Synthesis of silicon analogues of acyclonucleotides incorporable in oligonucleotide solid-phase synthesis

Article abstract of DOI:10.1021/jo962165p

The synthesis of the four silicon analogues of acyclonucleosides was described. In every case, the silicon atom was introduced onto an allyl group on the natural nucleobase following a hydrosilylation reaction. Diols obtained were protected as 4,4'-dimethoxytrityl ethers and subsequently activated as 2-cyanoethyl N,N-diisopropylchlorophosphoramidite in order to be suitable for oligonucleotide solid phase synthesis.

Full text of DOI:10.1021/jo962165p

J . Org. Chem. 1997, 62, 4635-4642
4635
Syn th esis of Silicon An a logu es of Acyclon u cleotid es In cor p or a ble
in Oligon u cleotid e Solid -P h a se Syn th esis
J acques Thibon, Laurent Latxague, and Ge´rard De´le´ris*
Laboratoire de Chimie Bio-Organique, Universite´ Victor Segalen Bordeaux 2, 146 rue Le´o Saignat,
F-33076 Bordeaux Cedex, France
Received November 19, 1996X
The synthesis of the four silicon analogues of acyclonucleosides was described. In every case, the
silicon atom was introduced onto an allyl group on the natural nucleobase following a hydrosilylation
reaction. Diols obtained were protected as 4,4′-dimethoxytrityl ethers and subsequently activated
as 2-cyanoethyl N,N-diisopropylchlorophosphoramidite in order to be suitable for oligonucleotide
solid phase synthesis.
In tr od u ction
Modulation of gene expression as a therapeutic ap-
proach has generated much interest in recent years. Two
main strategies, which both use oligodeoxynucleotides
(ODNs), are currently studied: antigene agents that bind
to a double-strand DNA and then, form a localized triplex
preventing gene transcription1 and antisense agents
which target messenger RNA (mRNA) to form a duplex
preventing translation.2 Antisense ODNs act through
specific hybridization to coding (sense) sequences in the
mRNA by Watson-Crick base pairing; such ODNs can
be made of a small number of nucleotides (<20) with
enough specificity.3 However, the use of natural ODNs
is restricted by their low cellular uptake and their
susceptibility to enzymatic degradation. Several chemi-
cal modifications have been performed to date to over-
come these difficulties. Two ways,2,4 phosphodiester
linkage and nucleoside modifications (either of sugar or
heterocyclic bases), have been investigated.
F igu r e 1. Natural nucleoside vs our proposed acyclic sila
analogue. R ) Me or may be modified to add new functional-
ities.
dihydroxyalkyl or methoxydihydroxyalkyl chains, with
improved results.
Our strategy uses a bis(hydroxymethyl)silicon chain
in order to improve the overall lipophily of the resulting
ODN and to take advantage of the wide range of reactions
permitted by silicon. So far, silicon has been seldom used
in ODN analogues synthesis, except for alkoxysilane
internucleoside linkage,11 but the known sensitivity of
the alkoxysilane moiety to both acids and bases restricts
its use in vivo. In our work, a silicon atom replaced
carbon-4′ of the deoxyribose, while carbon-2′ and the
carbohydrate oxygen were removed; finally, to avoid
potential â-elimination during the course of the synthesis,
a propyl chain (instead of an ethyl) separates the
heterocyclic base from silicon (Figure 1).
Among the earliest and most widely used ODN ana-
logues are the phosphorothioates5 (one sulfur atom
replaces a nonbinding phosphate oxygen) which exhibit
a
better stability to nucleases or the methylphos-
phonates6 (a methyl group replaces a negatively charged
phosphate oxygen) with an improved lipophily, and in
the most recent approach, the whole phosphodiester was
replaced by a guanidinium linkage, affording a positively
charged ODN.7
We here describe the synthesis of the phosphoramidites
synthons corresponding to the four protected silicon
nucleoside analogues bearing cytosine, guanine, thymine,
and adenine nucleobases.
On the other hand, little work has been devoted to the
replacement of the carbohydrate moiety of the nucleoside
by an acyclic chain, which can be thought as another way
to increase the enzymatic stability of ODNs.8 Thus,
Schneider et al.9 report the use of glycerol-like chains in
ODN analogues and Vandendriessche et al.10 the use of
Resu lts a n d Discu ssion
Owing to the diverse reactivities of the four nucleo-
bases, their nucleoside analogues had to be synthesized
in slightly different ways. However, every time the key
step involved a hydrosilylation reaction in order to
introduce the silicon atom onto the molecule.
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
(1) Thuong, N. T.; He´le`ne, C. Angew. Chem., Int. Ed. Engl. 1993,
32, 666.
(2) Cohen, J . S., Ed. Oligodeoxynucleotides as Antisense Inhibitors
of Gene Expression; CRC Press: Boca Raton, FL, 1987.
(3) He´le`ne, C.; Toulme´, J . J . Biochim. Biophys. Acta 1990, 1049, 99.
(4) Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543.
(5) (a) Frey, P. A.; Sammons, R. D. Science 1985, 228, 541. (b)
Iyengar, R.; Eckstein, F.; Frey, P. A. J . Am. Chem. Soc. 1984, 106,
8309.
(6) Ts’O, P. O. P.; Miller, P. S.; Aurelian, R.; Murakami, A.; Agris,
C.; Blake, K. R.; Lin, S. B.; Lee, B. L.; Smith, C. C. Ann. N.Y. Acad.
Sci. 1988, 507, 220.
(7) Dempcy, R. O.; Browne, K. A.; Bruice, T. C. J . Am. Chem. Soc.
1995, 117, 6140.
(8) Ogilvie, K. K.; N’Guyen-Ba, N.; Gillen, M. F.; Radatus, B. K.;
Cheriyan, U. O.; Hanna, H. R.; Smith, K. O.; Galloway, K. S. Can. J .
Chem. 1984, 62, 241.
For this purpose, we used two silanes, bis(chlorometh-
yl)methylsilane (1a ) and (chloromethyl)dimethylsilane
(1b), readily obtained from hydride reduction of the
corresponding chlorosilanes (Scheme 1).
(9) Schneider, K. C.; Benner, S. A. J . Am. Chem. Soc. 1990, 112,
453.
(10) Vandendriessche, F.; Augustyns, K.; Van Aerschot, A.; Busson,
R.; Hoogmartens, J .; Herdewijn, P. Tetrahedron 1993, 49, 7223.
(11) (a) Ogilvie, K. K.; Cormier, J . F. Tetrahedron Lett. 1985, 26,
4159. (b) Saha, A. K.; Sardaro, M.; Waychunas, C.; Delecki, D.; Kutny,
R.; Cavanaugh, P.; Yawman, A.; Upson, D. A.; Kruse, L. I. J . Org.
Chem. 1993, 58, 7827.
S0022-3263(96)02165-2 CCC: $14.00 © 1997 American Chemical Society

4636 J . Org. Chem., Vol. 62, No. 14, 1997
Thibon et al.
Sch em e 1
Sch em e 3
Sch em e 2
protected with benzoyl chloride to give compound 8
allowing a good yield for hydrosilylation step to product
9a . The later was acetoxylated to give 10a which was
saponified in an aqueous sodium hydroxide solution to
give compound 11a with one remaining benzoyl group.
Interestingly, there was no need to remove it, since it is
also a suitable protective group during the oligonucleotide
synthesis.
Compounds 1a and 1b were then reacted with an
allylic precursor of the nucleoside analogues to give the
hydrosilylated key synthetic intermediates. We used
either a solution of chloroplatinic acid in isopropyl alcohol
or tetrabutylammonium hexachloroplatinate as catalyst.
Both gave similar results in hydrosilylation product, but
we found the use of the later preferable to H2PtCl6 which
is very sensitive to moisture and light exposure. Finally,
as already emphasized in a preliminary work,12 most of
the labile protons had to be masked by a suitable
protective group prior to hydrosilylation.
Th ym id in e An a logu es. The previously known N-1-
allylthymine13,14 (2) was prepared from thymine by
reacting its 2,4-bis((trimethylsilyl)oxy) derivative with
allyl bromide in DMF (Scheme 2); N,N-1,3-bis(allyl)-
thymine (15%) was also isolated as a byproduct. Several
unsuccessful hydrosilylations of unprotected 2 led us to
mask its N-3 labile proton to afford the trimethylsilyl
ether 3 which gave moderate yields of the desired
compounds 4a and 4b. Acetoxylation of the later gave
compounds 5a and 5b subsequently saponified under
anhydrous conditions (K2CO3/methanol) to afford the
hydroxylated compounds 6a and 6b.
An alternative way, starting from 6-chloropurine, is
described in Scheme 4.
Similar to adenine, 6-chloropurine reacted with allyl
bromide to give 9-allyl-6-chloropurine (12). Hydrosilyl-
ation of this compound with 1a or 1b afforded respec-
tively 13a and 13b which after acetoxylation yielded 14a
and 14b.
Displacement of chlorine with NH2 in 14a and 14b was
conducted by ammoniolysis in a steel bomb (overnight
at 90 °C) to yield directly the hydroxylated coumpounds
15a and 15b.
Benzoyl chloride reaction gave exclusively the per-
acylated compound which was further treated with a 1
N NaOH solution to cleave one of the amino benzoyl
groups to give 11a .
Cytid in e An a logu es. In a first attempt, we directly
synthesized a protected N-1-allylcytosine by reacting
cytosine with N,N-dimethylformamide diallyl acetal in
anhydrous DMF according to Helfer et al.16 Unfortu-
nately, hydrosilylation of the resulting 1-allyl-N-4-[(di-
methylamino)methylene]cytosine led to a complex mix-
ture of various products we were unable to identify. A
direct allylation of cytosine using sodium hydride and
allyl bromide, or via the activated 2,4-bis((trimethylsilyl)-
oxy)cytosine, was unsuccessfull in our hands.
Thus, we used an indirect pathway starting from
uracil. Actually, N-1-allyluracil (16) was readily obtained
Ad en osin e An a logu es. Under alkaline conditions
using sodium hydride in DMF, adenine was alkylated
with allyl bromide to afford N-9-allyladenine (7) as the
major product15 (Scheme 3). Prior to the hydrosilylation
step, the exocyclic 6-amino group of the purine ring was
(12) Latxague, L.; Thibon, J .; Guillot, C.; Moreau, S.; De´le´ris, G.
Tetrahedron Lett. 1994, 35, 5869-5872.
(13) Skaric, V.; Erben, D.; Z., R.; Skaric, D. Croat. Chem. Acta 1979,
52, 281-292.
(14) Tanabe, T.; Yamauchi, K.; M., K. Bull. Chem. Soc. J pn. 1978,
52, 259-260.
(15) Kondo, K.; Kuwata, K.; Takemoto, K. Makromol. Chem. 1972,
160, 341-346.
(16) Helfer, D. L.; Hosmane, R. S.; Leonard, N. J . J . Org. Chem.
1981, 46, 4803-4804.

Synthesis of Si Analogues of Acyclonucleotides
J . Org. Chem., Vol. 62, No. 14, 1997 4637
Sch em e 4
Sch em e 5
Sch em e 6
and subjected to hydrosilylation yielding 17a and 17b
followed by acetoxylation to yield 18a and 18b (Scheme
5). At this stage of the synthesis, we underwent the
uracil-cytosine transformation via 1-(mesitylene-2-sul-
fonyl)-3-nitro-1,2,4-triazole (MSNT), known as a condens-
ing reagent in oligonucleotide synthesis. Reese et al.17,18
reported that MSNT, when reacted with tri-O-acetyl-
uridine, afforded 4-(3-nitro-1,2,4-triazolo)pyrimidinone
which further gave cytidine when treated with am-
monium hydroxide. Thus, reaction of 18a and 18b with
MSNT in pyridine at room temperature afforded 19a and
19b in high yields. Subsequent treatment with aqueous
ammonia in dioxane, followed by saponification of the
acetoxy moiety, afforded 20a and 20b.
Gu a n osin e An a logu es. Commercially available
2-amino-6-chloropurine was alkylated in dry acetonitile
with sodium hydride/allyl bromide to afford its N-9-allyl
derivative 21 (Scheme 6).
The exocyclic 2-amino group was protected with ben-
zoyl chloride to give 22 which was reacted with 1a in the
presence of tetrabutylammonium hexachloroplatinate to
yield compound 23a . The later was acetoxylated and
refluxed with hydrochloric acid to give in a single step
the dihydroxylated guanosine analogue 25a in a 45%
yield.
P h osp h or a m id ite Syn th esis. Solid support synthe-
sis of oligonucleotides requires the functional protection
of the 5′-hydroxy function of nucleosides. For this
purpose, the 4,4′-dimethoxytrityl (DMTr) group is one of
the most popular; however, the exocyclic amino function
of cytosine, adenine, or guanine nucleosides must be
protected first, in order to prevent undesired tritylation.
Among our proposed nucleoside analogues, the adenosine
11a and guanidine 25a analogues were already protected
during the course of the synthesis. The cytidine analogue
20a was protected with benzoyl chloride (Scheme 7).
Yields of the subsequent tritylation step were lowered
by the presence of two identical primary hydroxy groups.
Therefore, 27a , 28a , 29a , and 30a were obtained as
mixtures of mono- and diprotected derivatives, along with
unreacted starting material. Nevertheless, following
purification on silica gel, the diprotected derivatives could
be recovered and treated with trifluoroacetic acid in
(17) Reese, C. B.; Ubasawa, A. S. Nucleic Acids Research: Sympo-
sium Series 1980, 7, 5-21.
(18) Reese, C. B.; Ubasawa, A. S. Tetrahedron Lett. 1980, 21, 2265-
2268.

4638 J . Org. Chem., Vol. 62, No. 14, 1997
Thibon et al.
Sch em e 7
83 °C/760 mmHg; 1H NMR (CDCl3) δ 0.20 (d, 6H, J ) 3.6 Hz),
2.80 (d, 2H, J ) 2.4 Hz), 3.90-4.10 (m, 1H); IR (film) 2947,
dichloromethane to give another crop of dihydroxylated
compounds.
Finally, a coupling reaction of the remaining hydroxy
group with 2-cyanoethyl N,N-diisopropylchlorophos-
phoramidite led to the four end products 31a , 32a , 33a ,
and 34a .
Su m m a r y of th e Resu lts. In conclusion, the syn-
thesis of the four novel silicon analogues of acyclonucleo-
sides was achieved. In every case, silicon was introduced
onto the heterocyclic moiety following a hydrosilylation
reaction. In order to be suitable for use in solid phase
oligonucleotide synthesis, nucleoside analogues were
protected as 4,4′-dimethoxytrityl ethers and subsequently
activated as 2-cyanoethyl N,N-diisopropylchlorophos-
phoramidites. Insertion of the obtained analogues of
nucleotides within oligonucleotides (17 mer) is now in
progress, and the physico-chemical properties for hybrid-
ization either with DNA or RNA complementary se-
quences will be determined.
2131, 1394, 1255, 882 cm-1
.
Gen er a l P r oced u r e for th e P r ep a r a tion of Allyl De-
r iva tives. To a stirred suspension of nucleobase in dry
dimethylformamide (DMF) was added in small portions so-
dium hydride (80% in oil) at room temperature. After 2 h of
stirring, freshly distilled allyl bromide was added dropwise,
and the mixture was heated to 70 °C for 2 h. The clear
reaction mixture was concentrated to dryness under reduced
pressure, the remaining solid was washed with dichloro-
methane and filtrated, and the filtrate was concentrated to
an oil purified on a silica gel column. N-1-Allylthymine was
prepared differently via its bis(trimethylsilyl) derivative.
N-9-Allyla d en in e (7). Following the general procedure,
adenine (5 g, 0.037 mol) treated with sodium hydride (0.9 g,
0.037 mol) and allyl bromide (7 g, 0.058 mol) gave 7 separated
from N-7-allyladenine on a silica gel column using ethyl
1
acetate as eluant: yield 3.87 g (59%); H NMR (DMSO-d6) δ
4.77 (d, 2H, J ) 6 Hz), 5.09 (m, 2H), 5.95-6.14 (m, 1H), 7.25
(s, 2H), 8.10 (s, 1H), 8.12 (s, 1H); 13C NMR (DMSO-d6) δ 44.89,
117.34, 118.60, 133.17, 140.68, 149.40, 152.53, 155.98.
N-9-Allyl-6-ch lor op u r in e (12). Following the general
procedure, 6-chloropurine (5 g, 0.032 mol) was treated with
sodium hydride (1.36 g, 0.056 mol) and allyl bromide (7 g, 0.058
mol) The reaction gave a mixture of N-9-allyl-6-chloropurine
(12) and N-7-allyl-6-chloropurine which were separated on a
silica gel column using ethyl acetate as eluant: yield 3.8 g
(60%); 1H NMR (CDCl3) δ 4.88 (d, 2H, J ) 5.8 Hz), 5.18-5.36
(m, 2H), 5.92-6.11 (m, 1H), 8.10 (s, 1H), 8.71 (s, 1H); 13C NMR
(CDCl3) δ 46.35, 101.68, 120.05, 130.91, 131.55, 145.01, 151.10,
152.07.
Exp er im en ta l Section
Gen er a l. 1H, 13C, and 31P NMR spectra were recorded at
200, 50, and 81 MHz, respectively; chemical shifts are given
in ppm from tetramethylsilane (1H and 13C) or H3PO4 (31P) as
an internal standard. Infrared spectra were measured using
neat samples on NaCl plates for liquids or using the KBr
technique for solids. Melting points were taken on a hot stage
apparatus and are uncorrected. Mass spectra were obtained
under FAB conditions. Thin layer chromatography (TLC) was
carried out on aluminum-backed silica gel 60 F254 0.25 mm
plates (Merck). Column chromatography was performed using
silica gel (70-230 mesh) and flash column chromatography
using silica gel (230-400 mesh) at 0.4 bar.
N-1-Allylu r a cil (16). Following the general procedure,
uracil (10.5 g, 0.093 mol) treated with sodium hydride (2.5 g,
0.104 mol) and allyl bromide (15 g, 0.123 mol) gave 16
separated from N1,N3-bis(allyl)uracil on recrystallization in
propan-2-ol: yield 7.5 g (47%); 1H NMR (CDCl3) δ 4.30 (d, 2H,
J ) 8 Hz), 5.19-5.31 (m, 2H), 5.91-5.69 (m, 2H), 7.24 (d, 1H,
J ) 8 Hz), 9.66 (s, 1H); 13C NMR (CDCl3) δ 49.91, 102.42,
119.37, 131.44, 143.81, 150.96, 164.06.
N-1-Allylth ym in e (2). A mixture of thymine (10.4 g, 0.038
mol), 1,1,1,3,3,3-hexamethyldisilazane (HMDS, 10 mL), and
a few milligrams of of ammonium sulfate was refluxed under
an inert atmosphere until a clear solution was obtained. The
excess of HMDS was coevaporated with toluene, and to the
resulting 2,4-bis(trimethylsilyl)thymine was added dry DMF
(25 mL) and allyl bromide (25 mL). The mixture was stirred
for 3 days at 80 °C under an inert atmosphere. After removal
of the solvent and excess allyl bromide, the remaining oil was
flash chromatographed (CH2Cl2-MeOH 98:2) to leave a pale
yellow solid recrystallized from toluene: yield 4.08 g (64%);
Bis(ch lor om et h yl)m et h ylsila n e (1a ). To a solution of
bis(chloromethyl)methylchlorosilane (5 mL, 0.03 mol) in an-
hydrous ether (30 mL) stirred at 0 °C under nitrogen was
added lithium aluminum hydride (0.76 g, 0.02 mol) over a
period of 4 h. The suspension was stirred for 3 h at 0 °C and
then 1 h at room temperature and carefully hydrolyzed with
a 1 N HCl solution (2.5 mL) and stirred for a further 12 h.
The mixture was filtered, and the filtrate was concentrated
under reduced pressure and then distilled off to yield 4.05 g
of 1a (93%) as a colorless liquid: bp 53 °C/25 mmHg; 1H NMR
(CDCl3) δ 0.33 (d, 3H, J ) 7.2 Hz), 2.98 (d, 4H, J ) 3 Hz),
4.13-4.19 (m, 1H); IR (film) 2935, 2153, 1394, 1264, 873 cm-1
.
(Ch lor om eth yl)d im eth ylsila n e (1b). Under similar con-
ditions, compound 1b was obtained in 78% yield starting from
(chloromethyl)dimethylchlorosilane: colorless liquid, bp 82-

Synthesis of Si Analogues of Acyclonucleotides
J . Org. Chem., Vol. 62, No. 14, 1997 4639
mp 112 °C; 1H NMR (CDCl3) δ 1.90 (d, 3H, J ) 1 Hz), 4.30 (d,
2H, J ) 6 Hz), 5.20-5.30 (m, 2H), 5.70-5.90 (m, 1H), 6.90 (d,
1H, J ) 1 Hz), 9.00 (large s, 1H); 13C NMR (CDCl3) δ 12.2,
49.6, 110.8, 118.9, 131.7, 139.8, 151.2, 164.7; IR (KBr) 3146,
2980, 1710, 1650, 1480, 1413, 1362, 1245, 902 cm-1; MS (EI
70 eV) m/ e 166 (M+), 151 (M+ - 15), 147, 123, 110, 94.
6-(N,N-Diben zoylam in o)-N-9-allylpu r in e (8). To a stirred
solution of N-9-allyladenine (5 g, 0.028 mol) in pyridine (100
mL), protected from moisture with a drying tube and cooled
in an ice bath, was added benzoyl chloride (40 g, 0.284 mol)
dropwise. After 2 h, the mixture was left at room temperature
for 1 h and was hydrolyzed with a 1 N NaHCO3 solution (100
mL) followed by water (100 mL). After concentration under
reduced pressure, the mixture was dissolved in methylene
chloride, and the solution was washed twice with a 1 N
NaHCO3 solution and dried on sodium sulfate. The crude
product was chromatographed on a silica gel column using a
stepwise gradient of methanol-methylene chloride (0:100-5:
95) to afford 8 recrystallized in propan-2-ol: yield 5 g (50%);
1H NMR (CDCl3) δ 4.83 (d, 2H, J ) 6 Hz), 5.19-5.35 (m, 2H),
5.95-6.09 (m, 1H), 7.31-7.45 (m, 6H), 7.82 (m, 4H), 8.04 (s,
1H), 8.65 (s, 1H); 13C NMR (CDCl3) δ 46.09, 119.81, 127.21,
128.62, 129.37, 131.04, 132.89, 134.04, 144.65, 151.66, 152.14,
153.05, 172.25.
7.24-7.46 (m, 6H), 7.82 (m, 4H), 7.85 (m, 1H), 8.05 (s, 1H),
8.64 (s, 1H); 13C NMR (CDCl3) δ -7.43, 8.26, 23.91, 26.73,
46.83, 127.23, 128.60, 129.36, 132.87, 134.03, 144.85, 151.61,
152.01, 153.13, 172.23.
Bis(chloromethyl)methyl[3-[N-1-(2,4-dioxopyrimidinyl)]-
p r op yl]sila n e (17a ). A mixture of allyluracil 16 (1.2 g, 0.0079
mol), HMDS (5 mL), trimethylchlorosilane (0.5 mL), and a few
crystals of ammonium sulfate was heated at reflux, under inert
atmosphere, for 5 h; then, HMDS in excess was removed by
distillation under reduced pressure. To the protected allylu-
racil was added THF (20 mL), bis(chloromethyl)methylsilane
(1.5 g, 0.0103 mol), and hexachloroplatinic acid as described
in the general procedure for hydrosilylation: yield 1.2 g (52%);
1H NMR (CDCl3) δ 0.24 (s, 3H), 0.73-0.82 (m, 2H), 1.68-1.84
(m, 2H), 2.90 (s, 4H), 3.67-3.74 (t, 2H), 5.67 (d, 1H, J ) 7.8
Hz), 7.12 (d, 1H, J ) 7.8 Hz), 9.19 (s, 1H); 13C NMR (CDCl3)
δ -7.40, 7.91, 22.92, 26.80, 51.33, 102.17, 144.29, 150.75,
163.63; IR (film) 3052.9, 2358.9, 1681.9, 1455.8, 1258.6, 816.7
cm-1
.
Bis(ch lor om eth yl)m eth yl[3-[N-9-(6-ch lor opu r in yl)]pr o-
p yl]sila n e (13a ). Following the general procedure for hy-
drosilylation, a mixture of N-9-allyl-6-chloropurine (12) (0.800
g, 0.0041 mol) in THF (20 mL) and bis(chloromethyl)methyl-
silane (1a ) (1 g, 0.0069 mol) stirred in the presence of
hexachloroplatinic acid (0.2 mL) at 60 °C for 2 h yielded 0.400
g (58%) of the title compound: 1H NMR (CDCl3) δ 0.22 (s, 3H),
0.75-0.84 (m, 2H), 1.94-2.10 (m, 2H), 2.88 (s, 4H), 4.30 (t,
2H), 8.11(s, 1H), 8.72 (s, 1H); 13C NMR (CDCl3) δ -7.43,
151.86, 151.75, 150.99, 145.01, 131.55, 47.02, 26.80, 23.92,
8.27.
(Ch lor om eth yl)d im eth yl[3-[N-9-(6-ch lor op u r in yl)]p r o-
p yl]sila n e (13b). Following the general procedure for hy-
drosilylation, a mixture of N-9-allyl-6-chloropurine (12) (0.500
g, 0.0025 mol) in anhydrous THF (20 mL) and (chloromethyl)-
dimethylsilane (1b) (1 g, 0.0093 mol) stirred in the presence
of hexachloroplatinic acid (0.2 mL) at 60 °C for 2 h yielded
0.158 g (20%) of the title compound: 1H NMR (CDCl3) δ 0.08
(s, 6H), 0.57-0.68 (m, 2H), 1.85-2.01 (m, 2H), 2.83 (s, 2H),
4.26 (t, 2H), 8.10 (s, 1H), 8.72 (s, 1H); 13C NMR (CDCl3) δ
-4.67, 10.79, 24.34, 29.71, 47.32, 145.20, 151.00, 151.92.
N-9-Allyl-N-2-a m in o-6-ch lor op u r in e (21). To a stirred
suspension of 2-amino-6-chloropurine (1 g, 0.0060 mol) in dry
acetonitrile (120 mL) was added at room temperature sodium
hydride (60% dispersion in mineral oil, 0.26 g, 0.0065 mol),
and the solution was stirred for 1 h under
a nitrogen
atmosphere. To this mixture was slowly added a solution of
allyl bromide (8 mL) in dry acetonitrile (15 mL). The reaction
mixture was stirred at room temperature for 24 h and filtered,
and the yellow filtrate was evaporated to dryness. The residue
was purified on a flash silica gel column using CH2Cl2/CH3OH
(95/5) as the eluant to yield the title compound as a yellow
amorphous solid, whose NMR spectra was identical to previ-
ously reported data.19 Yield: 700 mg (56%).
N-9-Allyl-2-(N-ben zoyla m in o)-6-ch lor op u r in e (22). To
a cold (0 °C) solution of coumpound 21 (1.2 g, 0.0057 mol) in
dry pyridine (15 mL) was slowly added benzoyl chloride (1 mL).
The resulting mixture was stirred 1 h at 0 °C and washed with
a saturated solution of NaHCO3 (10 mL) followed by 10 mL of
water. The organic layer was extracted with methylene
chloride, washed with a saturated solution of NaHCO3, dried
(MgSO4), and filtered, and the filtrate was concentrated under
reduced pressure. The resulting residue was purified on a
flash silica gel column using CH2Cl2/CH3OH (98/2) as the
eluant to yield the title compound: yield 520 mg (29%); 1H
NMR (CDCl3) δ 4.68 (d, 2H, J ) 6.7 Hz), 5.09-6.00 (m, 2H),
5.78-5.97 (m, 1H), 7.20-7.45 (m, 3H), 7.85-7.93 (m, 2H), 8.00
(s, 1H), 9.40 (s, 1H); 13C NMR (CDCl3) δ 46.07, 119.95, 127.57,
128.02, 128.52, 130.90, 132.32, 133.74, 144.76, 150.54, 152.06
152.38, 165.05.
(Ch lor om et h yl)d im et h yl[3-[N-1-(2,4-d ioxop yr im id in -
yl)]p r op yl]sila n e (17b). Allyluracil 16 (3 g, 0.0197 mol) was
protected as described for compound 17a using HMDS (30 mL),
trimethychlorolsilane (0.5 mL), and ammonium sulfate. THF
(40 mL), (chloromethyl)dimethylsilane (1b) (2.3 g, 0.0213 mol),
and hexachloroplatinic acid were then added according to the
general procedure for hydrosilylation to give 17b: yield 2 g
(40%); 1H NMR (CDCl3) δ 0.11 (s, 6H), 0.57-0.66 (m, 2H),
1.65-1.77 (m, 2H), 2.75 (s, 2H), 3.65-3.73 (t, 2H), 5.66 (d, 1H,
J ) 7.8 Hz), 7.12 (d, 1H, J ) 7.8 Hz), 9.29 (s, 1H); 13C NMR
(MeOD) δ -3.89, 12.02, 25.05, 31.30, 53.31, 102.94, 148.30,
153.70, 167.68; IR (film) 3052.9, 2358.98, 1681.9, 1455.8,
1258.6, 816.7 cm-1
.
Gen er a l P r oced u r e for Hyd r osilyla tion . To a stirred
solution of the protected allylnucleobase in anhydrous THF
Bis(ch lor om eth yl)m eth yl[3-[N-1-(2,4-dioxo-5-m eth ylpy-
r im id in yl)]p r op yl]sila n e (4a ). Allylthymine 2 (1g, 0.006
mol) was protected as described for compound 17a using
HMDS (10 mL), trimethychlorolsilane (1 mL), and ammonium
sulfate. Then, THF (10 mL), bis(chloromethyl)methylsilane
(1a ) (1.14 g, 0.008 mol), and hexachloroplatinic acid were
added according to the general procedure for hydrosilylation.
Compound 4a was isolated as a white amorphous solid: yield
650 mg (35%); mp 156 °C; 1H NMR (CDCl3) δ 0.24 (s, 3H),
0.73-0.80 (m, 2H), 1.58-1.79 (m, 2H), 1.91 (d, 3H, J ) 1 Hz),
2.91 (s, 4H), 3.67 (t, 2H), 6.97 (d, 1H, J ) 1 Hz), 8.36 (large s);
13C NMR (CDCl3) δ 7.90, 12.30, 22.94, 26.85, 51.00, 110.71,
140.25, 150.95, 164.38.
heated to reflux was added 1a or 1b under
a nitrogen
atmosphere, followed by 0.1 mL of a 0.1 M solution of H2PtCl6
in propan-2-ol or a few milligrams of (Bu4N)2PtCl6. The
progress of the reaction was monitored by TLC (CH2Cl2/MeOH,
95:5).
After concentration under reduced pressure, the residue was
hydrolyzed, the product was extracted with methylene chlo-
ride, and the combined extracts were dried with sodium
sulfate. The crude product was chromatographed on a silica
gel column using ethyl acetate as eluting solvent or a stepwise
gradient of methanol-methylene chloride (0:100-5:95).
Bis(ch lor om e t h yl)m e t h yl[3-[N-9-(6-(N,N-d ib e n zoyl-
a m in o)p u r in yl)]p r op yl]sila n e (9a ). Following the general
procedure for hydrosilylation, a mixture of 8 (0.5 g, 0.00013
mol) in THF (15 mL, 0.184 mol) and an excess of 1a (1 g, 0.0069
mol) was reacted with hexachloroplatinic acid at 60 °C for 2
h: yield 0.400 g (58%); 1H NMR (CDCl3) δ 0.22 (s, 3H), 0.74-
0.83 (m, 2H), 1.96-2.04 (m, 2H), 2.88 (s, 4H), 4.25 (t, 2H),
(Ch lor om eth yl)d im eth yl[3-[N-1-(2,4-d ioxo-5-m eth ylp y-
r im id in yl)]p r op yl]sila n e (4b). Allylthymine 2 (1g, 0.006
mol) was treated as described for compound 4a , using (chlo-
romethyl)dimethylsilane (1b) (0.65 g, 0.006 mol) according to
the general procedure for hydrosilylation. Compound 4b was
isolated as a white amorphous solid: yield 340 mg (20%); mp
1
147 °C; H NMR (CDCl3) δ 0.12 (s, 6H), 0.57-0.66 (m, 2H),
1.60-1.77 (m, 2H), 1.91 (s, 3H), 2.77 (s, 2H), 3.66 (t, 2H, J )
(19) Gundersen, L. L.; Benneche, T.; Rise, F.; Gogoll, A.; Undheim,
K. Acta Chem. Scand. 1992, 46, 761.
7.3 Hz), 6.96 (s, 1H).

4640 J . Org. Chem., Vol. 62, No. 14, 1997
Thibon et al.
Bis(ch lor om eth yl)m eth yl[3-[N-9-(2-(N-ben zoyla m in o)-
6-ch lor op u r in yl)]p r op yl]sila n e (23a ). A stirred solution of
compound 22 (520 mg, 0.00165 mol) in dry THF (25 mL) and
bis(chloromethyl)methylsilane (1a ) (286 mg, 0.002 mol) was
heated at 65 °C under a nitrogen atmosphere. A catalytic
amount of tetrabutylammonium hexachloroplatinate was added,
and the mixture was kept at 60-70 °C for 24 h. After
concentration under reduced pressure, the residue was purified
on a flash silica gel column using CH2Cl2/CH3OH (96/4) as the
eluant to give the title compound as a pale yellow oil: yield
410 mg (54%); 1H NMR (CDCl3) δ 0.12 (s, 3H), 0.62-0.71 (m,
2H), 1.85-2.05 (m, 2H), 2.80 (s, 4H), 4.14 (t, 2H, J ) 6.8 Hz),
7.32-7.45 (m, 3H), 7.87-7.91 (m, 2H), 8.00 (s, 1H), 9.14 (s,
1H); 13C NMR (CDCl3) δ -7.31, 8.23, 23.64, 27.00, 47.01,
127.72, 128.42, 128.84, 132.57, 134.06, 145,09, 150,79,152.13,
152.83, 164.98.
Gen er a l P r oced u r e for Acetoxyla tion . A mixture of the
chloro derivative, freshly dried sodium acetate, and dry DMF
was stirred at 100-140 °C for 24 h under an inert atmosphere.
The solvent was removed by distillation, the residue was
washed with water, and the product was extracted with
dichloromethane. The combined extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure. Flash
chromatography afforded the pure acetoxy compounds.
Bis(a cet oxym et h yl)m et h yl[3-[N-1-(2,4-d ioxo-5-m et h -
ylp yr im id in yl)]p r op yl]sila n e (5a ). Compound 4a (1 g,
0.0032 mol) was treated according to the general procedure
with sodium acetate (1.05 g, 0.0128 mol) and DMF (25 mL).
Flash chromatography using ethyl acetate-toluene (9:1) gave
the title compound which slowly crystallized as white needles
in cold (4 °C) diethyl ether: yield 820 mg (72%); mp 72 °C; 1H
NMR (CDCl3) δ 0.11 (s, 3H), 0.60-0.69 (m, 2H), 1.62-1.74 (m,
2H), 1.89 (d, 3H, J ) 0.8 Hz), 2.01 (s, 6H), 3.64 (t, 2H, J ) 7.3
Hz), 3.83 (s, 4H), 6.96 (d, 1H), 9.27 (large s, 1H); 13C NMR
(CDCl3) δ -8.07, 7.73, 11.88, 20.21, 22.55, 50.51, 53.84, 109.95,
140.15, 150.81, 164.37, 171.07.
2H), 3.85 (s, 4H), 5.66 (d, 1H, J ) 7.8 Hz), 7.12 (d, 1H, J ) 7.8
Hz), 9.36 (s, 1H); 13C NMR (CDCl3) δ -7.73, 8.18, 20.61, 22.95,
51.33, 54.18, 102.08, 144.35, 150.77, 163.75, 171.57; IR
(KBr): 3188.1, 3054.2, 2955.5, 2251.7, 1674.5, 1456.4, 1368.5,
1219.0, 1030.4, 915.3, 806.1, 725.9 cm-1
.
(Acet oxym et h yl)d im et h yl[3-[N-1-(2,4-d ioxop yr im id i-
n yl)]p r op yl]sila n e (18b). Compound 17b (0.9 g, 0.0035 mol)
treated according to the general procedure with sodium acetate
(0.640 g, 0.0078 mol) in DMF (20 mL) was purified by column
chromatography using ethyl acetate to give the title com-
1
pound: yield 0.630 g (64%); H NMR (CDCl3) δ 0.07 (s, 6H),
0.41-0.50 (m, 2H), 1.54-1.62 (m, 2H), 1.92 (s, 3H), 3.56-3.65
(m, 4H), 5.56 (d, 1H, J ) 7.8 Hz), 7.10 (d, 1H, J ) 7.8 Hz),
10.32 (s, 1H); 13C NMR (CDCl3) δ -5.00, 10.43, 20.61, 23.16,
51.36, 56.30, 101.84, 144.65, 151.08, 164.39, 171.63.
Bis(acetoxym eth yl)[3-[N-9-(2-(N-ben zoylam in o)-6-ch lo-
r op u r in yl)]p r op yl]sila n e (24a ). To a stirred solution of
compound 23a (410 mg, 0.0009 mol) in dry DMF (20 mL) was
added freshly dried sodium acetate (0.3 g, 0.0036 mol). The
mixture was heated at 120 °C for 21 h under a nitrogen
atmosphere and filtered, and the filtrate was evaporated in
vacuo to yield an oil purified on a flash silica gel column using
CH2Cl2/CH3OH (95/5) as the eluant to give the title compound
as a viscous yellow oil: yield 300 mg (60%); 1H NMR (CDCl3)
δ -0.09 (s, 3H), 0.42-0.50 (m, 2H), 1.60-1.71 (m, 2H), 1.78
(s, 6H), 3.66 (s, 4H), 3.82 (t, 2H, J ) 7 Hz), 7.20-7.39 (m, 3H),
7.48 (s, 1H), 7.82-7.86 (m, 2H); 13C NMR (CDCl3) δ -8.13,
7.47, 20.12, 23.33, 45.80, 53.71, 120.29, 127.61, 128.12, 131.24,
132.78, 138.76, 147.40, 148.03, 155.16, 168.23, 171.29.
Bis(acetoxym eth yl)m eth yl[3-[N-1-(2-oxo-4-(3-n itr o-1,2,4-
tr ia zolo)p yr im id in yl)]p r op yl]sila n e (19a ). Compound 18a
(2 g, 0.0058 mol) was coevaporated twice with 20 mL of dry
pyridine and then stirred under a nitrogen atmosphere with
1-(2-mesitylenesulfonyl)-3-nitro-1,2,4-triazole (MSNT, 2.4 g,
0.008 mol) and a solution of diphenyl phosphate (0.4 g, 0.0016
mol) in pyridine (20 mL) for 72 h at room temperature. Water
(20 mL) was added, and the solvent evaporated under reduced
pressure; the residue was coevaporated twice with toluene (40
mL) and purified on a silica gel column using a stepwise
gradient of methanol-dichloromethane (0:100-5:95): yield 2.3
g (92%);
(Acetoxym eth yl)dim eth yl[3-[N-1-(2,4-dioxo-5-m eth ylpy-
r im id in yl)]p r op yl]sila n e (5b). Compound 4b (340 mg,
0.00123 mol) was treated according to the general procedure
with sodium acetate (201 mg, 0.0024 mol) and DMF (20 mL).
Flash chromatography using dichloromethane-methanol (98:
2) gave the title compound as a light yellow solid: yield 200
1H NMR (DMSO-d6) δ 0.07 (s, 3H), 0.60-0.68 (m, 2H),
1.75 (m, 2H), 1.98 (s, 6H), 3.81 (s, 4H), 3.88-3.95 (t, 2H), 6.97
1
mg (54%); mp 99 °C; H NMR (CDCl3) δ 0.04 (s, 6H), 0.50-
(d, 1H, J ) 7.8 Hz), 8.55 (d, 1H, J ) 7.8 Hz), 9.71 (s, 1H); 13
C
0.58 (m, 2H), 1.57-1.73 (m, 2H), 1.89 (d, 3H, J ) 1.3 Hz), 2.01
(s, 3H), 3.64 (t, 2H), 3.74 (s, 2H), 6.96 (d, 1H), 9.34 (large s,
1H); 13C NMR (CDCl3) δ -4.92, 10.56, 12.27, 20.72, 23.31,
51.22, 56.36, 110.48, 140.39, 150.87, 164.36, 171.76.
NMR (DMSO-d6) δ -7.57, 7.68, 20.44, 22.08, 53.28, 54.19,
93.33, 145.90, 153.88, 154.57, 157.88, 163.09, 170.98; IR:
2358.9, 2340.7, 1732.6, 1682.5, 1558.3, 1300.7, 820.4, 794.6
cm-1
.
Another run starting from 3, conducted without isolation
of 4b, gave better results (22% overall yield from 3).
(Acetoxym eth yl)dim eth yl[3-[N-1-(2-oxo-4-(3-n itr o-1,2,4-
tr ia zolo)p yr im id in yl)]p r op yl]sila n e (19b). Compound 18b
(0.650 g, 0.0021 mol), treated like 18a with MSNT (1 g, 0.0033
mol) and diphenyl phosphate (0.1 g, 0.0004 mol) in pyridine
(5 mL) for 24 h at room temperature, afforded the title
compound: yield 0.450 g (52%); 1H NMR (CDCl3) δ 0.02 (s,
6H), 0.52-0.61 (m, 2H), 1.81 (m, 2H), 1.97 (s, 3H), 3.71 (s, 2H),
3.91-3.98 (t, 2H), 7.00 (d, 1H, J ) 7.8 Hz), 7.98 (d, 1H, J ) 7.8
Hz), 9.26 (s, 1H); 13C NMR (CDCl3) δ -4.97, 10.73, 20.67, 23.07,
54.88, 56.30, 93.80, 144.38, 152.23, 154.14, 158.11, 163.48,
171.63.
Bis(a cetoxym eth yl)m eth yl[3-[N-9-(6-ch lor op u r in yl)]-
p r op yl]sila n e (14a ). Following the general procedure for
acetoxylation, compound 13b (2.5 g, 0.0074 mol) was stirred
overnight at 70 °C with sodium acetate (2 g, 0.024 mol) in DMF
1
(50 mL) to provide the title compound: yield 2.2 g (77%); H
NMR (CDCl3) δ 0.09 (s, 3H), 0.62-0.71 (m, 2H), 1.97 (m, 8H),
3.81 (s, 4H), 4.23 (t, 2H), 8.12 (s, 1H), 8.72 (s, 1H); 13C NMR
(CDCl3) δ -7.45, 8.48, 20.53, 23.85, 47.09, 54.08, 131.65,
145.37, 151.00, 151.74, 171.2.
Bis(a cet oxym et h yl)m et h yl[3-[N-9-(6-(N,N-d ib en zoy-
la m in o)p u r in yl)]p r op yl]sila n e (10a ). Compound 9a (0.900
g, 0.0017 mol) treated according to the general procedure with
sodium acetate (0.600 g, 0.0072 mol) in DMF (20 mL) was
purified by column chromatography using ethyl acetate to give
Gen er a l P r oced u r e for Hyd r oxyla tion . A stirred solu-
tion of the acetoxylated compound in anhydrous methanol was
reacted with dry potassium carbonate under an inert atmo-
sphere at room temperature. After completion of the reaction
(monitored by TLC), a 1 N HCl solution was added. The
resulting neutral solution was concentrated under reduced
pressure, and the residue was taken up in dichloromethane,
dried (MgSO4), and filtered. The filtrate was evaporated to
an oil applied to a silica gel column eluted with dichlo-
romethane-methanol (9:1) to afford the pure hydroxylated
compounds.
1
the title compound: yield 0.510 g (57%); H NMR (CDCl3) δ
0.09 (s, 3H), 0.62-0.71 (m, 2H), 1.97 (m, 8H), 3.81 (s, 4H), 4.09
(t, 2H), 7.29-7.35 (m, 6H), 7.79-7.83 (m, 4H), 8.03 (s, 1H),
8.61 (s, 1H); 13C NMR (CDCl3) δ -7.70, 8.67, 20.60, 23.98,
46.90, 54.15, 126.91, 128.22, 129.34, 132.86, 134.04, 144.86,
151.59, 151.96, 153.17, 171.48, 172.24.
Bis(a cetoxym eth yl)m eth yl[3-[N-1-(2,4-d ioxop yr im id i-
n yl)]p r op yl]sila n e (18a ). Compound 17a (2.8 g, 0.0095 mol)
treated according to the general procedure with sodium acetate
(3 g, 0.037 mol) in DMF (90 mL) was purified by column
chromatography using ethyl acetate to give the title com-
pound: yield 2 g (62%); 1H NMR (CDCl3) δ 0.09 (s, 3H), 0.60-
0.69 (m, 2H), 1.69-1.76 (m, 2H), 2.00 (s, 6H), 3.64-3.72 (t,
Bis(h yd r oxym et h yl)m et h yl[3-[N-1-(2,4-d ioxo-5-m et h -
ylp yr im id in yl)]p r op yl]sila n e (6a ). Compound 5a (820 mg,
0.0023 mol) treated according to the general procedure with
potassium carbonate (636 mg, 0.0046 mol) in methanol (50 mL)
and 9.2 mL of 1 N HCl solution was purified by flash
chromatography to give an oil which slowly crystallized in
vacuo as a white amorphous solid: yield 476 mg (76%); mp

Synthesis of Si Analogues of Acyclonucleotides
J . Org. Chem., Vol. 62, No. 14, 1997 4641
1
116 °C; H NMR (CD3OD) δ 0.07 (s, 3H), 0.62-0.71 (m, 2H),
1.58-1.61 (m, 2H), 3.19 (s, 4H), 3.56 (t, 2H), 3.98 (s, 2H), 5.61
(d, 1H, J ) 7 Hz), 6.92 (s, 2H), 7.52 (d, 1H, J ) 7 Hz); 13C
NMR (DMSO-d6) δ -7.90, 7.53, 23.17, 50.25, 51.61, 92.93,
146.27, 155.57, 165.70; HRMS (FAB+) calcd 258.12739, found
258.1279.
1.66-1.82 (m, 2H), 1.85 (d, 3H, J ) 1 Hz), 3.43 (s, 4H), 3.69
(t, 2H, J ) 7.3 Hz), 7.42 (d, 1H); 13C NMR (CD3OD) δ -8.25,
8.34, 12.20, 24.17, 52.13, 52.50, 110.86, 143.22, 152.82, 166.76;
MS (FAB), m/ e (rel intensity) 273.1 (90, M + 1), 241.1 (100).
(H yd r oxym et h yl)d im et h yl[3-[N-1-(2,4-d ioxo-5-m et h -
ylp yr im id in yl)]p r op yl]sila n e (6b). Compound 5b (200 mg,
0.67 mmol) treated according to the general procedure with
potassium carbonate (92 mg, 0.67 mmol) in methanol (20 mL)
and 1.3 mL of a 1 N HCl solution was purified by flash
chromatography to give 6b as a white amorphous solid: yield
100 mg (60%); mp 138 °C; 1H NMR (CDCl3) δ 0.01 (s, 6H),
0.49-0.58 (m, 2H), 1.64-1.70 (m, 2H), 1.84 (d, 3H, J ) 1 Hz),
3.35 (s, 2H), 3.62 (t, 2H, J ) 7.4 Hz), 6.98 (d, 1H); 13C NMR
(CDCl3) δ -5.16, 10.35, 12.32, 23.54, 51.41, 54.89, 110.47,
140.55, 150.88, 164.19; MS (FAB), m/ e (rel intensity) 257.1
(100, M + 1), 225.1 (88).
(Hyd r oxym eth yl)d im eth yl[3-[N-1-(4-a m in o-2-oxop yr i-
m id in yl)]p r op yl]sila n e (20b). A solution of compound 19b
(0.400 g, 0.001 mol) in dioxane (2 mL) treated as described
for compound 19a with ammonium hydroxide (4 mL), metha-
nol (20 mL), and potassium carbonate (0.400 g, 0.0029 mol)
gave the crude product purified on a silica gel column using
methanol-dichloromethane-ethyl acetate (20:40:40): yield
100 mg (41%); 1H NMR (DMSO-d6) δ -0.05 (s, 6H), 0.39-0.47
(m, 2H), 1.50-1.59 (m, 2H), 3.11 (s, 2H), 3.56 (t, 2H), 3.98 (s,
1H), 5.59 (d, 1H, J ) 7 Hz), 6.94 (s, 2H), 7.52 (d, 1H, J ) 7
Hz); 13C NMR (DMSO-d6) δ -4.81, 10.10, 23.26, 51.61, 52.28,
92.90, 146.11, 155.79, 165.88; MS (FAB), m/ e (rel intensity)
241.1 (100, M + 1).
Bis(h yd r oxym eth yl)m eth yl[3-[N-9-(N-6-ben za m id op u -
r in yl)]p r op yl]sila n e (11a ). A solution of compound 10a
(0.400 g, 0.0007 mol) in ethanol (8 mL) was stirred for 1 h
with a 2 N NaOH solution (4 mL). The mixture was neutral-
ized with aqueous ammonium chloride and concentrated under
reduced pressure. The aqueous solution was extracted with
dichloromethane, and the combined extracts were dried (Na2-
SO4) and concentrated under reduced pressure. The residue
was purified on a silica gel column using a stepwise gradient
of methanol-methylene chloride (0:100-15:85): yield 0.150
Bis(h ydr oxym eth yl)m eth yl[3-[N-9-(2-(N-ben zoylam in o)-
6-oxop u r in yl)]p r op yl]sila n e (25a ). A mixture of 24a (300
mg, 0.0006 mol), in hydrochloric acid (1 N, 10 mL), was heated
under refux for 1 h. The cooled solution was neutralized by
addition of aqueous NaOH (1 N) and evaporated in vacuo to
dryness. The crude product was taken up in isopropyl alcohol
and filtered, and the filtrate was evaporated in vacuo to an
oil purified on a silica gel column using CH2Cl2/CH3OH (90/
10) as the eluant to give the title compound as a white solid:
1
1
g (56%); H NMR (CDCl3) δ 0.05 (s, 3H), 0.64-0.72 (m, 2H),
yield 110 mg (45%); H NMR (CD3OD) δ -0.02 (s, 3H), 0.53-
2.01 (m, 2H), 2.74 (s, 2H), 3.53 (s, 4H), 4.25 (t, 2H), 7.46 (m,
3H), 8.00 (m, 3H), 8.73 (s, 1H); 13C NMR (CDCl3) δ -8.03, 8.12,
24.31, 46.81, 53.50, 122.76, 128.18, 129.79, 132.67, 133.52,
143.13, 149.50, 151.96, 152.26, 165.14.
0.81 (m, 2H), 1.77-1.92 (m, 2H), 3.34 (s, 4H), 4.00 (t, 2H, J )
7.0 Hz), 7.32-7.51 (m, 3H), 7.79-7.84 (m, 4H); 13C NMR (CD3-
OD) δ -8.15, 8.76, 25.47, 47.84, 52.51, 121.09, 129.22, 129.88,
133.28, 134.28, 141.53, 149.26, 150.32, 157.27, 170.73.
Bis(h ydr oxym eth yl)m eth yl[3-[1-(2-oxo-4-ben zam idopy-
r im id in yl)]p r op yl]sila n e (26a ). Compound 20a (0.700 g,
0.0027 mol) was coevaporated twice with 20 mL of dry pyridine
and dissolved in the same solvent (25 mL) under an inert
atmosphere. To this solution cooled in an ice bath was added
dropwise trimethylchlorosilane (2 g, 0.018 mol), and the
mixture was stirred for 1 h, followed by the carefull addition
of benzoyl chloride (3 g, 0.021 mol). The ice bath was removed,
and the mixture was stirred at room temperature overnight.
The medium was chilled again (ice bath), and cold water (10
mL) was added followed after 15 min by ammonium hydroxide
(10 mL). After 1 h, the solvent was removed under reduced
pressure, and the product was dissolved in isopropyl alcohol
and filtered. The filtrate was concentrated under reduced
presure and the crude product purified on a silica gel column
using a stepwise gradient of dichloromethane-methanol
(95:5-90:10): yield 0.450 g (45%); 1H NMR (CDCl3) δ 0.03 (s,
3H), 0.66-0.75 (m, 2H), 1.87 (m, 2H), 3.58 (s, 4H), 3.88 (t, 2H),
7.50 (m, 5H), 7.90 (m, 3H); 13C NMR (CDCl3) δ -7.96, 7.89,
23.14, 53.03, 53.76, 97.09, 127.92, 128.71, 132.86, 132.98,
149.36, 156.09, 162.79, 167.12.
Bis(h yd r oxym eth yl)m eth yl[3-[N-9-(6-a m in op u r in yl)]-
p r op yl]sila n e (15a ). Compound 14a (0.550 g, 0.0014 mol)
was dissolved in 20 mL of methanol and then chilled at -80
°C in a steel bomb, and liquid ammonia (10 g) was then added.
The mixture was stirred at 90 °C overnight. Solvent was
evaporated, and the residue was purified on a silica gel column
using a stepwise gradient of methanol-methylene chloride (5:
1
95-25:75, v/v): yield 0.330 g (76%); H NMR (D2O) δ -0.04
(s, 3H), 0.46-0.54 (m, 2H), 1.77 (m, 2H), 3.34 (s, 4H), 4.00 (t,
2H), 7.93 (s, 1H), 7.95 (s, 1H); 13C NMR (D2O) δ -6.86, 9.39,
26.13, 49.32, 53.74, 144.77, 151.00, 153.35, 153.65, 156.92; 13
C
NMR (DMSO-d6) δ -7.93, 7.74, 24.11, 45.91, 50.22, 118.71,
141.11, 149.48, 151.84, 155.55; IR 998.0, 1249.0, 1417.0,
1475.0, 1601.0, 1651.0, 2884.0, 3198.0, 3345.0 cm-1; HRMS
calcd 282.1386, found 282.1388.
(H yd r oxym et h yl)d im et h yl[3-[N-9-(6-a m in op u r in yl)]-
p r op yl]sila n e (15b). Following the general procedure for
acetoxylation, compound 13b (0.270 g, 0.00089 mol) was
stirred overnight at 100 °C with sodium acetate (0.320 g,
0.0039 mol) in DMF (20 mL). The solvent was evaporated
under reduced pressure and the residue dissolved in 30 mL of
methanol. The solution was chilled at -80 °C in a steel bomb,
and liquid ammonia (20 g) was then added. The mixture was
stirred at 90 °C overnight. The solvent was evaporated, and
the residue was purified on a silica gel column using a stepwise
gradient of methanol-methylene chloride (5:95-25:75, v/v):
yield 0.100 g (42%); 1H NMR (CDCl3) δ 0.04 (s, 6H), 0.55-
0.63 (m, 2H), 1.86-201 (m, 3H), 3.40 (s, 2H), 4.19 (t, 2H), 5.76
Gen er a l P r oced u r e for Mon otr ityla tion . The dihy-
droxylated derivatives were coevaporated twice with dry
pyridine and then dissolved in the same solvent. The solution
was stirred with 4,4′-dimethoxytrityl chloride at room tem-
perature for 4 h, the mixture was hydrolyzed with water (10
mL), the solvent was evaporated under reduced pressure, and
the monotritylated compounds were separated from the ditri-
tylated derivatives on a silica gel column.
(large exchanged with D2O, 2H), 7.79 (s, 1H), 8.34 (s, 1H); 13
C
NMR (CDCl3) δ -5.18, 10.56, 24.74, 46.69, 54.40, 140.41,
152.84, 155.33; MS (FAB), m/ e (rel intensity) 266.1 (100, M
+ 1); HRMS calcd 266.1437, found 266.1439.
(Hyd r oxym eth yl)(((4,4′-d im eth oxytr ityl)oxy)m eth yl)-
m eth yl[3-[N-1-(2,4-d ioxo-5-m eth ylp yr im id in yl)]p r op yl]-
sila n e (27a ). Compound 6a (0.500g, 0.0018 mol) treated
according to the general procedure with pyridine (15 mL) and
4,4′-dimethoxytrityl chloride (0.680 g, 0.002 mol) was hydro-
lyzed with water (10 mL). The crude product was chromato-
graphed on a silica gel column using ethyl acetate-triethy-
lamine (98:2) as eluant: yield 0.500 g (48%); 1H NMR (CDCl3)
δ 0.11 (s, 3H), 0.60-0.70 (m, 2H), 1.70 (m, 2H), 1.89 (s, 3H),
2.86 (s, 2H), 3.53 (s, 2H), 3.55-3.69 (m, 3H), 3.79 (s, 6H), 6.80
(m, 5H), 7.22 (m, 9H).
Bis(h yd r oxym eth yl)m eth yl[3-[N-1-(4-a m in o-2-oxop yr i-
m id in yl)]p r op yl]sila n e (20a ). A solution of compound 19a
(2.3 g, 0.0052 mol) in dioxane (20 mL) was stirred overnight
with ammonium hydroxide (40 mL) at room temperature. After
concentration under reduced pressure the resulting brown oil
was disolved in methanol (40 mL) and reacted with potassium
carbonate (1 g, 0.0072 mol) for 12 h at room temperature and
neutralized with a 1 N HCl solution, and the solvent was
evaporated under reduced pressure. The crude product was
(Hyd r oxym eth yl)(((4,4′-d im eth oxytr ityl)oxy)m eth yl)-
m eth yl[3-[N-9-(6-ben za m id op u r in yl)]p r op yl]sila n e (28a ).
Compound 11a (0.200 g, 0.00052 mol) treated according to the
general procedure with pyridine (5 mL) and 4,4′-dimethox-
purified on
a silica gel column using methanol-dichlo-
romethane-ethyl acetate (33:33:33) as eluant: yield 0.850 g
(63%); 1H NMR (DMSO-d6) δ -0.05 (s, 3H), 0.44-0.52 (m, 2H)

4642 J . Org. Chem., Vol. 62, No. 14, 1997
Thibon et al.
ytrityl chloride (0.110 g, 0.00032 mol) was hydrolyzed with
water (10 mL). The crude product was chromatographed on
a silica gel column using a stepwise gradient of dichlo-
romethane-triethylamine-methanol (98:2:0-93:2:5): yield
ethyl acetate (40 mL) were added before washing with
NaHCO3 (20 mL) and brine (10 mL). The title product was
purified on a silica gel column using ethyl acetate-dichlo-
romethane-triethylamine (45:45:10) as eluant: yield 0.110 g
(47%); 31P NMR (CDCl3) δ 151.41; 1H NMR (CDCl3) δ 0.13 (s,
3H), 0.66-0.74 (m, 2H), 0.95-1.15 (m, 12H), 1.93 (m, 2H), 2.51
(t, 2H), 2.75 (s, 2H), 3.20-3.52 (m, 4H), 3.75 (s, 8H), 4.20 (t,
2H), 6.75 (m, 4H), 7.20-7.35 (m, 9H), 7.49-7.65 (m, 3H), 7.93-
8.03 (m, 3H), 8.75 (s, 1H), 8.98 (s, 1H); 13C NMR (CDCl3) δ
-7.39, 8.73, 20.28, 20.40, 22.86, 24.55, 42.74, 42.99, 46.87,
51.78, 52.78, 55.12, 58.03, 58.39, 87.41, 112.84, 122.85, 126.55,
127.58, 127.79, 128.22, 128.76, 130.13, 132.61, 133.70, 135.83,
142.95, 144.71, 149,32, 151.96, 152.26, 158.26, 164.69; MS
(FAB), m/ e (rel intensity) 888.9 (40, M + 1), 448.3 (100).
Sila cytid in e An a logu e P h osp h or a m id ite (1-O-DMT-2-
m eth yl-2-[3-[N-1-(2-oxo-4-ben zam idopyr im idin yl)]pr opyl]-
2-sila p r op a n ol 3-O-(2-cya n oeth yl N,N-d iisop r op ylp h os-
p h or a m id ite) (33a ). Compound 29a (0.100 g, 0.00015 mol)
was treated according to the general procedure with dichlo-
romethane (1 mL), diisopropylethylamine (0.2 mL), and cya-
noethyl diisopropylchlorophosphoramidite (0.080 g, 0.00033
mol) dissolved in dichloromethane (0.25 mL). After 1 h of
stirring, methanol (0.006 mL) and triethylamine (2 mL) in
ethyl acetate (15 mL) were added before washing with
NaHCO3 (20 mL) and brine (10 mL). The title product was
purified on a silica gel column using ethyl acetate-dichlo-
romethane-triethylamine (45:45:10) as eluant: yield 0.090 g
(70%); 31P NMR (CDCl3) δ 151.38; 1H NMR (CDCl3) δ 0.14 (s,
3H), 0.64-0.74 (m, 2H), 0.95-1.16 (m, 12H), 1.67-1.82 (m,
2H), 2.54 (t, 2H), 2.76 (s, 2H), 3.20-3.55 (m, 4H), 3.76 (m,
10H), 6.77 (m, 4H), 7.22-7.40 (m, 11H), 7.49-7.65 (m, 3H),
7.86-7.89 (m, 2H); 13C NMR (CDCl3) δ -7.39, 8.40, 20.32,
23.26, 24.62, 42.75, 42.99, 51.85, 52.79, 53.46, 55.12, 58.12,
58.49, 87.44, 97.09, 112.88, 126.56, 127.43, 127.62, 128.22,
128.98, 130.16, 132.86, 133.07, 135.83, 144.75, 149.36, 158.27,
161.91, 156.09, 167.13; MS (FAB), m/ e (rel intensity) 862.4
(62, M + 1), 404.6 (100).
1
0.120 g (33%); H NMR (CDCl3) δ 0.08 (s, 3H), 0.64-0.73 (m,
2H), 1.93 (m, 2H), 2.81 (s, 2H), 3.52 (s, 2H), 3.75 (s, 6H), 4.21
(t, 2H), 6.75 (m, 4H), 7.20 (m, 10H), 7.49 (m, 3H), 8.00 (m,
3H), 8.75 (s, 1H).
(Hyd r oxym eth yl)(((4,4′-d im eth oxytr ityl)oxy)m eth yl)-
m eth yl[3-[N-1-(2-oxo-4-ben za m id op yr im id in yl)]p r op yl]-
sila n e (29a ). Compound 26a (0.360 g, 0.001 mol) treated
according to the general procedure with pyridine (10 mL) and
4,4′-dimethoxytrityl chloride (0.370 g, 0.0011 mol) at room
temperature for 4 h was hydrolyzed with water (10 mL). The
crude product was chromatographed on a silica gel column
using a stepwise gradient of dichloromethane-triethylamine-
methanol (98:2:0-93:2:5): yield 0.170 g (26%); 1H NMR
(CDCl3) δ 0.10 (s, 3H), 0.64-0.73 (m, 2H), 1.77 (m, 2H), 2.83
(s, 2H), 3.53 (s, 2H), 3.75 (s, 6H), 3.83 (t, 2H), 6.77 (m, 4H),
7.58 (m, 15H), 7.85 (m, 2H).
(Hyd r oxym eth yl)(((4,4′-d im eth oxytr ityl)oxy)m eth yl)-
m eth yl[3-[N-9-(2-(N-ben zoylam in o)-6-oxopu r in yl)]pr opyl]-
sila n e (30a ). Compound 25a (0.100 g, 0.00023 mol) treated
according to the general procedure with pyridine (5 mL) and
4,4′-dimethoxytrityl chloride (0.080g, 0.000236 mol) was hy-
drolyzed with water (5 mL). The crude product was chro-
matographed on a silica gel column using a stepwise gradient
of ethyl acetate-triethylamine-methanol (98:2:0-78:2:20):
1
yield 0.080 g (45%); H NMR (CD3OD) δ 0.06 (s, 3H), 0.65-
0.82 (m, 2H), 2.02 (m, 2H), 2.85 (s, 2H), 3.53 (s, 2H), 3.75 (s,
6H), 4.00-4.07 (t, 2H, J ) 6.8 Hz), 6.72-6.77 (m, 4H), 7.18-
7.61 (m, 19H).
Gen er a l P r oced u r e for th e Nu cleosid e An a logu es
Syn th esis. The monotritylated derivative was coevaporated
twice with dry pyridine, stored under vacuum overnight, and
then dissolved under a nitrogen atmosphere, in a solution of
freshly distilled dichloromethane and diisopropylethylamine.
Cyanoethyl diisopropylchlorophosphoramidite in dichlo-
romethane was added dropwise at room temperature to the
stirred solution. After 1 h, methanol was added to neutralize
the chlorophosphoramidite excess, followed by ethyl acetate
and triethylamine. The solution was washed with a 1 N
solution of sodium hydrogenocarbonate and brine and was
dried on sodium sulfate before concentration under reduced
pressure. The crude product was purified on a silica gel
column.
Sila th ym id in e An a logu e P h osp h or a m id ite (1-O-DMT-
2-m eth yl-2-[3-[N-1-(2,4-d ioxo-5-m eth ylp yr im id in yl)]p r o-
p yl]-2-sila p r op a n ol 3-O-(2-cya n oeth yl N,N-d iisop r op y-
lp h osp h or a m id ite)) (31a ). Compound 27a (0.500 g, 0.00087
mol) was treated according to the general procedure with
dichloromethane (4 mL), diisopropylethylamine (0.8 mL), and
cyanoethyl diisopropylchlorophosphoramidite (0.424 g, 0.0018
mol) dissolved in dichloromethane (1 mL). After 1 h of stirring,
methanol (0.030 mL) and triethylamine (2 mL) in ethyl acetate
(40 mL) were added before washing with NaHCO3 (20 mL)
and brine (20 mL). The title product was purified on a silica
gel column using ethyl acetate-hexane-triethylamine (68:30:
2) as eluant: yield 0.500 g (74%); 31P NMR (CDCl3) δ 151.38;
1H NMR (CDCl3) δ 0.14 (s, 3H), 0.64-0.72 (m, 2H), 0.95-1.15
(m, 12H), 1.67 (m, 2H), 1.85 (s, 3H), 2.53 (t, 2H), 2.75 (s, 2H),
3.22-3.67 (m, 9H), 3.77 (s, 6H), 6.77 (m, 5H), 7.20-7.35 (m,
9H); 13C NMR (CDCl3) δ -7.42, 8.37, 12.19, 20.29, 20.41, 23.41,
24.62, 42.75, 43.00, 51.15, 51.88, 52.85, 55.12, 58.06, 58.46,
87.41, 110.24, 112.88, 126.56, 127.62, 128.22, 130.16, 135.86,
140.53, 144.81, 150.63, 158.30, 164.12; MS (FAB), m/ e (rel
intensity) 774.1 (100, M - 1).
Sila gu a n osin e An a logu e P h osp h or a m id ite (1-O-DMT-
2-m et h yl-2-[3-[N-9-(2-(N-b en zoyla m in o)-6-oxop u r in yl)]-
p r op yl]-2-sila p r op a n ol 3-O-(2-cya n oeth yl N,N-d iisop r o-
p ylp h osp h or a m id ite)) (34a ). Compound 30a (0.080 g,
0.00011 mol) was treated according to the general procedure
with dichloromethane (0.5 mL), diisopropylethylamine (0.1
mL), and cyanoethyl diisopropylchlorophosphoramidite (0.047
g, 0.0002 mol) dissolved in dichloromethane (0.25 mL). After
1 h of stirring, methanol (0.010 mL) and triethylamine (1 mL)
in ethyl acetate (6 mL) were added before washing with
NaHCO3 (10 mL) and brine (10 mL). The title product was
purified on a silica gel column using ethyl acetate-triethy-
lamine-methanol (98:2:0-88:2:10) as eluant: yield 0.080 g
1
(77%); 31P NMR (CDCl3) δ 151.38; H NMR (CD3OD) δ 0.075
(s, 3H), 0.71-0.88 (m, 2H), 1.03-1.12 (m, 12H), 2.02 (m, 2H),
2.48-2.54 (m, 2H), 2.75 (s, 2H), 3.26-3.50 (m, 4H), 3.73 (s,
7H), 4.00-4.08 (t, 2H, J ) 6.8 Hz), 6.71-6.76 (m, 4H), 7.17-
7.70 (m, 19H); 13C NMR (CDCl3) δ -7.36, 8.97, 20.28, 20.40,
24.43, 24.58, 24.98, 42.71, 42.96, 47.08, 52.18, 52.57, 52.75,
55.12, 58.00, 58.33, 87.47, 112.84, 117.69, 126.67, 127.34,
127.61, 128.22, 128.73, 128.82, 130.16, 135.82, 131.31, 132.22,
133.28, 135.83, 144.92, 147.04, 148.20, 155.56, 158.32, 167.18,
167.63; MS (FAB), m/ e (rel intensity) 901.7 (100, M - 1), 903.4
(84.8), 903.0 (83.4), 903.9 (66).
Ack n ow led gm en t. Association pour la Recherche
sur le Cancer and Conseil Re´gional d’Aquitaine are
greatfully acknowledged for their financial support.
Sila a d en osin e An a logu e P h osp h or a m id ite (1-O-DMT-
2-m eth yl-2-[3-[N-9-(6-ben za m id op u r in yl)]p r op yl]-2-sila -
p r op a n ol 3-O-(2-cya n oeth yl N,N-d iisop r op ylp h osp h or -
a m id ite) (32a ). Compound 28a (0.180 g, 0.00026 mol) was
treated according to the general procedure with dichlo-
romethane (1 mL), diisopropylethylamine (0.2 mL), and cya-
noethyl diisopropylchlorophosphoramidite (0.100 g, 0.00042
mol) dissolved in dichloromethane (0.25 mL). After 1 h of
stirring, methanol (0.008 mL) and triethylamine (2 mL) in
Su p p or tin g In for m a tion Ava ila ble: NMR, IR MS, and
HRMS spectra (70 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O962165P