A versatile intermediate for the synthesis of 3′-substituted 2′,3′-didehydro-2′,3′-dideoxyadenosine (d4A): Preparation of 3′-C-stannyl-d4A via radical-mediated desulfonylative stannylation

Article abstract of DOI:10.1016/S0040-4020(02)00153-9

A method is described for the introduction of a tributylstannyl group to the 3′-position of 2′,3′-didehydro-2′,3′-dideoxyadenosine (2: d4A). Transalkoxylation of Bu₃SnOMe with d4A and subsequent anionic O→C stannyl migration gave 3′-C-tributyls

Full text of DOI:10.1016/S0040-4020(02)00153-9

TETRAHEDRON
Pergamon
Tetrahedron 58+2002) 2497±2503
A versatile intermediate for the synthesis of 30-substituted
20,30-didehydro-20,30-dideoxyadenosine ꢀd4A): preparation of
30-C-stannyl-d4A via radical-mediated desulfonylative stannylation
Sayoko Onuma, Hiroki Kumamoto, Misono Kawato and Hiromichi Tanakap
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Received 11 January 2002; accepted 8February 2002
AbstractÐA method is described for the introduction of a tributylstannyl group to the 30-position of 20,30-didehydro-20,30-dideoxyadeno-
sine +2: d4A). Transalkoxylation of Bu3SnOMe with d4A and subsequent anionic O!C stannyl migration gave 30-C-tributylstannyl-d4A +5),
but only in a low yield. An alternative route involves several reactions starting from 9-[2,3-anhydro-5-O-+tert-butyldimethylsilyl)-b-d-
ribofuranosyl]-N6-pivaloyladenine +14): ring opening with NaSPh, oxidation of the 30-C-phenylthio group, removal of the N6-pivaloyl group,
20-O-mesylation, elimination of methanesulfonic acid, and tin radical-mediated substitution of the 30-C-benzenesulfonyl group. The overall
yield of this approach was 55% from 14. The synthetic utility of 50-O-+tert-butyldimethylsilyl)-30-C-tributylstannyl-d4A +18) thus obtained
was brie¯y exempli®ed by the preparation of some 30-substituted analogues +19±23: I, Br, Ph, vinyl, and phenylethynyl). q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
20,30-Didehydro-20,30-dideoxynucleosides constitute an
important class of compounds for anti-HIV drug candi-
dates.1 Although approval of stavudine +20,30-didehydro-
30-deoxythymidine: d4T, 1)2 as a drug for the treatment of
AIDS has stimulated the synthesis3 and evaluation4±7 of this
class of nucleosides, there seems to be no general synthetic
method available to provide diversity at the 30- +or 20-)
substituent.
In this article, we describe a method for the introduction of a
tributylstannyl group to the 30-position of 20,30-didehydro-
20,30-dideoxyadenosine +d4A, 2) based on radical-mediated
desulfonylative stannylation. Also described here is further
manipulations of the introduced stannyl group, which
allows the preparation of various types of 30-substituted
d4A analogues.
1.1. Attempted anionic stannyl migration of d4A
Since the transformation of a trialkylstannyl group attached
to an sp2-carbon atom to halogen and a range of carbon-
substituents is well appreciated,8 construction of a vinyl-
stannane structure in d4A would be an ideal intermediate
for the present purpose. As a part of our lithiation studies of
Scheme 1.
Keywords: nucleosides; tin and compounds; radicals and radical reactions.
Corresponding author. Tel.: 181-3-3784-8186; fax: 181-3-3784-8252; e-mail: hirotnk@pharm.showa-u.ac.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+02)00153-9

2498
S. Onuma et al. / Tetrahedron 58 )2002) 2497±2503
Scheme 2.
nucleosides,9 we recently reported that reaction between
Bu3SnOMe and d4T +1) yielded the transalkoxylation
product 3, and that treatment of this compound with
LTMP +lithium 2,2,6,6-tetramethylpiperidide)-HMPA in
THF gave the 30-C-tributylstannyl-d4T +4), as a result of
lithiation-mediated stannyl migration from the 50-oxygen
to the 30-carbon +Scheme 1).10 We therefore initiated the
present study which examines a purine version of this
anionic migration.
which is assumed to have resulted from deprotonation of
H-40, was also detected. The depicted regiochemistry of 5
and 6 came from the 1H NMR observation of 3JSn,H-splitting
+28.0 Hz) in H-20 of 5 +d 5.91) and H-30 of 6 +d 6.40). The
observed low yield formation of the desired 5, which cannot
be separated from 6, led us to investigate an alternative
method.
1.2. Radical-mediated desulfonylative stannylation
Transalkoxylation between d4A +2) and Bu3SnOMe
+3 equiv.) was carried out neat at 908C for 2 h. The resulting
product showed ®ve 119Sn-resonances +d 27.2, 29,1, 86.3,
101.6, and 107.2) in its NMR spectrum measured in
benzene-d6. The two resonances, d 86.3 and 101.6, were
attributable to those of +Bu3Sn)2O11 and Bu3SnOMe, respec-
tively. Among the remaining three 119Sn-resonances, one at
the lowest ®eld +d 107.2) was assigned to a tin atom
attached to the 50-oxygen by comparison with our previous
data of 3.10 Unfortunately, this compound was not pure
enough to con®rm the presence of a 50-O-Sn bond based
Literature survey as well as our own report suggested that
tin radical-mediated substitution of vinyl selenides,12
sul®des,13 and sulfones14 would be an appropriate approach
to prepare the 30-C-stannylated d4A, although the detailed
mechanism of these reactions is not clear at the present
time. Since 20,30-anhydroribonucleosides are known to
undergo nucleophilic ring-opening regioselectively at the
30-position,15 one would readily propose a synthetic plan
shown in Scheme 3.
We ®rst attempted to construct a vinyl selenide structure
+Scheme 4). Silylation of 9-+2,3-anhydro-b-d-ribofuranosyl)-
adenine +7)16 by a conventional method gave 8 in 88% yield.
Nucleophilic opening of the oxirane ring of 8 with a sele-
nide anion was carried out by using +PhSe)2/LiAlH4 which
has been successfully employed for ring cleavage of various
types of anhydro-uracilnucleosides.17 The reaction pro-
ceeded with complete regioselectivity, forming the
30-phenylselenenyl derivative 9 in 87% yield. When 9 was
3
1
on JSn,H-splitting of H-50 by H NMR spectroscopy.
When the above stannylated d4A derivative was treated
with LTMP +7.5 equiv.) in the presence of HMPA
+15 equiv.) in THF at 2788C, an inseparable mixture of
the 30- and 20-stannylated products +5/6ˆ1/0.3) was
obtained in only 20% yield with a large amount of d4A
+2) being recovered +Scheme 2). Formation of adenine,
Scheme 3.
Scheme 4.

S. Onuma et al. / Tetrahedron 58 )2002) 2497±2503
2499
Scheme 5.
reacted with MsCl in pyridine +08C, overnight), however,
reductive elimination took place to give 10 in 72% yield.18
Although the expected mesylate was formed upon con-
ducting the reaction at 08C in CH3CN containing iPr2NEt
and DMAP, it was further converted to 10 during column
chromatography. Simple extractive workup followed by
treatment with KOBu-t/DMF also resulted in the sole
formation of 10. Although these results are in contrast to a
transformation of 1-+2,3-anhydro-b-d-lyxofuranosyl)uracil
to a vinyl selenide,19 we turned our attention to prepare
the vinyl sul®de and vinyl sulfone derivatives of d4A
+Scheme 5).
b-hydroxysulfone 16 +100%). Removal of the N6-pivaloyl
group in 16 and subsequent mesylation by a conventional
method +MsCl/DMAP/pyridine) directly furnished the vinyl
sulfone 17 +81% for two steps).20
Radical-mediated desulfonylative stannylation of 17
proceeded ef®ciently by reacting with Bu3SnH +3 equiv.)/
AIBN in re¯uxing benzene for 5.5 h. Quite unexpectedly,
however, elution of the reaction mixture from silica gel
column gave only a trace amount of the desired product
+18). After several attempts to overcome this problem, we
found that the presence of Et3N +4 equiv.) in the reaction
medium enabled column chromatographic isolation of 18
in 76% yield, together with recovered 17 +17%). No appre-
ciable amount of the reduced product +10) was formed in
this reaction. ipso-Substitution with the tin radical was
con®rmed by HMBC +heteronuclear multiple bond connec-
tivity) experiment of 18 in CDCl3: the 30-quaternary carbon
+d 149.6) showed correlation to H-10 as well as to H-50.
Introduction of a phenylthio group into the 30-position of 8
was carried out simply by reacting with NaSPh to give 11 in
quantitative yield. Mesylation of 11 gave 12 +98%). The
vinyl sul®de 13 was prepared in 78% yield by reacting 12
with DBN in re¯uxing CH3CN. Compound 13 was,
however, recovered unchanged +88%) upon treatment with
Bu3SnH/AIBN in re¯uxing benzene for 8h. Similar reaction
in re¯uxing toluene also met with recovery of 13. This
failure combined with successful precedents13 led us to
assume that, for reaction of tin-radical, conjugation of the
20,30-double bond with a carbonyl or sulfonyl group would
be necessary, although this may not be the case for the
reported similar reaction of vinyl selenides.12
Finally, transformation of the 30-C-stannyl derivative +18)
was brie¯y examined. Iodination of 18 with iodine in THF
gave 19 only in 42%, presumably due to depurination.
Simple replacement of iodine with NIS increased the yield
of 19 to 70%. Bromination was carried out in a similar
manner by using NBS to give 20 in quantitative yield.
The 30-C-phenyl derivative 21 +66%) was prepared by the
Stille reaction21 between 18 and iodobenzene in DMF. As an
example of reversed version of the Stille reaction, 19 was
reacted with tributylvinyltin to give the 30-C-vinyl deriva-
tive +22) in 51% yield. Cross-coupling reaction of 19 with a
terminal alkyne22 gave 23 in 89% yield.
Since attempted chemoselective oxidation of 13 resulted in
concurrent N-oxidation of the adenine moiety, construction
of a vinyl sulfone structure was started with N6-pivaloyl-
ation of 8 +yield of 14: 97%). Ring opening of 14 +yield of
15: 90%) was followed by m-CPBA oxidation to give the

2500
S. Onuma et al. / Tetrahedron 58 )2002) 2497±2503
0
0
10.8Hz, H-5 ), 3.83 +1H, dd, Jˆ6.0 and 10.8Hz, H-5 ),
0
4.09 +1H, d, Jˆ2.8Hz, H-2 ), 4.37 +1H, dd, Jˆ4.8and
6.0 Hz, H-40), 4.40 +1H, d, Jˆ2.8Hz, H-3 ), 5.69 +2H, br,
0
NH2), 6.22 +1H, s, H-10), 8.08 and 8.35 +2H, each as s, H-2
and H-8); FAB-MS m/z 364 +M11H). Anal. calcd for
C16H25N5O3Si: C, 52.87; H, 6.93; N, 19.27. Found: C,
52.62; H, 6.64; N, 19.44.
3.1.2. 9-[5-O-ꢀtert-Butyldimethylsilyl)-3-deoxy-3-C-phenyl-
selenenyl-b-d-xylofuranosyl]adenine ꢀ9). To a solution of
+PhSe)2 +1.20 g, 3.84 mmol) in dioxane +10 mL) was added
LiAlH4 +109 mg, 2.88 mmol) under positive pressure of dry
Ar, and the mixture was stirred for 0.5 h. To this was added
a dioxane +10 mL) solution of 8 +583 mg, 1.60 mmol). The
reaction mixture was stirred for 20 min at room temperature
and then was re¯uxed for 4 h. After being quenched with
AcOH, the reaction mixture was evaporated. Column
chromatography +CHCl3/MeOHˆ20/1) of the residue gave
9 +721 mg, 87%) as a foam: UV +MeOH) lmax 261 nm +1
17,700), lmin 230 nm +1 5900); 1H NMR +CDCl3) d 20.11
and 20.10 +6H, each as s, SiMe), 0.69 +9H, s, SiBu-t), 3.90±
3.96 +2H, m, H-50 and H-30), 4.06 +1H, dd, Jˆ2.0 and
11.6 Hz, H-50), 4.67±4.70 +1H, m, H-40), 4.82 +1H, dd,
Jˆ5.6 and 10.0 Hz, H-20), 5.76 +1H, d, Jˆ5.6 Hz, H-10),
6.13 +2H, br, NH2), 7.28±7.30 +3H, m, Ph), 7.67±7.71
+2H, m, Ph), 8.07 and 8.77 +2H, each as s, H-2 and H-8);
FAB-MS m/z: 520 for 78Se and 522 for 80Se +M11H). Anal.
calcd for C22H31N5O3SeSi: C, 50.76; H, 6.00; N, 13.45.
Found: C, 50.80; H, 6.07; N, 13.33.
2. Conclusions
Synthesis of 50-O-+tert-butyldimethylsilyl)-30-C-+tributyl-
stannyl)-20,30-didehydro-20,30-dideoxyadenosine +18) was
accomplished in 55% overall yield by a sequence of reac-
tions starting from 9-[2,3-anhydro-5-O-+tert-butyldimethyl-
silyl)-b-d-ribofuranosyl]adenine +14). The ®nal and key
step, radical-mediated displacement with tributylstannyl
group did not work with vinyl sul®de, and it seems crucial
to activate the 20,30-double bond by conjugation with the
30-C-benzenesulfonyl group. Compound 18 can be readily
converted to the 30-iodo derivative 19. The synthetic utility
of these compounds +18 and 19) was brie¯y exempli®ed by
the preparation of the 30-carbon-substituted d4T analogues
21±23.
3. Experimental
Melting points are uncorrected. NMR was measured at
400 MHz. Chemical shifts are reported relative to Me4Si,
except the cases of 119Sn NMR where Me4Sn was used as an
internal standard. Mass spectra +MS) were taken in FAB
mode with m-nitrobenzyl alcohol as a matrix. Column
chromatography was carried out on silica gel +Silica Gel
60, Merck). Thin layer chromatography +TLC) was per-
formed on silica gel +precoated silica gel plate F254, Merck).
3.1.3. 50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-20,30-
dideoxyadenosine ꢀ10). This compound was obtained as a
foam: UV +MeOH) lmax 260 nm +1 14,300), lmin 226 nm +1
1
900); H NMR +CDCl3) d 0.05 +6H, s, SiMe), 0.89 +9H, s,
SiBu-t), 3.79±3.87 +2H, m, H-50), 4.97±5.00 +1H, m, H-40),
5.07 +2H, br, NH2), 6.04±6.06 +1H, m, H-20), 6.39±6.41
+1H, m, H-30), 7.10±7.11 +1H, m, H-10), 8.10 and 8.37
+2H, each as s, H-2 and H-8); FAB-MS m/z: 348+M 11
H). Anal. calcd for C16H25N5O2Si: C, 55.30; H, 7.25; N,
20.25. Found: C, 55.16; H, 7.26; N, 20.00.
3.1. Anionic stannyl migration of d4A
A mixture of 2 +300 mg, 1.28mmol) and Bu 3SnOMe
+1.1 mL, 3.85 mmol) was heated at 908C for 2 h with
stirring. The mixture was dried under reduced pressure
and then dissolved in THF +8mL). The resulting solution
was added to a mixture of LTMP +9.65 mmol) and HMPA
+3.35 mL, 19.3 mmol) in THF +15 mL) at 2788C, under
positive pressure of dry Ar. After 20 min, the reaction
mixture was treated with saturated aqueous NH4Cl, and
extracted with EtOAc. The extract was puri®ed twice by
column chromatography +hexane/EtOAcˆ1/5) to give a
mixture of 5 and 6 +132 mg, 20%, 5/6ˆ1/0.3 calculated
by integrating H-20 of 5 and H-30 of 6).
3.1.4.
9-[5-O-ꢀtert-Butyldimethylsilyl)-3-deoxy-3-C-
phenylthio-b-d-xylofuranosyl]adenine ꢀ11). A mixture
of PhSH +5.5 mL, 53.5 mmol) and NaOMe +2.0 g,
38.3 mmol) in MeOH +50 mL) was stirred for 20 min at
room temperature. To this was added
8 +2.78g,
7.65 mmol). The reaction mixture was re¯uxed for 6.5 h,
and then evaporated. Column chromatography +CHCl3/
MeOHˆ10/1) of the residue gave 11 +3.6 g, 100%) as a
foam: UV +MeOH) lmax 258nm + 1 21,400), lmin 231 nm
+1 4900); 1H NMR +CDCl3) d 20.85 and 0.00 +6H, each as
s, SiMe), 0.70 +9H, s, SiBu-t), 3.90 +1H, dd, Jˆ2.4 and
11.6 Hz, H-50), 4.00±4.05 +2H, m, H-50 and H-30), 4.64±
4.67 +1H, m, H-40), 4.78+1H, dd, Jˆ5.6 and 9.6 Hz, H-20),
5.84 +1H, d, Jˆ5.6 Hz, H-10), 5.94 +2H, br, NH2), 7.22±7.33
+3H, m, Ph), 7.51±7.54 +2H, m, Ph), 8.10 and 8.28 +2H, each
as s, H-2 and H-8); FAB-MS m/z: 474 +M11H). Anal. calcd
for C22H31N5O3SSi: C, 55.79; H, 6.60; N, 14.79. Found: C,
55.90; H, 6.75; N, 14.61.
3.1.1. 9-[2,3-Anhydro-5-O-ꢀtert-butyldimethylsilyl)-b-d-
ribofuranosyl]adenine ꢀ8). A mixture of 7 +5.0 g, 20.06
mmol), tert-butyldimethylsilyl chloride +6.0 g, 40.12
mmol), and imidazole +4.1 g, 60.18mmol) in DMF
+40 mL) was stirred at 08C for 25 min. The reaction mixture
was partitioned between saturated aqueous NaHCO3 and
CHCl3. Column chromatography +CHCl3/MeOHˆ30/1) of
the organic layer gave 8 +6.4 g, 88%) as a solid: mp 166±
1748C; UV +MeOH) lmax 259 nm +1 14,300), lmin 226 nm
3.1.5.
9-[5-O-ꢀtert-Butyldimethylsilyl)-3-deoxy-2-O-
1
methanesulfonyl-3-C-phenylthio-b-d-xylofuranosyl]-
adenine ꢀ12). To a pyridine +13 mL) solution containing 11
+1 300); H NMR +CDCl3) d 0.02 and 0.04 +6H, each as s,
SiMe), 0.85 +9H, s, SiBu-t), 3.76 +1H, dd, Jˆ4.8and

S. Onuma et al. / Tetrahedron 58 )2002) 2497±2503
2501
0
+500 mg, 1.05 mmol) and DMAP +193 mg, 1.58mmol) was
added MsCl +325 mL, 4.2 mmol) at 08C. After stirring for
2 h at room temperature, the reaction mixture was par-
titioned between CHCl3 and saturated aqueous NaHCO3.
Column chromatography +CHCl3/MeOHˆ30/1) of the
organic layer gave 12 +569 mg, 98%) as a foam: UV
+MeOH) lmax 257 nm +1 20,900), lmin 230 nm +1 5300);
1H NMR +CDCl3) d 0.22 +6H, s, SiMe), 0.99 +9H, s, SiBu-t),
3.05 +3H, s, OMs), 4.07 +1H, dd, Jˆ3.2 and 11.6 Hz, H-50),
4.12±4.17 +2H, m, H-50and H-30), 4.66±4.70 +1H, m, H-40),
5.50 +1H, dd, Jˆ4.4 and 6.4 Hz, H-20), 6.27 +1H, d, Jˆ
4.4 Hz, H-10), 7.28±7.36 +5H, m, Ph), 8.31 and 8.41 +2H,
each as s, H-2 and H-8); FAB-MS m/z: 552 +M11H). Anal.
calcd for C23H33N5O5S2Si: C, 50.07; H, 6.03; N, 12.69.
Found: C, 50.31; H, 6.03; N, 12.46.
H-50 and H±30), 4.66±4.68+1H, m, H-4 ), 4.82 +1H, ddd,
Jˆ2.8, 5.2, and 9.5 Hz, H-20), 5.32 +1H, d, Jˆ2.8Hz,
D2O-exchangeable, OH), 5.89 +1H, d, Jˆ5.2 Hz, H-10),
7.23±7.33 +3H, m, Ph), 7.50±7.52 +2H, m, Ph), 8.25 and
8.71 +2H, each as s, H-2 and H-8), 8.54 +1H, br, NH); FAB-
MS m/z 558+M 11H). Anal. calcd for C27H39N5O4SSi: C,
58.14; H, 7.05; N, 12.56. Found: C, 57.92; H, 7.15; N, 12.37.
3.1.9. 9-[3-C-Benzenesulfonyl-5-O-ꢀtert-butyldimethyl-
silyl)-3-deoxy-b-d-xylofuranosyl]-N6-pivaloyladenine
ꢀ16). A mixture of 15 +2.3 g, 4.12 mmol) and m-CPBA
+.65%, 2.6 g, 9.06 mmol) in MeOH +30 mL) was stirred
at 08C for 2.5 h. After treatment with Et3N +1.26 mL,
9.06 mmol), the reaction mixture was evaporated and par-
titioned between saturated aqueous NaHCO3 and CHCl3.
Column chromatography +CHCl3/MeOHˆ30/1) of the
organic layer gave 16 +2.43 g, 100%) as a foam: UV
+MeOH) lmax 272 nm +1 16,100), lmin 233 nm +1 1400);
1H NMR +CDCl3) d 0.04 and 0.06 +6H, each as s, SiMe),
0.83 +9H, s, SiBu-t), 1.42 +9H, s, COBu-t), 4.09±4.12 +1H,
m, H-30), 4.29±4.30 +2H, m, H-50), 4.76±4.80 +1H, m,
3.1.6. 50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-20,30-
dideoxy-30-C-phenylthioadenosine ꢀ13). A mixture of 12
+544 mg, 0.98mmol) and DBN +363 mL, 2.94 mmol) in
CH3CN +9 mL) was re¯uxed for 12 h. Evaporation of the
solvent followed by column chromatography +CHCl3/
MeOHˆ30/1) of the residue gave 13 +348mg, 78%) as a
foam: UV +MeOH) lmax 262 nm +1 20,000), lmin 229 nm +1
9200); 1H NMR +CDCl3) d 0.13 +6H, s, SiMe), 0.95 +9H, s,
SiBu-t), 3.89±3.96 +2H, m, H-50), 4.93±4.94 +1H, m, H-40),
5.29±5.30 +1H, m, H-20), 5.62 +2H, br, NH2), 7.01±7.02
+1H, m, H±10), 7.39±7.43 +3H, m, Ph), 7.56±7.59 +2H, m,
Ph), 8.19 and 8.33 +2H, each as s, H-2 and H-8); FAB-MS
m/z: 456 +M11H). Anal. calcd for C22H29N5O2SSi: C,
57.99; H, 6.42; N, 15.37. Found: C, 57.76; H, 6.49; N, 15.16.
H-40), 5.24 +1H, dd, Jˆ5.8and 7.9 Hz, H-2 ), 5.60 +1H,
0
0
br, D2O-exchangeable, OH), 5.85 +1H, d, Jˆ5.8Hz, H-1 ),
7.56±7.59 +2H, m, Ph), 7.65±7.68 +1H, m, Ph), 8.01±8.03
+2H, m, Ph), 8.24 and 8.44 +2H, each as s, H-2 and H-8),
8.52 +1H, br, NH); FAB-MS m/z 590 +M11H). Anal. calcd
for C27H39N5O6SSi´1/4H2O: C, 54.57; H, 6.70; N, 11.78.
Found: C, 54.30; H, 6.55; N, 11.40.
3.1.10. 30-C-Benzenesulfonyl-50-O-ꢀtert-butyldimethyl-
silyl)-20,30-didehydro-20,30-dideoxyadenosine ꢀ17). Com-
pound 16 +6.3 g, 10.75 mmol) in NH3/MeOH +90 mL) was
placed in a sealed tube and kept in a refrigerator overnight.
After evaporation to dryness, the resulting foam was
dissolved in pyridine +120 mL) containing DMAP +1.9 g,
16.1 mmol). To this was added MsCl +3.32 mL, 43 mmol)
at 08C, and the mixture was stirred at 08C for 1 h and then at
room temperature overnight. Partition of the reaction
mixture +CHCl3-saturated aqueous NaHCO3) followed
by column chromatography +CHCl3/MeOHˆ30/1) of the
organic layer gave 17 +4.26 g, 81%) as a foam: UV
+MeOH) lmax 260 nm +1 17,400), lmin 230 nm +1
3.1.7. 9-[2,3-Anhydro-5-O-ꢀtert-butyldimethylsilyl)-b-d-
ribofuranosyl]-N6-pivaloyladenine ꢀ14). A mixture of 8
+5.9 g, 16.23 mmol), pivaloyl chloride +3.5 mL, 29.21
mmol), and i-Pr2NEt +5.0 mL, 29.21 mmol) in CH2Cl2
+70 mL) was stirred at 08C for 90 min. The reaction mixture
was partitioned between saturated aqueous NaHCO3 and
CHCl3. Column chromatography +CHCl3/MeOHˆ40/1) of
the organic layer gave 14 +7.0 g, 97%) as a foam: UV
+MeOH) lmax 271 nm +1 14,600), lmin 230 nm +1 600);
1H NMR +CDCl3) d 0.01 and 0.03 +6H, each as s, SiMe),
0.84 +9H, s, SiBu-t), 1.41 +9H, s, COBu-t), 3.74 +1H, dd,
Jˆ4.6 and 10.9 Hz, H-50), 3.79 +1H, dd, Jˆ6.5 and 10.9 Hz,
H-50), 4.11 +1H, d, Jˆ2.7 Hz, H-20), 4.38+1H, dd, Jˆ4.6
and 6.4 Hz, H-40), 4.45 +1H, d, Jˆ2.7 Hz, H-30), 6.25 +1H, s,
H-10), 8.22 +1H, s, H-2 or H-8), 8.51 +1H, br, NH), 8.76 +1H,
s, H-2 or H-8); FAB-MS m/z 448+M 11H). Anal. calcd for
C21H33N5O4Si: C, 56.35; H, 7.43; N, 15.65. Found: C,
56.36; H, 7.46; N, 15.43.
1
16,000); H NMR +CDCl3) d 0.00 and 0.01 +6H, each as
s, SiMe), 0.82 +9H, s, SiBu-t), 3.94 +1H, dd, Jˆ2.0 and
12.0 Hz, H-50), 4.06 +1H, dd, Jˆ2.8and 12.0 Hz, H-5 ),
0
0
5.06±5.08+1H, m, H-4 ), 5.94 +2H, br, NH2), 6.70±6.71
+1H, m, H-20), 7.06±7.07 +1H, m, H-10), 7.59±7.63 +2H,
m, Ph), 7.69±7.73 +1H, m, Ph), 7.97±7.99 +2H, m, Ph),
8.13 and 8.30 +2H, each as s, H-2 and H-8); FAB-MS
m/z 488 +M11H). Anal. calcd for C22H29N5O4SSi´1/
10H2O: C, 53.99; H, 6.01; N, 14.31. Found: C, 53.73; H,
5.91; N, 14.19.
3.1.8.
9-[5-O-ꢀtert-butyldimethylsilyl)-3-deoxy-3-C-
phenylthio-b-d-xylofuranosyl]-N6-pivaloyladenine ꢀ15).
A MeOH +60 mL) solution of thiophenol +5.13 mL,
50 mmol) and NaOMe +1.35 g, 25 mmol) was stirred for
20 min at room temperature. Compound 14 +5.6 g,
12.5 mmol) was added to this solution, and the mixture
was stirred at re¯uxing temperature for 2.5 h. The whole
reaction mixture was evaporated and puri®ed by column
chromatography +CHCl3/MeOHˆ30/1) to give 15 +6.2 g,
90%) as a foam: UV +MeOH) lmax 260 nm +1 17,300),
3.1.11.
50-O-ꢀtert-Butyldimethylsilyl)-30-C-ꢀtributyl-
stannyl)-20,30-didehydro-20,30-dideoxyadenosine ꢀ18). A
mixture of 17 +286 mg, 0.586 mmol), Et3N +326 mL,
2.34 mmol), Bu3SnH +472 mL, 1.76 mmol), and AIBN
+29 mg, 0.176 mmol) in benzene +8.3 mL) was heated at
808C with stirring. After 2.5 h, the same amount of AIBN
was added to the reaction mixture, and heating was contin-
ued for further 3 h. The reaction mixture was partitioned
between EtOAc and saturated aqueous NaHCO3. Short
column chromatography +hexane/EtOAcˆ1/2) of the
1
lmin 233 nm +1 4500); H NMR +CDCl3) d 0.00 +6H, s,
SiMe), 0.69 +9H, s, SiBu-t), 1.41 +9H, s, COBu-t), 3.91
+1H, dd, Jˆ2.5 and 11.3 Hz, H-50), 4.01±4.06 +2H, m,

2502
S. Onuma et al. / Tetrahedron 58 )2002) 2497±2503
organic layer gave 18 +284 mg, 76%, solid). Elution with
EtOAc gave the recovered 17 +48mg, 17%).
20.21 and 20.17 +6H, each as s, SiMe), 0.72 +9H, s,
0
SiBu-t), 3.95 +1H, dd, Jˆ2.8and 12.0 Hz, H-5 ), 4.00
+1H, dd, Jˆ2.0 and 12.0 Hz, H-50), 5.45±5.48+1H, m,
H-40), 5.91 +2H, br, NH2), 6.18±6.19 +1H, m, H-2 0), 7.21±
7.22 +1H, m, H-10), 7.36±7.45 +5H, m, Ph), 8.37 and 8.40
+2H, each as s, H-2 and H-8); FAB-MS m/z 424 +M11H).
Anal. calcd for C22H29N5O2Si: C, 62.38; H, 6.90; N, 16.53.
Found: C, 62.36; H, 6.91; N, 16.43.
Physical data of 18: mp 8 2±8 38C; UV +MeOH) lmax 260 nm
+1 17,200), lmin 231 nm +1 5200); 1H NMR +CDCl3) d 0.00
and 0.01 +6H, each as s, SiMe), 0.85 +9H, s, SiBu-t), 0.91
+9H, t, Jˆ7.2 Hz, Sn+CH2)3CH3), 1.04±1.08+6H, m,
Sn+CH2)3), 1.30±1.39 +6H, m, Sn+CH2)3), 1.50±1.58+6H,
m, Sn+CH2)3), 3.75±3.82 +2H, m, H-50), 5.01±5.04 +1H, m,
0
3.1.15.
50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-
H-40), 5.62 +2H, br, NH2), 5.99 +1H, m, JSn,H-2 ˆ28.0 Hz,
20,30-dideoxy-30-C-vinyladenosine ꢀ22). A mixture of 19
+70 mg, 0.147 mmol), Bu3SnCHvCH2 +128 mL, 0.441
mmol), +MeCN)2PdCl2 +3.8mg, 0.0147 mmol), and CuI
+5.5 mg, 0.0294 mmol) in DMF +1 mL) was stirred at
room temperature for 42 h. The reaction mixture was par-
titioned between EtOAc and saturated aqueous NaHCO3.
Column chromatography +CHCl3/MeOHˆ30/1) of the
organic layer gave 22 +28mg, 51%) as a solid: mp 154±
1578C; UV +MeOH) lmax 259 nm +1 20,900), lmin 245 nm
+1 17,600); 1H NMR +CDCl3) d 20.01 +6H, s, SiMe), 0.86
+9H, s, SiBu-t), 3.97±4.01 +2H, m, H-50), 5.12±5.13 +1H, m,
H-20), 7.01±7.02 +1H, m, H-10), 7.95 and 8.38 +2H, each as
s, H-2 and H-8); FAB-MS m/z 674 for 118Sn and 676 for
120Sn +M11H). Anal. calcd for C28H51N5O2SiSn: C, 52.84;
H, 8.08; N, 11.00. Found: C, 53.23; H, 8.23; N, 10.86.
3.1.12.
50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-
20,30-dideoxy-30-iodoadenosine ꢀ19). A mixture of 18
+246 mg, 0.386 mmol) and NIS +104 mg, 0.463 mmol) in
THF +2.5 mL) was stirred at room temperature under
positive pressure of dry Ar for 4.5 h in total. Additional
NIS was added to the mixture after 3 h +69 mg,
0.308mmol) and after 4 h +43 mg, 0.193 mmol). The reac-
tion mixture was partitioned between EtOAc and aqueous
Na2S2O3. Column chromatography +CHCl3/MeOHˆ30/1)
of the organic layer gave 19 +127 mg, 70%) as a solid: mp
199±2048C; UV +MeOH) lmax 260 nm +1 15,500), lmin
H-40), 5.40±5.50 +2H, m, CHvCH2), 5.58+2H, br, NH ),
2
5.96 +1H, m, H-20), 6.55 +1H, dd, Jˆ11.2 and 17.6 Hz,
CHvCH2), 7.06 +1H, m, H±10), 8.21 and 8.38 +2H, each
as s, H-2 and H-8); FAB-MS m/z 374 +M11H). Anal. calcd
for C18H27N5O2Si: C, 57.88; H, 7.29; N, 18.75. Found: C,
58.16; H, 7.45; N, 18.48.
1
232 nm +1 2200); H NMR +CDCl3) d 0.11 +6H, s, SiMe),
0.92 +9H, s, SiBu-t), 3.91 +1H, dd, Jˆ1.6 and 12.0 Hz,
3.1.16.
20,30-dideoxy-30-C-ꢀphenyl)ethynyladenosine ꢀ23).
50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-
H-50), 4.06 +1H, dd, Jˆ2.4 and 12.0 Hz, H-50), 4.85±4.86
0
+1H, m, H-40), 5.62 +2H, br, NH2), 6.38+1H, m, H-2 ),
A
7.02±7.03 +1H, m, H-10), 8.22 and 8.38 +2H, each as s,
H-2 and H-8); FAB-MS m/z 474 +M11H). Anal. calcd for
C16H24IN5O2Si: C, 40.60; H, 5.11; N, 14.79. Found: C,
40.82; H, 4.94; N, 14.62.
mixture of 19 +50 mg, 0.105 mmol), phenylacetylene
+20 mL, 0.157 mmol), Pd+PPh3)2Cl2 +8.5 mg, 0.011 mmol),
and CuI +4.6 mg, 0.021 mmol) in DMF +2 mL) containing
Et3N +25 mL, 0.157 mmol) was heated at 808C for 2 h. After
passing through a short column +CHCl3/MeOHˆ10/1), the
reaction mixture was bubbled with H2S gas, and then par-
titioned between EtOAc and saturated aqueous NaHCO3.
Column chromatography +CHCl3/MeOHˆ30/1) of the
organic layer gave 23 +42 mg, 89%) as a solid: mp 136±
1398C; UV +MeOH) lmax 260 nm +1 37,200), 273 nm +1
45,500), and 288 nm +1 31,600), lmin 231 nm +1 16,700),
263 nm +1 36,900), and 283 nm +1 25,600); 1H NMR
+CDCl3) d 0.10 +6H, s, SiMe), 0.91 +9H, s, SiBu-t), 4.01
+1H, dd, Jˆ2.0 and 11.6 Hz, H-50), 4.07 +1H, dd, Jˆ2.8and
11.6 Hz, H-50), 4.99±5.01 +1H, m, H-40), 5.69 +2H, br,
NH2), 6.24±6.25 +1H, m, H-20), 7.20±7.21 +1H, m, H-10),
7.34±7.50 +5H, m, Ph), 8.29 and 8.38 +2H, each as s, H-2
and H-8); FAB-MS m/z 448+M 11H). Anal. calcd for
C24H29N5O2Si: C, 64.40; H, 6.53; N, 15.65. Found: C,
64.49; H, 6.67; N, 15.31.
3.1.13. 30-Bromo-50-O-ꢀtert-butyldimethylsilyl)-20,30-di-
dehydro-20,30-dideoxyadenosine ꢀ20). A mixture of 18
+100 mg, 0.157 mmol) and NBS +55 mg, 0.314 mmol) in
THF +4 mL) was stirred at room temperature for 5.5 h
under positive pressure of dry Ar. The reaction mixture
was partitioned between CHCl3 and aqueous NaHCO3.
Column chromatography +CHCl3/MeOHˆ30/1) of the
organic layer gave 20 +66 mg, 100%) as a solid: mp 173±
1788C; UV +MeOH) lmax 259 nm +1 19,100), lmin 230 nm
+1 9000); 1H NMR +CDCl3) d 20.01 and 0.00 +6H, each as
s, SiMe), 0.81 +9H, s, SiBu-t), 3.82 +1H, dd, Jˆ1.6 and
12.0 Hz, H-50), 3.91 +1H, dd, Jˆ2.4 and 12.0 Hz, H-50),
0
4.76±4.78+1H, m, H-4 ), 5.70 +2H, br, NH2), 6.09±6.10
+1H, m, H-20), 6.93±6.94 +1H, m, H-10), 8.17 and 8.26
+2H, each as s, H-2 and H-8); FAB-MS m/z 426 and 428
+M11H). Anal. calcd for C16H24BrN5O2Si: C, 45.07; H,
5.67; N, 16.42. Found: C, 45.09; H, 5.65; N, 16.32.
References
3.1.14.
50-O-ꢀtert-Butyldimethylsilyl)-20,30-didehydro-
20,30-dideoxy-30-C-phenyladenosine ꢀ21). A mixture of
18 +230 mg, 0.361 mmol), PhI +121 mL, 1.08mmol),
Pd+PPh3)4 +41 mg, 0.036 mmol), and CuI +13 mg, 0.072
mmol) in DMF +1.5 mL) was stirred at room temperature
for 28h. The reaction mixture was partitioned between
EtOAc and saturated aqueous NaHCO3. Column chroma-
tography +CHCl3/MeOHˆ20/1) of the organic layer gave 21
+100 mg, 66%) as a foam: UV +MeOH) lmax 257 nm +1
29,000), lmin 224 nm +1 9600); 1H NMR +CDCl3) d
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2503
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