (Na2SO4), and evaporated. FC
(AcOEt/hexane 2 :3) and crystallization from AcOEt/hexane gave 13 (8.0 g, 78%). Colourless crystals.
Rf(AcOEt/hexane 1:2) 0.38. M.p. 152.5 ± 1548. [a]2D5 ˆ ‡20.1 (c ˆ 2.8, CHCl3). IR (CHCl3): 3384w, 2944s, 2866m,
1
1721m, 1695s, 1575m, 1384m, 1338m, 1148m, 1088m, 1067m, 881m. H-NMR (200 MHz, CDCl3): see Table 2;
additionally, 9.37 (br. s, NH); 1.57, 1.38 (2s, Me2C); 1.05 ± 0.95 (m, (Me2CH)3Si). 13C-NMR (50 MHz, CDCl3):
see Table 3; additionally, 113.3 (s, Me2C); 26.8, 25.0 (2q, Me2C); 17.5 (q, (Me2CH)3Si); 11.6 (d, (Me2CH)3Si).

Helvetica Chimica Acta ± Vol. 83 (2000)
1325
‡
‡
FAB-MS (NOBA: 589 (29, [M ‡ Na] ), 567 (38, [M ‡ H] ). Anal. calc. for C21H35IN2O6Si (566.51): C 44.52,
H 6.23, N 4.94; found: C 44.61, H 6.02, N 5.12.
2',3'-O-Isopropylidene-5'-O-(triisopropylsilyl)uridin-6-yl-(6 ! 7'-C)-1-(6,7-dideoxy-2,3-O-isopropylidene-
b-d-allo-hept-6-ynofuranosyl)uracil (14). A soln. of 10 (1 g, 3.2 mmol), 13 (1.93 g, 3.4 mmol), [Pd2(dba)3]
(153 mg, 0.16 mmol), CuI (61 mg, 0.32 mmol), and P(fur3) (79 mg, 0.32 mmol) in degassed Et3N/toluene 1:1
(60 ml) was stirred for 20 h at 238. After evaporation, FC (AcOEt/hexane 6 :1) gave 14 (1.5 g, 70%). Brown
foam. Rf(AcOEt) 0.45. [a]2D5 ˆ ‡6.5 (c ˆ 0.4, CHCl3). IR (CHCl3): 3386w (br.), 3008w, 2944w, 2225w, 1697s,
1
1598w, 1456m, 1385m, 1270w, 1088m, 882w. H-NMR (400 MHz, CDCl3): see Table 4; additionally, 1.58, 1.53,
1.37, 1.33 (4s, 2 Me2C); 1.10 ± 1.00 (m, (Me2CH)3Si). 13C-NMR (100 MHz, CDCl3): see Table 5; additionally,
114.7 (s, Me2C); 113.8 (s, Me2C); 27.22, 27.21, 25.4, 25.3 (4q, 2 Me2C); 17.9 (q, (Me2CH)3Si); 12.0
‡
‡
‡
(d, (Me2CH)3Si). FAB-MS (NOBA): 747 (32, [M ‡ H] ), 731 (26, [M À Me] ), 703 (100, [M À Me2CH] ).
Anal. calc. for C35H50N4O12Si (746.89): C 56.29, H 6.75, N 7.50; found: C 56.17, H 6.81, N 7.36.
Table 4. Selected 1H-NMR Chemical Shifts [ppm] and Coupling Constants [Hz] of the Dimers 14, 19, and 20, in
CDCl3. Assignments based on selective homodecoupling experiments
14
19
20
14
19
20
HÀC(5/I)
HÀC(6/I)
HÀC(1'/I)
HÀC(2'/I)
HÀC(3'/I)
HÀC(4'/I)
HÀC(5'/I)
HÀC(5/II)
HÀC(1'/II)
HÀC(2'/II)
HÀC(3'/II)
HÀC(4'/II)
HÀC(5'/II)
HÀC(7'/II)
5.76
7.45
5.69
5.04
5.09
4.35
4.92
6.00
6.21
5.20
4.84
4.18
3.87
±
5.72
7.36
5.83
4.91
4.99
4.22
5.04
5.97
6.14
5.24
5.05
4.01
4.64
±
5.72
7.32
5.73
4.97
4.99
4.22
5.03
5.93
6.21
5.19
5.04
4.04
4.64
2.43
J(5,6/I)
8.1
2.6
6.5
3.2
4.2
1.4
6.4
4.3
6.6
±
8.1
2.4
6.6
4.3
4.6
1.2
6.5
3.6
8.1
±
8.1
1.9
6.6
3.6
5.5
1.5
6.6
3.6
8.6
2.1
J(1',2'/I)
J(2',3'/I)
J(3',4'/I)
J(4',5'/I)
J(1',2'/II)
J(2',3'/II)
J(3',4'/II)
J(4',5'/II)
J(5',7'/II)
Table 5. Selected 13C-NMR Chemical Shifts [ppm] of the Dimers 14, 19, and 20 in CDCl3, and of 15 in D2O
Solution
14
19a)
20
15a)
14
19a)
20
15a)
C(2/I)
C(4/I)
C(5/I)
C(6/I)
C(1'/I)
C(2'/I)
C(3'/I)
C(4'/I)
C(5'/I)
C(6'/I)
C(7'/I)
163.5
150.5
102.8
142.9
95.9
84.0
82.3
89.6
62.8
163.3
150.0
102.7
141.6
93.0
84.0
80.0
88.5
63.6
162.9
149.8
102.8
142.2
94.2
84.0
80.7
89.0
63.7
168.8
154.4
105.2
144.7
92.1
75.8
72.6
88.0
64.8
C(2/II)
C(4/II)
C(5/II)
C(6/II)
C(1'/II)
C(2'/II)
C(3'/II)
C(4'/II)
C(5'/II)
C(6'/II)
C(7'/II)
162.5
149.5
108.4
137.5
94.1
83.7
80.3
88.2
64.2
±
162.4
149.4
108.5
137.6
94.6
83.8
82.7
91.2
63.8
161.9
149.3
108.3
137.5
94.7
83.9
82.7
91.3
63.3
167.4
153.3
111.1
140.6
96.7
74.1
72.0
86.6
64.1
±
100.0
76.6
100.4
76.7
101.0
76.6
102.4
79.1
106.3
87.8
83.8
73.7
±
±
a) Assignment based on a HSQC.GRASP spectrum.
Uridin-6-yl-(6 ! 7'-C)-1-(6,7-dideoxy-b-d-allo-hept-6-ynofuranosyl)uracil (15). A soln. of 14 (400 mg,
0.54 mmol) in MeCN/H2O/40% HF/37% HCl 100 :50 :2 :2 (25 ml) was stirred at 238 for 8 h. Evaporation and
RP-HPLC (H2O/MeOH 10 :0 ! 5 :5 ! 1 :9) gave 15 (200 mg, 73%). White powder. [a]2D5 ˆ À7.1 (c ˆ 0.4, H2O).
IR (KBr): 3412s (br.), 2250w, 1684s, 1459m, 1388m, 1266w, 1114m, 1053m, 883w, 766w, 719w. 1H-NMR
(400 MHz, D2O): 7.77 (d, J ˆ 8.1, HÀC(6/I)); 6.14 (s, HÀC(5/II)); 6.05 (d, J ˆ 3.7, HÀC(1'/II)); 5.92 (d, J ˆ 4.7,

1326
Helvetica Chimica Acta ± Vol. 83 (2000)
HÀC(1'/I)); 5.84 (d, J ˆ 8.1, HÀC(5/I)); 4.97 (d, J ˆ 4.0, HÀC(5'/I)); 4.77 (dd, J ˆ 6.3, 3.7, HÀC(2'/II)); 4.42
(t, J ˆ 5.5, HÀC(2'/I)); 4.39 (t, J ˆ 5.5, HÀC(3'/I)); 4.35 (t, J ˆ 6.4, HÀC(3'/II)); 4.23 (t, J ˆ 4.0, HÀC(4'/I));
3.91 (dd, J ˆ 6.4, 3.2, HÀC(4'/II)); 3.84 (dd, J ˆ 12.4, 3.2, HÀC(5'/II)); 3.71 (dd, J ˆ 12.4, 6.1, HÀC(5'/II)).
‡
‡
13C-NMR (100 MHz, D2O): see Table 4. ESI-MS (pos.-ion mode): 549 (20, [M ‡ K] ), 533 (100, [M ‡ Na] );
ESI-MS (neg.-ion mode): 509 (100, [M À H]À), 545 (80, [M ‡ Cl]À).
1-[6,7-Dideoxy-2,3-O-isopropylidene-5-O-(triisopropylsilyl)-b-d-allo-hept-6-ynofuranosyl]uracil (16).
A
soln. of pyridine (5.0 ml, 62 mmol, distilled from CaH2) and 10 (2.4 g, 7.8 mmol) in CH2Cl2 (100 ml) was
treated dropwise with TIPSOTf (4.8 ml, 16 mmol), stirred at 238 for 7 h, washed with brine (3 Â 100 ml), dried
(Na2SO4), and evaporated. FC (AcOEt/hexane 1:3) and crystallization from AcOEt/hexane gave 16 (3.2 g,
84%). Colourless crystals. Rf(AcOEt/hexane 1 :1) 0.50. M.p. 136.5 ± 137.58. [a]2D5 ˆ À32.8 (c ˆ 1.3, CHCl3). IR
(CHCl3): 3390w, 3304w, 2947m, 2869m, 2120w, 1695s, 1459m, 1385m, 1262m, 1091m, 883w. 1H-NMR (300 MHz,
CDCl3): see Table 2; additionally, 8.90 (br. s, NH); 1.54, 1.35 (2s, Me2C); 1.10 ± 1.05 (m, (Me2CH)3Si). 13C-NMR
(75 MHz, CDCl3): see Table 3; additionally, 115.1 (s, Me2C); 27.4, 25.5 (2q, Me2C); 18.2, 18.1 (2q, (Me2CH)3Si);
‡
‡
‡
12.6 (d, (Me2CH)3Si). FAB-MS (NOBA): 929 (7, [2M ‡ H] ), 487 (11, [M ‡ Na] ), 465 (80, [M ‡ H] ), 421
‡
(100, [M À Me2CH] ). Anal. calc. for C23H36N2O6Si (464.63): C 59.46, H 7.81, N 6.03; found: C 59.69, H 7.78,
N 6.08.
1-[6,7-Dideoxy-2,3-O-isopropylidene-7-C-(triethylsilyl)-b-d-allo-hept-6-ynofuranosyl]-6-iodouracil (17).
At À788, a soln. of (i-Pr)2NH (22.5 ml, 0.159 mol, distilled from CaH2) in THF (600 ml) was treated dropwise
with 1.65m BuLi in hexane (97 ml, 0.159 mol), stirred at À788 for 15 min and at 08 for 15 min, cooled to À788,
treated dropwise with a soln. of 7 (14.6 g, 0.035 mol) in THF (400 ml), stirred for 2.5 h, treated dropwise with
NIS (36 g, 0.159 mol) in THF (400 ml), stirred for 1.5 h, treated with AcOH (30 ml), and allowed to warm to
238. After evaporation, the residue was dissolved in AcOEt, washed with sat. aq. NaHCO3 soln. and brine, dried
(Na2SO4), and evaporated. FC (AcOEt/hexane 2 :3) gave 17 (13.2 g, 62%) and 7 (3.5 g, 24%). Colourless
crystals. Rf (AcOEt/hexane 1 :1) 0.58. M.p. 177.5 ± 178.08. [a]2D5 ˆ À13.4 (c ˆ 1.4, CHCl3). IR (CHCl3): 3425w
(sh), 3382w (br), 2993w, 2962w, 2180w, 1697s, 1574m, 1385m, 1338w, 1087m, 848m. 1H-NMR (300 MHz,
CDCl3): see Table 2; additionally, 9.16 (br. s, NH); 3.81 (br. s, OH); 1.63, 1.37 (2s, Me2C); 0.99 (t, J ˆ 7.5,
(MeCH2)3Si); 0.62 (q, J ˆ 7.5, (MeCH2)3Si). 13C-NMR (75 MHz, CDCl3): see Table 3; additionally, 114.4
(s, Me2C); 27.4, 25.2 (2q, Me2C); 7.4 (q, (MeCH2)3Si); 4.2 (t, (MeCH2)3Si). FAB-MS (NOBA): 571 (5, [M ‡
‡
‡
‡
Na] ), 549 (6, [M ‡ H] ), 533 (45, [M À Me] ). Anal. calc. for C20H29IN2O6Si (548.45): C 43.80, H 5.33, N 5.11;
found: C 43.95, H 5.37, N 5.11.
1-[6,7-Dideoxy-2,3-O-isopropylidene-7-C-(triethylsilyl)-5-O-(triisopropylsilyl)-b-d-allo-hept-6-ynofuranosyl]-
6-iodouracil (18). A soln. of pyridine (5.4 ml, 67 mmol, distilled from CaH2) and 17 (5.0 g, 3.92 mmol) in CH2Cl2
(150 ml) was treated dropwise with TIPSOTf (5.4 ml, 20 mmol), stirred at 238 for 20 min, washed with brine
(3 Â 100 ml), dried (Na2SO4), and evaporated. FC (AcOEt/hexane 1:2) gave 18 (5.7 g, 89%). Colourless
powder. Rf(AcOEt/hexane 1:1) 0.88. [a]2D5 ˆ ‡14.2 (c ˆ 6.1, CHCl3). IR (CHCl3): 3384m, 2955s, 2868m, 2172w,
1721s, 1696s, 1572m, 1463m, 1417m, 1384m, 1338m, 1266m, 1148m, 1096m, 881m. 1H-NMR (300 MHz, CDCl3):
see Table 2; additionally, 9.50 (br. s, NH); 1.55, 1.35 (2s, Me2C); 1.10 ± 1.05 (m, (Me2CH)3Si); 0.99 (t, J ˆ 7.5,
(MeCH2)3Si); 0.62 (q, J ˆ 7.5, (MeCH2)3Si). 13C-NMR (75 MHz, CDCl3): see Table 3; additionally, 113.7
(s, Me2C); 27.1, 25.1 (2q, Me2C); 18.1 (q, (Me2CH)3Si); 12.4 (d, Me2CH)3Si); 7.4 (q, (MeCH2)3Si); 4.2 (t,
‡
‡
(MeCH2)3Si). FAB-MS (NOBA): 705 (8, [M ‡ H] ), 689 (15, [M À Me] ). Anal. calc. for C29H49IN2O6Si
(704.79): C 49.42, H 7.01, N 3.97; found: C 49.50, H 7.01, N 3.91.
1-[6,7-Dideoxy-2,3-O-isopropylidene-7-C-(triethylsilyl)-5-O-(triisopropylsilyl)-b-d-allo-hept-6-ynofurano-
syl]uracil-6-yl-(6! 7'-C)-1-[6,7-dideoxy-2,3-O-isopropylidene-5-O-(triisopropylsilyl)-b-d-allo-hept-6-ynofurano-
syl]uracil (19). A soln. of 18 (4.0 g, 5.7 mmol), 16 (2.5 g, 5.4 mmol), Pd2(dba)3 (256 mg, 0.27 mmol), CuI (72 mg,
0.38 mmol) and P(fur)3 (87 mg, 0.38 mmol) in degassed Et3N/toluene 1:1 (350 ml) was stirred for 80 h at 238.
After evaporation, FC (AcOEt/hexane 1:3) gave 19 (4.2 g, 63%). Brown foam. Rf(AcOEt/hexane 1:1) 0.36.
[a]2D5 ˆ ‡10.2 (c ˆ 1.7, CHCl3). IR (CHCl3): 3387w, 2947m, 2868m, 2230w, 2180w, 1697s, 1596w, 1456m, 1384m,
1093m, 882m. 1H-NMR (400 MHz, CDCl3): see Table 4; additionally, 9.50 (br. s, NH); 9.38 (br. s, NH); 1.59,
1.52, 1.37, 1.31 (4s, 2 Me2C); 1.15 ± 1.05 (m, 2 (Me2CH)3Si); 0.94 (t, (MeCH2)3Si); 0.56 (q, (MeCH2)3Si).
13C-NMR (100 MHz, CDCl3): see Table 5; additionally, 115.0 (s, Me2C); 113.4 (s, Me2C); 27.2, 27.1, 25.4, 24.9 (4q,
2 Me2C); 18.08, 18.06, 18.0, 17.9 (4q, 2 (Me2CH)3Si); 12.5, 12.4 (2d, 2 (Me2CH)3Si); 7.3 (q, (MeCH2)3Si); 4.2
‡
‡
(t, (MeCH2)3Si). FAB-MS (NOBA): 1064 (7, [M ‡ Na] ), 998 (21, [M À Me2CH] ). Anal. calc. for
C52H84N4O12Si3 (1041.51): C 59.97, H 8.13, N 5.38; found: C 59.92, H 7.94, N 5.38.
1-[6,7-Dideoxy-2,3-O-isopropylidene-5-O-(triisopropylsilyl)-b-d-allo-hept-6-ynofuranosyl]uracil-6-yl-(6 !
7'-C)-1-[6,7-dideoxy-2,3-O-isopropylidene-5-O-(triisopropylsilyl)-b-d-allo-hept-6-ynofuranosyl]uracil (20).
A
soln. of 19 (4.3 g, 4.1 mmol) in MeOH/AcOEt 1:1 (200 ml) was treated dropwise with a soln. of AgNO3

Helvetica Chimica Acta ± Vol. 83 (2000)
1327
(8.4 g, 49.5 mmol) in H2O/MeOH 1:1 (30 ml), stirred at 238 under exclusion of light for 4 h, treated with a soln.
of KCN (8.4 g) in H2O (20 ml), and stirred for 1 h. After evaporation, the residue was diluted with AcOEt,
washed with brine, dried (Na2SO4), and evaporated. FC (AcOEt/hexane 1 :2) gave 20 (2.4 g, 63%). Colourless
foam. Rf(AcOEt/hexane 1:1) 0.33. [a]2D5 ˆ ‡8.0 (c ˆ 2.4, CHCl3). IR (CHCl3): 3387w, 3306w, 2945m, 2867w,
2260w, 2150w, 1697s, 1596w, 1456m, 1384m, 1094s, 1068m, 882m. 1H-NMR (400 MHz, CDCl3): see Table 4;
additionally, 8.90 (br. s, NH); 8.75 (br. s, NH); 1.58, 1.53, 1.37, 1.33 (4s, 2 Me2C); 1.25 ± 1.15 (m, 2 (Me2CH)3Si);
1.15 ± 1.09 (m, 2 (Me2CH)3Si). 13C-NMR (100 MHz, CDCl3): see Table 5; additionally, 114.8 (s, Me2C); 113.5
(s, Me2C); 27.14, 27.09, 25.3, 25.0 (4q, 2 Me2C); 18.0, 17.9 (2q, (Me2CH)3Si); 12.44, 12.40 (2d, 2 (Me2CH)3Si).
‡
‡
‡
FAB-MS (NOBA): 928 (23, [M ‡ H] ), 912 (13, [M À Me] ), 884 (85, [M À Me2CH] ). MALDI-MS (Indole-3-
‡
‡
acetic acid): 949 ([M ‡ Na] ), 965 ([M ‡ K] ). Anal. calc. for C46H70N4O12Si2 (927.31): C 59.58, H 7.61, N 6.04;
found: C 59.59, H 8.04, N 6.00.
Appendix. ± Calculation of Acetyleno Analogues of RNA Oligonucleotides. Calculations were performed
with Macromodel V.4.5 (Amber* force field, gas phase) [15]). To obtain hetero- and homoduplexes possessing a
modified backbone, the A helix of an RNA oligomer was built with the grow tool of Macromodel, energy-
minimised, and modified. A priori, there are two possibilities to bridge the base and the furanosyl unit, with the
neighbouring unit either towards the upstream or towards the downstream end, leading either to retention or to
inversion of the direction of the strand, respectively. If the neighbouring ribofuranosyl group is on the same side
as the attachment point at the base, the desired modified backbone appears feasible, requiring only a different
orientation of the ribofuranosyl moiety. If, however, the neighbouring ribofuranosyl group is on the side
opposite to the attachment point at the base, then the new backbone requires both a different orientation of the
ribofuranosyl moiety and a rotation of the base (c ! c ‡ 1808). This implies that base pairing must be
interrupted and reestablished after rotation, and it is uncertain if a corresponding helix can be formed. The new
backbone was built by connecting the base with the ribofuranosyl unit located at the same side of the base as the
attachment point. If the attachment point of the base is in the major groove (for C(5) and C(6) of uridine, and
for C(8) of adenine), this means a connection with the neighbouring ribofuranosyl unit towards the downstream
end, and if the attachment point of the base is in the minor groove (C(2) of adenine), it means connection with
the neighbouring ribofuranosyl unit towards the upstream end.
To evaluate the appropriate length of the unsaturated furanosyl unit, in a first set of calculations, we
modified the minimised A helix of the hexamer (3'-5')U6 ´ (5'-3')A6 (see Fig. 5). The phosphinato groups and
O(5') of the uridine strand were replaced by a) CꢀC bridges between C(5) of uracil and C(5') of the
neighbouring nucleoside towards the downstream end ( ! heteroduplex (7'À5)rHepU6 ´ (5'-3')A6), b) by
CꢀCÀCꢀC bridges between C(5) of uracil and C(5') of the neighbouring nucleoside towards the downstream
end ( ! heteroduplex (9'À5)rNonU6 ´ (5'-3')A6), and c) CꢀC bridges between C(5) of uracil and C(4') of the
next nucleoside (replacing C(5') with retention of configuration ( ! heteroduplex (6'À5)rHexU6 ´ (5'-3')A6).

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Helvetica Chimica Acta ± Vol. 83 (2000)
These three heteroduplexes were minimised, and their base pairing was compared with that of (3'-5')U6 ´
(5'-3')A6. All three modified structures retain the double-helix. Characteristic is the change of the furanose ring
conformation from 3E to 4E. The heptynofuranose derivative (7'À5)rHepU6 ´ (5'-3')A6 is a good mimic as it
shows similar buckle and propeller twists as (3'-5')U6 ´ (5'-3')A6. The nonadiynofuranose derivative (9'À5)rNon-
U6 ´ (5'-3')A6 is a less appropriate mimic as it shows similar buckle and propeller twists as (3'-5')U6 ´ (5'-3')A6, but
CꢀCÀCꢀC angles of ca. 1508. The strongly buckle- and propeller-twisted base pairs of (6'±5)rHexU6 ´ (5'-3')A6
suggest that hex-5-ynofuranose derivatives are inappropriate mimics. Hept-6-ynofuranose derivatives appear to
be valuable mimics for (3'-5')polyU. Further calculations to evaluate the best connection point at the nucleobase
were performed only with hept-6-ynofuranose derivatives.
Calculation of 14-meric duplexes allows the analysis of a complete turn of 11 units, even if the terminal
units deviate from regularity. The A helix of (3'-5')U14 ´ (5'-3')A14 was built and minimised. The tertiary structure
of minimised (3'-5')U14 ´ (5'-3')A14 shows the characteristic properties of an A helix; i.e., the regular pattern (11
units per turn, axial rise h ˆ 2.74 Š) with a large central hole and inclined base pairs. The uridine and the
adenosine strand of minimised (3'-5')U14 ´ (5'-3')A14 were modified to afford the heteroduplexes (7'À5)rHe-
pU14 ´ (5'-3')A14, (7'À6)rHepU14 ´ (5'-3')A14, (3'-5')U14 ´ (7'À2)rHepA14, and (3'-5')U14 ´ (8À7')rHepA14. Mini-
misation of these heteroduplexes was performed in two steps: first, with constrained interhelix CˆO ´´´ HÀN
distances to keep the base pairs together during the strong changes of the backbone followed by a minimisation
without any constraint. The rather small energy gain (100 ± 200 kJ/mol) observed for the second minimisation
indicates only minor geometrical changes. The natural strand of the heteroduplexes (7'À5)rHepU14 ´ (5'-3')A14
and (7'À6)rHepU14 ´ (5'-3')A14 was modified to afford the homoduplexes (7'À5)rHepU14 ´ (7'À2)rHepA14
,
(7'À5)rHepU14 ´ (8À7')rHepA14, and (7'À6)rHepU14 ´ (8À7')rHepA14. Analogous minimisations as performed
for the heteroduplexes gave the minimised structure of the homoduplexes.
The minimised, modified hetero- and homoduplexes were analysed and compared with the natural
homoduplex (3'-5')U14 ´ (5'-3')A14. Some structural parameters of these calculated duplexes are listed in the
Table 6. All hetero- and homoduplexes of acetyleno-oligonucleosides retain more or less the starting helix,
although some lengthening of the helices is indicated by increased values for the axial rise. In the heteroduplex
series, the best results are obtained for (7'À6)rHepU14 ´ (5'-3')A14 and (3'-5')U14 ´ (8À7')rHepA14. Both have 11
residues per turn and retain the large central hole. The less distorted A helix and the smaller axial rise clearly
indicate that the 6-linked (7'À6)rHepU14 ´ (5'-3')A14 is a better mimic than the 5-linked (7'À5)rHepU14 ´ (5'-
3')A14, whereas the 8-linked (3'-5')U14 ´ (8À7')rHepA14 is only a slightly better mimic than the 2-linked (3'-
5')U14 ´ (7'À2)rHepA14. In the homoduplex series, the similarity to an A helix decreases from the 6- and 8-linked
(7'À6)rHepU14 ´ (8À7')rHepA14 via the 5- and 8-linked (7'À5)rHepU14 ´ (8À7')rHepA14 to the 5- and 2-linked
(7'À5)rHepU14 ´ (7'À2)rHepA14. These calculations suggest that C(6) of uridine and both C(2) and C(8) of
adenosine may act as attachment points for the heptynose. Similar calculations were performed in the DNA
series starting from the B helix of (3'-5')dT14 ´ (5'-3')dA14 and led exactly to the same result as in the RNA series.
Table 6. Chain Direction, Helix Type, Number of Residues per Turn, Axial Rise, and Furanose Ring
Conformations of the Calculated 14meric ribo-Configured Hetero- and Homoduplexes
RNA
Chain
Helix
n
h
Furanose ring conformation
Direction
[Š]
U strand
A strand
(3'-5')U14 ´ (5'-3')A14
antiparallel
parallel
parallel
antiparallel
parallel
parallel
A
A to B
11
10
11
11
11
10
10
11
2.74
3.01
2.89
2.87
2.85
3.08
3.03
2.90
3E
4E
4E
3T2
3T2
4E
4E
4E
3T2
(7'À5)rHepU14 ´ (5'-3')A14
(7'À6)rHepU14 ´ (5'-3')A14
(3'-5')U14 ´ (7'À2)rHepA14
(3'-5')U14 ´ (8À7')rHepA14
(7'À5)rHepU14 ´ (7'À2)rHepA14
(7'À5)rHepU14 ´ (8À7')rHepA14
(7'-6)rHepU14 ´ (8À7')rHepA14
3T2
A
A
A
A
A
A
3T2
4E
4E
E2
4E to E2
4E
antiparallel
antiparallel
To evaluate the influence of an OH group at C(5') on the tertiary structure, Hpro-RÀC(5') of the
homoduplexes (7'À5)rHepU14 ´ (8À7')rHepA14 and (7'À6)rHepU14 ´ (8À7')rHepA14 were replaced by OH
groups affording (7'À5)aHepU14 ´ (8À7')aHepA14 and (7'À6)aHepU14 ´ (8À7')aHepA14. Intraresidue H-bonds
O(5')ÀH ´´´ O(4') set by adjusting the dihedral angles C(4')ÀC(5')ÀOÀH were kept during the minimisation.

Helvetica Chimica Acta ± Vol. 83 (2000)
1329
The configuration at each C(5') of these homoduplexes was inverted affording (7'À5)tHepU14 ´ (8À7')tHepA14
and (7'À6)tHepU14 ´ (8À7')tHepA14 that were energy minimised (no intramolecular H-bonds for O(5')H). The
result shows that the additional OH group and the configuration at C(5') have only a weak influence upon the
tertiary structure of the homoduplexes (only small changes of the axial rises; Dh ꢁ 0.03 Š) although HOÀC(5')
of the d-allo-configured duplexes are directed towards the major groove and HOÀC(5') of the l-talo-
configured duplexes towards the minor groove.
To evaluate the compatibility of a single acetyleno-nucleoside unit in a natural duplex, the fourth
nucleoside of one strand of the natural duplex (3'-5')U14 ´ (5'-3')A14 was replaced by a (7'À5)-linked aHepU, a
(7'À6)-linked aHepU, a (7'À2)-linked aHepA, and a (8À7')-linked aHepA unit, resp., and minimised (500
iterations). Strong propeller twists (60 ± 908) and medium-to-strong buckle twists (30 ± 608) clearly indicate that
the presence of a (7'À5)aHepU, a (7'À6)aHepU, and (8À7')aHepA unit leads to complete interruption of the
base-pairing. However, the presence of a (7'À2)aHepA unit may be tolerated in a natural strand as indicated by
similar propeller and buckle twists as in (3'-5')U14 ´ (5'-3')A14
.
These force-field calculations show that acetyleno-oligonucleosides may form similar hetero- and
homoduplexes as natural oligonucleotides. The hept-6-ynofuranosyl unit may either be attached at C(2) or
C(8) of the neighbouring adenine but should be attached at C(6) of the neighbouring uracil. The presence or
absence of the HOÀC(5') groups has only a weak influence upon the tertiary structure.
Experimental. ± Force-Field Calculations. Calculations were performed with Macromodel V. 4.5 (Amber*
force field, gas phase) [15]. To evaluate the length of the unsaturated furanosyl unit, the A helix of the RNA
hexamer (3'-5')U6 ´ (5'-3')A6 was built with the grow tool of Macromodel, minimised (500 iterations), and
modified to afford the heteroduplexes (7'À5)rHepU6 ´ (5'-3')A6, (9'À5)rNonU6 ´ (5'-3')A6, and (6'À5)rHexU6 ´
(5'-3')A6. These three heteroduplexes were minimised (500 iterations) and then their base pairing compared
with that of (3'-5')U6 ´ (5'-3')A6.
To evaluate the connection points between the base and heptynofuranose, the A helix of the RNA 14-mer
(3'-5')U14 ´ (5'-3')A14 was built with the grow tool of Macromodel, minimised (500 iterations), and modified. The
phosphinato bridges and O(5') of the uridine strand of (3'-5')U14 ´ (5'-3')A14 were deleted and replaced with
CꢀC bridges either between C(5) and C(5') of the neighbouring nucleoside towards the downstream end ( !
heteroduplex (7'À5)rHepU14 ´ (5'-3')A14) and between C(6) and C(5') of the neighbouring nucleoside towards
the downstream end ( ! heteroduplex (7'À6)rHepU14 ´ (5'-3')A14). The phosphinato bridges and O(5') of the
adenine strand of (3'-5')U14 ´ (5'-3')A14 were deleted and replaced either with CꢀC bridges between C(2) and
C(5') of the neighbouring nucleoside towards the upstream end ( ! heteroduplex (3'-5')U14 ´ (7'À2)rHepA14) or
with CꢀC bridges between C(8) and C(5') of the neighbouring nucleoside towards the downstream end ( !
heteroduplex (3'-5')U14 ´ (8À7')rHepA14), resp. Minimisations of these heteroduplexes were performed in two
steps: 1000 iterations with constrained interhelix CˆO ´´´ HÀN distances (1.73 Æ 0.03 Š) to keep the base pairs
together during the strong changes of the backbone followed by 1000 iterations without any constraint. The
rather small energy gains (100 ± 200 kJ/mol) observed for the second minimisations evidence only minor
geometrical changes. To get homoduplexes of acetyleno-oligonucleotides, the phosphinato bridges and O(5') of
the (5'-3')A14 strands of the heteroduplexes (7'À5)rHepU14 ´ (5'-3')A14 were replaced by CꢀC bridges between
C(2) and C(5') ( ! homoduplex (7'À5)rHepU14 ´ (7'À2)rHepA14) or between C(8) and C(5') ( ! homoduplex
(7'À5)rHepU14 ´ (8À7')rHepA14), and the phosphinato bridges and O(5') of the (5'-3')A14 strands of the
heteroduplex (7'À6)rHepU14 ´ (5'-3')A14 were replaced by CꢀC bridges between C(8) and C(5') ( ! homodu-
plex (7'À6)rHepU14 ´ (8À7')rHepA14). Analogous minimisations as performed for the heteroduplexes gave the
minimised structures of the homoduplexes.
To evaluate the influence of an OH group at C(5') on the tertiary structure, Hpro-RÀC(5') of the
homoduplexes (7'À5)rHepU14 ´ (8À7')rHepA14 and (7'À6)rHepU14 ´ (8À7')rHepA14 were replaced by OH
groups affording (7'À5)aHepU14 ´ (8À7')aHepA14 and (7'À6)aHepU14 ´ (8À7')aHepA14). Intraresidue H-bonds
O(5')ÀH ´´´ O(4') were set by adjusting the dihedral angles C(4')ÀC(5')ÀOÀH. These weak intraresidue H-
bonds were kept during the minimisations (1000 iterations). The configurations at C(5') of these homoduplexes
were inverted (no intramolecular H-bonds), affording the l-talo-configured (7'À5)tHepU14 ´ (8À7')tHepA14
and (7'À6)tHepU14 ´ (8À7')tHepA14, and minimised (1000 iterations).

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Received March 30, 2000