A practical synthesis of 2′-aminoacylamino-2′-deoxyadenosines

Article abstract of DOI:10.1016/j.tet.2007.04.038

A practical and efficient synthesis of 2′-aminoacylamino-2′-deoxyadenosine derivatives is reported. EDCI/HOBt-mediated coupling of a 3′,5′-diprotected 2′-amino-2′-deoxyadenosine derivative to various N-Cbz-l-amino acid derivatives followed by global depro

Full text of DOI:10.1016/j.tet.2007.04.038

Tetrahedron 63 (2007) 6901–6908
A practical synthesis of 20-aminoacylamino-20-deoxyadenosines
*
Gavin O’Mahony, Andreas Sundgren, Sara Svensson and Morten Grøtli
Department of Chemistry—Medicinal Chemistry, Go€teborg University, SE-412 96 Go€teborg, Sweden
Received 10 January 2007; revised 20 March 2007; accepted 12 April 2007
Available online 19 April 2007
Abstract—A practical and efficient synthesis of 20-aminoacylamino-20-deoxyadenosine derivatives is reported. EDCI/HOBt-mediated cou-
pling of a 30,50-diprotected 20-amino-20-deoxyadenosine derivative to various N-Cbz-L-amino acid derivatives followed by global deprotection
affords analytically pure 20-aminoacylamino-20-deoxyadenosine derivatives without the necessity for preparative HPLC purification. These
compounds are non-hydrolysable isosteres of 20-aminoacyladenosines, which are of use in X-ray studies for the elucidation of the editing
mechanism of various tRNA synthetases.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
10,000.4 The misincorporation of a non-cognate amino
acid is rectified by the so-called ‘proof-reading’ or editing
mechanism. This hydrolytic editing identifies misactivated
50-O-aminoacyl-adenylates (pre-transfer editing) and/or
mischarged tRNAs (post-transfer editing). The elucidation
of the mechanism of these editing steps generally depends
on the solution of the X-ray crystal structure of complexes
between the aaRS of interest and enzymatically non-hydro-
lysable substrate analogues. In the investigation of pre-
transfer editing,5 50-O-sulfamoyladenosine derivatives6,7
have been employed. A 20-aminoacylamino-20-deoxyadeno-
sine (2, R¼n-propyl, Fig. 1) has previously been employed
as a non-hydrolysable 20-aminoacyladenosine analogue in
the elucidation of the post-transfer editing mechanism of
Thermus thermophilus LeuRS5 and in a preliminary X-ray
crystallographic study of the editing domain of T. thermo-
philus IleRS (6a, Fig. 1).8,9 20-Aminoacylamino-20-deoxy-
adenosine derivatives have also been employed in the
study of ribosomal peptidyltransferases.10
20-Aminoacyladenosines (1, Fig. 1) are produced in vivo as
intermediates in protein biosynthesis, specifically in the
aminoacylation reaction catalysed by the aminoacyl tRNA
synthetases (aaRSs), a group of enzymes responsible for at-
taching a particular amino acid to its set of cognate tRNA
isoacceptors.1–3
The fidelity of this process is critically dependant on the rec-
ognition of the amino acid and the tRNA isoacceptor by the
enzyme. The ability of each aaRS to discriminate between
the various amino acids is therefore of fundamental impor-
tance in the accuracy of protein synthesis. This presents
a particular problem for pairs of structurally similar amino
acids, for example, threonine/serine, threonine/valine and
isoleucine/valine. For example, IleRS misincorporates one
valine for every 200 isoleucine positions, which is a great
deal higher than the maximum error tolerance of one in
As part of an investigation into the editing mechanism of the
aaRSs, we required access to appreciable quantities of these
compounds. Despite the increasing interest in these com-
pounds for use in such studies, no practical, general method
for their synthesis has been reported. Previous syntheses
of the analogous 30-aminoacylamino-30-deoxyadenosines
(mainly of interest as analogues of the nucleoside antibiotics
puromycin11 and the recently discovered cystocin12) gener-
ally employ N-Fmoc protected amino acids, and the removal
conditions necessitate purification of the final compounds by
preparative HPLC,13–15 although one very recent synthesis
of the unnatural L,L-puromycin employs N-Cbz-L-O-methyl-
tyrosine.16 The few published syntheses of 20-amido-20-
deoxyadenosine derivatives are not amenable to the routine
preparation of larger amounts of these compounds, in
HO
HO
Ad
Ad
O
O
OH
O
OH NH
R
R
O
O
2
1
NH2
NH2
Figure 1. General structure of 20-aminoacyladenosines (1, R¼amino acid
side chain) found as intermediates in the aminoacylation reaction catalysed
by aaRSs and 20-aminoacylamino-20-deoxyadenosines (2).
Keywords: tRNA synthetases; 20-Aminoacylamino-20-deoxyadenosine
derivatives.
* Corresponding author. Tel.: +46 31 7722905; fax: +46 31 7723840;
e-mail: grotli@chem.gu.se
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.04.038

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G. O’Mahony et al. / Tetrahedron 63 (2007) 6901–6908
that they require the use of expensive solid-phase reagents
(e.g., safety-catch resins17–20), the use of preparative
HPLC5 and TLC10 or ion-exchange purification tech-
niques.21,22 The aminoacyl derivatives present an additional
challenge in the necessity for protection/deprotection of the
amino group of the amino acid, as well as the increased com-
pound polarity due to the extra amino group.
The amino acids were employed, in general, as their N-Cbz
protected derivatives (6a–f). The N-Cbz protecting group
was chosen (in contrast to the previously used Fmoc
group5,13,24) due to the volatility and/or ease of removal of
the deprotection reagents and by-products. It was predicted
that this would minimise or indeed eliminate the purification
required for the final products (8a–g). The a-amino group of
compound 8g was protected as the corresponding N-acetate,
with the side chain primary amino group protected with a Cbz
group. Additionally, the order of removal of the protecting
groups of fully protected 20-aminoacylamino-20-deoxyade-
nosines 6a–g, i.e., removal of the tetraisopropyldisilyl
(TIPDS) group first, was predicted to be critical to the success
of this approach, as it was thought that N-Cbz compounds
7a–g would possess sufficient lipophilicity to allow purifica-
tion by normal phase silica gel chromatography, without hav-
ing to resort to the use of reverse phase preparative HPLC.
Herein, we report a general method for the practical and ef-
ficient synthesis of this important class of compounds on
a preparatively useful scale, which, most importantly, avoids
the necessity for difficult or expensive purification methods
(only silica gel column chromatography is used) and which
allows rapid access to a wide array of 20-aminoacylamino-20-
deoxyadenosine derivatives.
2. Results and discussion
The coupling of protected 20-amino-20-deoxyadenosine 5b
to various N-Cbz protected amino acid derivatives (6a–g,
Scheme 2) was carried out using standard EDCI/HOBt-
mediated amide bond formation25 in dichloromethane over-
night at room temperature.
Our synthetic pathway begins with 30,50-diprotected 20-ami-
no-20-deoxyadenosine 3b, which was prepared in good yield
from vidarabine 1 according to literature procedures
(Scheme 1).5,13,17,23,24
The fully protected 20-aminoacylamino-20-deoxyadenosines
were easily purified by aqueous workup followed by silica
gel column chromatography, affording pure compounds
7a–g in 62–76% yield. At room temperature, compound 7f
existed as a mixture of rotamers, due to hindered rotation
about the nitrogen–carbon bond of the tertiary carbamate.
For the preparation of N-acetyl lysine derivative 6g, EDCI/
HOBt-mediated coupling of N-acetyl-Lys(Cbz)-OH26 to
amine 5b afforded the corresponding fully protected 20-ami-
noacylamino-20-deoxyadenosine 6g in 79% isolated yield
after silica gel column chromatography. No epimerization
of the carboxy component was observed in any of these cou-
plings, with all compounds being isolated as single diaste-
reoisomers (by 1H NMR spectroscopy).
HO
O
Ad
Ad
HO
i
O
O
(i-Pr)2Si
RO
O
OH
3
(i-Pr)2Si O
4a: R = H
4b: R = S(O)2CF3
iii
ii
O
Ad
O
(i-Pr)2Si
O
R
(i-Pr)2Si
5a: R = N3
5b: R = NH2
O
iv
Scheme 1. Synthesis of 30,50-diprotected 20-amino-20-deoxyadenosine (5b).
(i) TIPDSCl2, pyridine, rt, 4 h, 86% yield; (ii) CF3SO2Cl, amino acids,
DMAP, DCM, 0 ꢀC, 1 h, 92% yield; (iii) NaN3, DMF, rt, 5 h, 94% yield;
(iv) 10% Pd/C, H2, MeOH, rt, 15 h, 99% yield.
The order of deprotection of fully protected compounds 6a–g
was important, as we wished to minimise the degree of
O
O
HO
Ad
NH
Ad
Ad
i
O
R
ii
O
(i-Pr)2Si
O
(i-Pr)2Si
O
O
(i-Pr)2Si
O
(i-Pr)2Si
O
NH2
OH NH
O
R
O
7a-g R2 = Cbz
5b
6a-g
iii
6a, 7a: R =
6b, 7b: R =
6e, 7e: R =
6f, 7f: R =
6g, 7g: R =
NHR2
NHR2
NHR2
NHR2
8a-g R2 = H
NR2
NH2
N
6c, 7c: R = HO
N
N
Ad =
NHAc
N
H2N
R2HN
6d, 7d: R =
O
NHR2
Scheme 2. Synthesis of 20-aminoacylamino-20-deoxyadenosines. (i) Protected amino acids, EDCI, HOBt, CH2Cl2, 0 ꢀC to rt, 16 h, 6a (62%), 6b (67%), 6c
(66%), 6d (71%), 6e (75%), 6f (76%), 6g (79%); (ii) NH4F, MeOH, reflux, 2 h, 7a (88%), 7b (67%), 7c (89%), 7d (78%), 7e (87%), 7f (89%), 7g (88%);
(iii) 10% Pd/C, H2, MeOH, rt, 16 h, 8a (96%), 8b (99%), 8c (97%), 8d (96%), 8e (81%), 8f (99%), 8g (86%).

G. O’Mahony et al. / Tetrahedron 63 (2007) 6901–6908
6903
purification required. It was intended that the N-Cbz group be
3. Conclusions
removed last, as the deprotection conditions and by-products
are more compatible with polar, water-soluble compounds.
Accordingly, the 30,50-O-TIPDS group of compounds 6a–g
was removed using ammonium fluoride (10 equiv) in reflux-
ing methanol.27 The N-Cbz group of the corresponding diols
7a–g conferred enough lipophilicity to permit purification by
aqueous workup followed by conventional silica gel flash
chromatography. Compounds 7a–g were, as expected, quite
polar (Rfw0.1 in all cases, eluting with 9:1 dichlorome-
thane/methanol), but the use of a short silica gel column
afforded analytically pure material in good yields (66–
89%). N-Cbz proline derivative 7f was again present as a
rotameric mixture at room temperature (as determined by
1H NMR spectroscopy).
In conclusion, we have developed a practical and efficient
synthetic route to a range of 20-aminoacylamino-20-deoxy-
adenosines. The synthetic pathway is compatible with the
introduction of a wide range of amino acids (both with and
without heteroatom-bearing side chains) as well as dipep-
tides at the 20-position of amine 5b. Key benefits of this pro-
tocol are the avoidance of expensive reagents and the fact
that only flash chromatography is required for purification.
Crucially, this route is also amenable to the preparation of
these useful compounds on a larger scale.
4. Experimental
The final deprotection step involved hydrogenolysis of the
N-Cbz group from compounds 7a–g. This was performed
under standard conditions, i.e., 10% Pd on carbon and bal-
loon pressure of hydrogen gas in methanol, with the reac-
tions being allowed to stir overnight at room temperature.
Simple filtration through a plug of CeliteÒ followed by con-
centration of the filtrate afforded analytically pure com-
pounds 8a–g in excellent yields (81–99%) without the
need for further purification. Proline derivative 8f exhibited
no signs of hindered rotation, confirming that the tertiary
carbamate of the Cbz group was responsible for the rota-
meric mixtures encountered for compounds 6f and 7f.
4.1. General experimental methods
All reactions were performed under a nitrogen atmosphere.
Solvents were dried using standard procedures. H NMR
1
spectra were recorded at 400 MHz and 13C NMR spectra re-
corded at 100 MHz in the solvents specified. Spectra were
referenced to residual non-deuterated solvent (1H NMR:
CDCl3 7.26 ppm, DMSO-d6 2.55 ppm and 13C NMR:
CDCl3 77.2 ppm, DMSO-d6 39.5 ppm). Coupling constant
(J) values are quoted in hertz. The matrix used for FAB
mass spectra was either 3-nitrobenzyl alcohol or glycerol.
Acceleration voltage was 6 kV and scan time was 5 s. IR
spectra were recorded as KBr disks. Flash chromatography
was performed using Merck Geduran Si 60 (0.063–
0.200 mm) silica gel. Thin layer chromatography (TLC)
was performed using Merck Silica Gel 60 F254 aluminium-
backed plates and visualised using UV light (254 and/or
366 nm). The solvents used to determine Rf values are the
same as that used for chromatographic purification, unless
otherwise stated. Nucleoside numbering is used throughout.
In an extension of this methodology, we accomplished the
synthesis of dipeptide–nucleoside conjugate 11 (Scheme
3). EDCI/HOBt-mediated coupling of N-protected dipeptide
N-Cbz-IlePhe-OH (Scheme 3) to amine 5b as before afforded
protected dipeptide–nucleoside conjugate 9. In common with
the coupling of the protected amino acids to amine 5b, no
epimerization of the carboxyl component was observed,
with compound 9 being isolated as a single diastereoisomer
(by 1H NMR spectroscopy) in 72% yield. Again, in order to
facilitate purification by silica gel column chromatography,
the 30,50-O-TIPDS protecting group of 9 was removed first
using ammonium fluoride in refluxing methanol, affording
diol 10 in 66% purified yield. The N-Cbz group of 8 was
removed using the same conditions as previously described
(vide supra), affording analytically pure, fully deprotected
dipeptide adduct 11 in 94% yield, without recourse to addi-
tional purification beyondremoval of the catalyst by filtration
and concentration of the filtrate under reduced pressure.
4.2. Coupling of protected amino acids 6a–g with
20-amino-20-deoxy-30,50-O-(tetraisopropyldisiloxane-
1,3-diyl)-adenosine 5b (general procedure A)
EDCI (1.1 equiv) and HOBt (1.1 equiv) were added at 0 ꢀC
to a solution of the appropriate protected amino acid
(1 equiv) in dry CH2Cl2. The mixture was stirred at room
temperature for 30 min. The mixture was cooled again to
0 ꢀC and a solution of 20-amino-20-deoxy-30,50-O-(tetraiso-
propyldisiloxane-1,3-diyl)-adenosine 5b (1 equiv) in dry
CH2Cl2 was added. The mixture was stirred at room temper-
ature under a nitrogen atmosphere until TLC analysis (9:1
CH2Cl2/MeOH) indicated that there was no 5b left. The re-
action mixture was diluted with CH2Cl2 (10 mL) and
washed with water. The combined aqueous extracts were
back-extracted with CH2Cl2 and the combined organic
layers washed with brine and dried over magnesium sulfate.
The solvent was removed under reduced pressure affording
the product as a solid, which was purified by silica gel col-
umn chromatography (eluting with 19:1 CH2Cl2/MeOH).
O
HO
Ad
Ad
i
O
ii
(i-Pr)2Si
O
5b
O
(i-Pr)2Si
O
NH
OH NH
O
O
O
O
HN
HN
NHR2
NHCbz
10 R2 = Cbz
11 R2 = H
9
4.2.1. 20-(N-a-Benzyloxycarbonyl-L-valinyl)-amino-
20-deoxy-30,50-O-(tetraisopropyldisiloxane-1,3-diyl)-
adenosine (6a). Using general procedure A, 144 mg of 5b
afforded 129 mg (62%) of 6a as a white solid, [a]2D0 ꢁ27.5
(c 0.01, CHCl3); nmax (KBr)/cmꢁ1 3331, 1641, 1598; dH
iii
Scheme 3. Synthesis of dipeptide conjugate 11. (i) N-Cbz-Ile-Phe-OH,
EDCI, HOBt, CH2Cl2, 0 ꢀC to rt, 16 h, 72%; (ii) NH4F, MeOH, reflux,
2 h, 66%; (iii) 10% Pd/C, H2, MeOH, rt, 16 h, 94%.

6904
G. O’Mahony et al. / Tetrahedron 63 (2007) 6901–6908
(400 MHz, CD3OD) 8.21 (1H, s), 8.12 (1H, s), 7.38–7.27
(5H, m), 5.90 (1H, d, J¼4.0 Hz), 5.22–5.17 (1H, m), 5.07–
5.04 (1H, m), 5.10 (1H, d, J¼12.5 Hz), 5.02 (1H, d,
J¼12.8 Hz), 4.10–4.02 (4H, m), 2.10–2.00 (1H, m), 1.17–
1.00 (28H, m), 0.89 (3H, d, J¼7.0 Hz), 0.82 (3H, d,
J¼7.0 Hz); dC (100 MHz, CD3OD) 156.0, 152.5, 140.5,
128.2, 127.8, 127.6, 88.3, 83.8, 70.2, 62.4, 66.5, 60.6,
55.1, 30.5, 18.5, 16.8, 16.6, 16.5, 16.4, 16.24, 16.19, 16.1,
13.5, 13.1, 12.8, 12.5; HRMS-FAB m/z [M+H+] calcd for
C35H55N7O7Si2: 742.378; found: 742.370. Anal. Calcd for
C35H55N7O7Si2: C, 56.65; H, 7.47; N, 13.21. Found: C,
56.68; H, 7.43; N, 13.18.
m); dC (100 MHz, CDCl3) 175.3, 173.2, 156.3, 156.2,
153.1, 148.7, 139.9, 136.0, 128.8, 128.5, 128.4, 119.5,
89.0, 84.1, 71.0, 67.6, 63.2, 56.9, 51.9, 37.0, 17.7, 17.6, 17.5,
17.4, 17.3, 17.22, 17.16, 13.3, 13.2, 12.89, 12.86; HRMS-
FAB m/z [M+H+] calcd for C34H52N8O8Si2: 757.345; found:
757.352. Anal. Calcd for C34H52N8O8Si2: C, 53.95; H, 6.92;
N, 14.80. Found: C, 53.91; H, 7.02; N, 14.71.
4.2.5. 20-(N-a-Benzyloxycarbonyl-L-phenylalaninyl)-
amino-20-deoxy-30,50-O-(tetraisopropyldisiloxane-1,3-
diyl)-adenosine (6e). Using general procedure A, 215 mg of
5b afforded 250 mg (75%) of 6e as a white solid, [a]2D0 ꢁ18.0
(c 0.02, CHCl3); nmax (KBr)/cmꢁ1 3400, 2944, 2866, 2359,
1715, 1645, 1600, 1498, 1464, 1455, 1331, 1296, 1248,
1214, 1142, 1037, 918, 885, 862, 745, 697, 648, 604, 458,
418; dH (400 MHz, CDCl3) 8.17 (1H, s), 7.95 (1H, s),
7.34–7.09 (10H, m), 5.89 (1H, d, J¼3.6 Hz), 5.28 (1H, m),
5.16 (1H, d, J¼12.5 Hz), 5.02 (1H, d, J¼12.5 Hz), 4.53
(1H, m), 4.02–3.97 (3H, m), 3.11 (1H, m, J¼7.3, 13.6 Hz,
CHCHHPh), 2.98 (1H, dd, J¼7.3, 13.6 Hz, CHCHHPh),
1.16–1.03 (28H, m); dC (100 MHz, CDCl3) 172.4, 156.4,
155.7, 152.6, 149.3, 140.2, 136.3, 129.2, 128.7, 128.6, 128.1,
127.0, 125.3, 119.8, 87.8, 83.8, 70.5, 67.0, 62.8, 56.5, 56.0,
38.0, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 13.2, 13.1, 12.8, 12.6;
HRMS-FAB m/z [M+H+] calcd for C39H55N7O7Si2:
790.370; found: 790.376; Anal. Calcd for C39H55N7O7Si2:
C, 59.4; H, 6.9; N, 12.4. Found: C, 59.5; H, 6.9; N, 12.4.
4.2.2. 20-(N-a-Benzyloxycarbonyl-L-isoleucinyl)-amino-
20-deoxy-30,50-O-(tetraisopropyldisiloxane-1,3-diyl)-
adenosine (6b). Using general procedure A, 150 mg of 5b
afforded 149 mg (67%) of 6b as a white solid, [a]2D0 ꢁ29.5
(c 0.005, CHCl3); nmax (KBr)/cmꢁ1 3417, 2946, 2868,
2365, 1712, 1667, 1640, 1597, 1502, 1466, 1248, 1124,
1085, 1038, 885, 698; dH (400 MHz, CD3OD) 8.12 (1H, s),
8.03 (1H, s), 7.28–7.14 (5H, m), 5.81 (1H, d, J¼4.0 Hz),
5.20–5.03 (3H, m), 5.10 (1H, d, J¼12.5 Hz), 5.01 (1H, d,
J¼12.4 Hz), 4.12–4.00 (5H, m), 1.73–1.62 (1H, m), 1.24–
1.13 (1H, m), 1.06–0.84 (29H, m), 0.75 (3H, d, J¼7.0 Hz),
0.67 (3H, t, J¼7.4 Hz); dC (100 MHz, CD3OD) 173.1,
157.3, 156.0, 152.5, 149.0, 140.5, 136.7, 128.2, 127.8,
127.6, 119.2, 88.0, 84.0, 70.3, 66.5, 62.5, 59.9, 55.1, 36.9,
24.3, 16.7, 16.5, 16.4, 16.3, 16.2, 16.1, 14.7, 13.2, 13.1,
12.9, 12.4, 10.3; HRMS-FAB m/z [M+H+] calcd for
C36H57N7O7Si2: 756.394; found: 756.395; Anal. Calcd for
C36H57N7O7Si2: C, 57.2; H, 7.6; N, 13.0. Found: C, 57.2;
H, 7.6; N, 12.8.
4.2.6. 20-(N-a-Benzyloxycarbonyl-L-prolinyl)-amino-20-
deoxy-30,50-O-(tetraisopropyldisiloxane-1,3-diyl)-adeno-
sine (6f). Using general procedure A, 222 mg of 5b afforded
245 mg (76%) 6f as a white solid, [a]2D0 ꢁ47.0 (c 0.01,
CHCl3); nmax (KBr)/cmꢁ1 3394, 2944, 2867, 2726, 1694,
1599, 1499, 1465, 1416, 1332, 1299, 1248, 1206, 1119,
1090, 919, 885, 863, 824, 772, 696, 647, 607, 451, 418;
dH (400 MHz, CDCl3) 8.28 (1H, s), 8.11 (1H, s), 8.06 (1H,
s), 8.05 (1H, s), 7.35–7.21 (5H, m), 5.88 (1H, s), 5.77 (1H,
d, J¼9.0 Hz), 4.96–5.09 (7H, m), 4.78 (1H, d, J¼13.2 Hz),
4.30–4.36 (2H, m), 3.92–4.00 (6H, m), 3.34–3.42 (4H, m),
2.07–2.18 (1H, m), 1.79–1.91 (6H, m) 0.91–1.15 (56H,
m); dC (100 MHz, CDCl3) 173.0, 156.0, 155.8, 152.7,
149.3, 140.3, 136.4, 128.5, 128.2, 127.8, 120.1, 88.3, 83.6,
70.5, 67.3, 62.8, 60.6, 56.5, 47.0, 28.7, 24.6, 17.5, 17.4,
17.2, 17.1, 13.2, 12.8, 12.6; HRMS-FAB m/z [M+H+] calcd
for C35H53N7O7Si2: 740.355; found: 740.362.
4.2.3. 20-(N-a-Benzyloxycarbonyl-L-threoninyl)-amino-
20-deoxy-30,50-O-(tetraisopropyldisiloxane-1,3-diyl)-
adenosine (6c). Using general procedure A, 150 mg of 5b
afforded 145 mg (67%) of 6c as a white solid, [a]2D0 ꢁ15.0
(c 0.01, CHCl3); nmax (KBr)/cmꢁ1 3334, 2947, 2862, 1648,
1499, 1248, 1040, 917, 882, 698, 605, 456; dH (400 MHz,
CD3OD) 8.19 (1H, s), 8.12 (1H, s), 7.40–7.24 (5H, m),
5.95 (1H, d, J¼3.7 Hz), 5.25 (1H, t, J¼7.0 Hz), 4.93–4.91
(1H, m), 4.18–4.00 (1H, m), 4.0–4.18 (6H, m); dC
(100 MHz, CD3OD) 172.3, 157.3, 156.0, 152.4, 148.9,
140.7, 136.6, 128.2, 127.8, 127.6, 119.3, 88.5, 83.7, 70.4,
66.9, 66.7, 62.5, 60.6, 55.6, 18.44, 16.6, 16.52, 16.49,
16.4, 16.24, 16.22, 16.1, 13.13, 13.07, 12.8, 12.5; HRMS-
FAB m/z [M+H+] calcd for C34H53N7O8Si2: 744.349; found:
744.357; Anal. Calcd for C34H53N7O8Si2: C, 54.9; H, 7.2; N,
13.2. Found: C, 54.8; H, 7.5; N, 13.5.
4.2.7. 20-(N-a-Acetyl-N-u-benzyloxycarbonyl-L-lysinyl)-
amino-20-deoxy-30,50-O-(tetraisopropyldisiloxane-1,3-
diyl)-adenosine (6g). Using general procedure A, 150 mg of
5b afforded 187 mg (79%) 6g as a white solid, [a]2D0 ꢁ43.6
(c 0.01, CH3OH); nmax (KBr)/cmꢁ1 1690, 1638, 1541, 1466,
1255, 1142, 1039, 884, 697, 604; dH (400 MHz, DMSO-
d6) 8.33 (1H, d, J¼7.7 Hz), 8.32 (1H, s), 8.07 (1H, s), 8.01
(1H, d, J¼8.0 Hz), 7.38–7.30 (7H, m), 7.24 (1H, t,
J¼5.5 Hz), 5.86 (1H, d, J¼2.6 Hz), 5.10–5.04 (2H, m),
5.00 (2H, s), 4.35 (1H, td, J¼8.8, 4.4 Hz), 4.02–3.89 (3H,
m), 2.94 (2H, br q, J¼6.3 Hz), 1.80 (3H, s), 1.69–1.59
(1H, m), 1.51–1.21 (5H, m), 1.06–0.97 (28H, m); dC
(100 MHz, DMSO-d6) 172.8, 169.7, 159.7, 156.6, 153.1,
149.3, 140.7, 137.9, 128.9, 128.3, 119.8, 88.0, 82.8, 70.0,
65.6, 62.2, 54.6, 53.0, 42.3, 40.3, 40.1, 39.9, 33.1, 29.8,
23.4, 23.0, 17.9, 17.8, 17.42, 17.39, 17.36, 13.3, 13.1,
12.7, 12.6; HRMS-TSI-TOF m/z [M+H+] calcd for
4.2.4. 20-(N-a-Benzyloxycarbonyl-L-asparaginyl)-amino-
20-deoxy-30,50-O-(tetraisopropyldisiloxane-1,3-diyl)-
adenosine (6d). Using general procedure A, 190 mg of 5b
afforded 201 mg (71%) of 6d as a white solid, [a]D20
ꢁ0.002 (c 0.01, CHCl3); nmax (KBr)/cmꢁ1 3410, 2945,
2867, 2362, 2341, 1653, 1600, 1507, 1468, 1421, 1331,
1297, 1250, 1212, 1145, 1039, 918, 885, 863, 825, 696,
603, 456, 421; dH (400 MHz, CDCl3) 8.24 (1H, s), 7.95
(1H, s), 7.67 (1H, d, J¼4.4 Hz), 7.42–7.30 (5H, m), 6.45
(1H, d, J¼8.4 Hz), 5.89 (1H, d, J¼4.0 Hz), 5.84 (2H, br s),
5.23–5.16 (2H, m), 5.06 (1H, d, J¼12.4 Hz), 4.85–4.77
(1H, m), 4.61–4.53 (1H, m), 4.10–3.99 (3H, m), 3.02–2.94
(1H, m), 2.52 (1H, dd, J¼15.8, 5.5 Hz), 1.19–0.98 (28H,

G. O’Mahony et al. / Tetrahedron 63 (2007) 6901–6908
6905
C38H60N8O8Si2: 813.415; found: 813.415. Anal. Calcd for
C38H60N8O8Si2: C, 56.1; H, 7.4; N, 13.8. Found: C, 55.7;
H, 7.4; N, 13.4.
5.04 (1H, d, J¼12.5 Hz), 4.36 (1H, d, J¼5.5 Hz), 4.24–
4.16 (1H, m, H40), 3.94 (1H, d, J¼7.0 Hz), 3.88 (1H, dd,
J¼12.3, 2.4 Hz), 3.77 (1H, dd, J¼12.3, 2.2 Hz), 1.73–1.60
(1H, m), 1.24–1.14 (1H, m), 0.69–0.81 (6H, m); dC
(100 MHz, CD3OD) 173.0, 157.3, 156.2, 152.2, 149.0,
140.4, 136.8, 128.2, 127.7, 127.6, 119.5, 88.7, 88.1, 71.2,
66.5, 62.4, 60.0, 55.6, 36.4, 24.3, 14.5, 10.1; HRMS-FAB
m/z [M+H+] calcd for C24H31N7O6: 514.234; found:
514.254. Anal. Calcd for C24H31N7O6: C, 56.1; H, 6.1; N,
19.1. Found: C, 56.4; H, 6.1; N, 18.9.
4.2.8. 20-(N-a-Benzyloxycarbonyl-L-IlePhe)-amino-20-
deoxy-30,50-O-(tetraisopropyldisiloxane-1,3-diyl)-adeno-
sine (9). Using general procedure A, 220 mg of 5b afforded
281 mg (72%) of 9 as a white solid, [a]2D0 ꢁ35.8 (c 0.01,
CHCl3); nmax (KBr)/cmꢁ1 3324, 1706, 1652; dH (400 MHz,
CDCl3) 8.21 (1H, s), 7.95 (1H, s), 7.43–7.03 (10H, m), 5.90
(1H, d, J¼3.4 Hz), 5.26 (1H, m), 5.10 (1H, d, J¼12.1 Hz),
5.02 (1H, d, J¼12.5 Hz), 4.78–4.73 (2H, m), 4.02–4.00
(4H, m), 3.12 (1H, dd, J¼12.1 Hz, CHCHHPh), 2.91 (1H,
dd, J¼12.5 Hz, CHCHHPh), 1.68–1.78 (1H, m), 1.32–1.24
(1H, m), 1.13–0.98 (29H, m), 0.81–0.77 (6H, m); dC
(100 MHz, CDCl3) 172.0, 156.5, 155.9, 152.9, 149.3,
140.4, 136.3, 136.2, 129.1, 128.5, 128.2, 128.0, 126.9,
120.0, 88.1, 83.5, 70.1, 67.0, 62.4, 59.8, 56.1, 54.4, 37.4,
37.0, 24.6, 17.5, 17.4, 17.3, 17.2, 17.08, 17.05, 17.0, 15.4,
13.1, 12.8, 12.6, 11.2; HRMS-FAB m/z [M+H+] calcd for
C45H66N8O8Si2: 903.462; found: 903.462. Anal. Calcd for
C45H66N8O8Si2: C, 59.84; H, 7.37; N, 12.41. Found: C,
59.71; H, 7.46; N, 12.34.
4.3.3. 20-(N-a-Benzyloxycarbonyl-L-threoninyl)-amino-
20-deoxyadenosine (7c). Using general procedure B,
133 mg of 6c afforded 80 mg (89%) of 7c as a white solid,
[a]2D0 ꢁ11.5 (c 0.01, MeOH); nmax (KBr)/cmꢁ1 3333,
2930, 1652, 1603, 1509, 1424, 1376, 1334, 1301, 1253,
1092, 904, 867, 797, 737, 698, 644; dH (400 MHz,
CD3OD) 8.21 (1H, s), 8.16 (1H, s), 7.37–7.74 (5H, m),
6.00 (1H, d, J¼8.0 Hz), 5.15–5.04 (3H, m), 4.40 (1H, d,
J¼5.5 Hz), 4.19–4.23 (1H, m), 3.95–4.05 (2H, m), 3.88
(1H, dd, J¼12.4, 2.6 Hz), 3.77 (1H, dd, J¼12.4, 2.6 Hz),
1.08 (3H, d, J¼6.2 Hz); dC (100 MHz, CD3OD) 172.0,
157.3, 156.2, 152.1, 148.9, 140.5, 136.7, 128.2, 127.8,
127.6, 119.6, 88.6, 88.5, 71.1, 66.9, 66.6, 62.4, 60.6, 56.0,
18.5; HRMS-FAB m/z [M+H+] calcd for C23H29N7O7:
502.205; found: 502.206.
4.3. Removal of the 1,1,3,3-tetraisopropyl-1,3-
disiloxane-1,3-diyl protecting group of compounds
6a–g (general procedure B)
4.3.4. 20-(N-a-Benzyloxycarbonyl-L-asparaginyl)-amino-
20-deoxyadenosine (7d). Using general procedure B,
89 mg of 6d afforded 47 mg (78%) of 7d as a white solid,
[a]2D0 ꢁ58.6 (c 0.01, MeOH); dH (400 MHz, CD3OD) 8.15
(1H, s), 8.09 (1H, s), 7.36–7.24 (5H, m), 5.93 (1H, d,
J¼8.4 Hz), 5.11 (1H, dd, J¼8.2, 5.3 Hz), 5.06 (2H, s),
4.36–4.24 (2H, m), 4.21 (1H, br s), 3.87 (1H, dd, J¼12.5,
2.2 Hz), 3.75 (1H, dd, J¼12.5, 2.4 Hz), 2.59 (1H, dd,
J¼15.6, 6.1 Hz), 2.49 (1H, dd, J¼15.6, 7.1 Hz); dC
(100 MHz, CD3OD) 175.0, 173.8, 158.3, 157.7, 153.5,
150.3, 142.1, 138.2 129.6, 129.2, 129.1, 121.2, 90.2, 89.9,
72.7, 68.0, 63.7, 57.3, 53.3, 37.9, 18.52; HRMS-FAB m/z
[M+H+] calcd for C22H26N8O7: 515.192; found: 515.200.
Anal. Calcd for C22H26N8O7: C, 51.36; H, 5.09; N, 21.78.
Found: C, 51.40; H, 5.16; N, 21.71.
30,50-O-(Tetraisopropyldisiloxane-1,3-diyl)-protected com-
pounds 6a–g (1 equiv) were suspended in methanol
(10 mL), ammonium fluoride (10 equiv) was added and
the mixture was stirred at room temperature until TLC anal-
ysis (9:1 CH2Cl2/MeOH) indicated that there was no starting
material left, usually taking at least 16 h. The solvent was re-
moved under reduced pressure and the residue purified by
column chromatography, eluting with 9:1 CH2Cl2/MeOH.
4.3.1. 20-(N-a-Benzyloxycarbonyl-L-valinyl)-amino-20-
deoxyadenosine (7a). Using general procedure B, 208 mg
of 6a afforded 123 mg (88%) of 7a as a white solid, [a]D20
ꢁ59.0 (c 0.01, MeOH); nmax (KBr)/cmꢁ1 3329, 1647,
1601; dH (400 MHz, CD3OD) 8.20 (1H, s), 8.16 (1H, s),
7.37–7.23 (5H, m), 5.98 (1H, d, J¼8.4 Hz), 5.99 (1H, dd,
J¼8.4, 3.2 Hz), 5.08 (1H, d, J¼12.5 Hz), 5.03 (1H, d,
J¼12.5 Hz), 4.36 (1H, d, J¼5.5 Hz), 4.24–4.16 (1H, m),
3.92–3.84 (2H, m), 3.77 (1H, dd, J¼12.4, 2.2 Hz), 1.98–
1.87 (1H, m), 0.82 (3H, d, J¼7.0 Hz), 0.75 (3H, d,
J¼7.0 Hz); dC (100 MHz, CD3OD) 173.1, 157.3, 156.2,
152.2, 149.0, 140.4, 136.8, 128.2, 127.8, 127.6, 119.6,
88.7, 88.3, 71.2, 66.5, 62.4, 60.8, 55.6, 30.1, 18.3, 16.9;
HRMS-FAB m/z [M+H+] calcd for C23H29N7O6: 500.218;
found: 500.211. Anal. Calcd for C23H29N7O6: C, 55.3; H,
5.9; N, 19.6. Found: C, 55.3; H, 6.0; N, 19.9.
4.3.5. 20-(N-a-Benzyloxycarbonyl-L-phenylalaninyl)-
amino-20-deoxyadenosine (7e). Using general procedure
B, 213 mg of 6e afforded 128 mg (87%) of 7e as a white
solid, [a]2D0 ꢁ81.0 (c 0.01, MeOH); nmax (KBr)/cmꢁ1 3310,
3170, 2918, 1731, 1652, 1603, 1516, 1496, 1454, 1375,
1336, 1301, 1223, 1093, 1044, 985, 905, 867, 797, 744,
697, 638, 492; dH (400 MHz, CD3OD) 8.27 (1H, s), 8.15
(1H, s), 7.36–7.16 (10H, m), 5.99 (1H, d, J¼8.1 Hz), 5.84
(1H, d, J¼4.4 Hz), 5.60 (1H, dd, J¼4.4, 7.0 Hz), 5.12–
5.07 (1H, m), 4.93 (1H, d, J¼12.5 Hz), 4.87 (1H, d,
J¼12.8 Hz), 4.27–4.24 (2H, m), 4.08 (1H, s), 2.91 (1H,
dd, J¼4.0, 13.5 Hz), 2.67 (1H, dd, J¼10.6, 13.9 Hz); dC
(100 MHz, CD3OD) 172.3, 156.7, 156.3, 152.9, 149.9,
140.3, 138.5, 137.5, 129.7, 128.9, 128.6, 128.2, 128.0,
126.8, 119.9, 88.0, 86.9, 71.0, 65.9, 62.5, 56.7, 55.3, 38.0;
HRMS-FAB m/z [M+H+] calcd for C27H29N7O6: 548.218;
found: 548.226.
4.3.2. 20-(N-a-Benzyloxycarbonyl-L-isoleucinyl)-amino-
20-deoxyadenosine (7b). Using general procedure B,
63 mg of 6b afforded 29 mg (67%) of 7b as a white solid,
[a]2D0 ꢁ89.0 (c 0.01, CHCl3); nmax (KBr)/cmꢁ1 3336, 2963,
2367, 2344, 1772, 1734, 1700, 1684, 1647, 1601, 1576,
1560, 1540, 1508, 1457, 1420, 1374, 1333, 1252, 1095,
867, 798, 753, 648, 697; dH (400 MHz, CD3OD) 8.21 (1H,
s), 8.17 (1H, s), 7.39–7.23 (5H, m), 6.00 (1H, d, J¼8.4 Hz),
5.19 (1H, dd, J¼5.5, 8.4 Hz), 5.08 (1H, d, J¼12.5 Hz),
4.3.6. 20-(N-a-Benzyloxycarbonyl-L-prolinyl)-amino-20-
deoxyadenosine (7f). Using general procedure B, 227 mg

6906
G. O’Mahony et al. / Tetrahedron 63 (2007) 6901–6908
of 6f afforded 136 mg (89%) of 7f as a white solid, [a]D20
ꢁ115.8 (c 0.01, MeOH); nmax (KBr)/cmꢁ1 3306, 2915,
2359, 1711, 1678, 1644, 1604, 1524, 1407, 1357, 1339,
1301, 1098, 984, 798, 743, 695, 647; dH (400 MHz,
CD3OD) 8.20 (1H, s), 8.11 (1H, s), 7.35–7.21 (5H, m),
5.95 (1H, d, J¼8.0 Hz), 5.75 (1H, s), 5.55–5.52 (1H, m),
5.07–4.93 (3H, m), 4.54 (1H, d, J¼13.2 Hz), 4.27–4.22
(2H, m), 4.04 (1H, d, J¼1.5 Hz), 3.70–3.67 (1H, m), 3.61–
3.55 (1H, m), 3.36–3.21 (2H, m), 2.09–1.96 (1H, m),
1.79–1.73 (3H, m); dC (100 MHz, CD3OD) 174.2, 156.2,
154.9, 152.3, 149.0, 140.2, 136.6, 126.8–128.2, 119.8,
88.8, 88.6, 71.2, 67.0, 62.6, 60.4, 55.9, 46.7, 29.8, 24.1;
HRMS-FAB m/z [M+H+] calcd for C23H27N7O6: 498.202;
found: 498.210.
4.4.1. 20-(L-Valinyl)-amino-20-deoxyadenosine (8a). Using
general procedure C, 109 mg of 7a and 23 mg 10% Pd on C
afforded 77 mg (96%) 8a as a white powder, [a]2D0 ꢁ15.0
(c 0.01, MeOH); nmax (KBr)/cmꢁ1 3333, 1649, 1603; dH
(400 MHz, CD3OD) 8.30 (1H, s), 8.18 (1H, s), 6.06 (1H,
d, J¼8.1 Hz), 5.26 (1H, dd, J¼8.2, 5.3 Hz), 4.39 (1H, dd,
J¼5.1, 1.1 Hz), 4.23–4.18 (1H, m), 3.87 (1H, dd, J¼12.5,
2.6 Hz), 3.77 (1H, dd, J¼12.5, 2.6 Hz), 3.55 (1H, d,
J¼3.6 Hz), 2.15–2.05 (1H, m), 1.00 (3H, d, J¼7.0 Hz),
0.94 (3H, d, J¼7.0 Hz); dC (100 MHz, CD3OD) 170.5,
156.2, 152.3, 149.0, 140.3, 119.5, 88.5, 87.7, 71.0, 62.3,
58.6, 55.8, 30.5, 17.7, 16.2; HRMS-FAB m/z [M+H+] calcd
for C15H23N7O4: 366.181; found: 366.186.
4.4.2. 20-(L-Isoleucinyl)-amino-20-deoxyadenosine (8b).
Using general procedure C, 42 mg of 7b and 9 mg 10% Pd
on C afforded 31 mg (99%) of 8b as a white powder, [a]D20
ꢁ102.7 (c 0.01, MeOH); nmax (KBr)/cmꢁ1 3333, 1648,
1603, 1516, 1479, 1423, 1375, 1303, 1248, 1093, 886,
648; dH (400 MHz, CD3OD) 8.29 (1H, s), 8.18 (1H, s),
6.03 (1H, d, J¼8.4 Hz), 5.21 (1H, dd, J¼8.4, 5.5 Hz), 4.37
(1H, d, J¼5.1 Hz), 4.23–4.19 (1H, m), 3.87 (1H, dd,
J¼2.9, 12.5 Hz), 3.77 (1H, dd, J¼2.6, 12.4 Hz), 3.39 (1H,
m), 1.69–1.61 (1H, m), 1.23–1.13 (2H, m), 0.85 (3H, d,
J¼7.0 Hz), 0.77 (3H, t, J¼7.3 Hz); dC (100 MHz, CD3OD)
175.5, 156.2, 152.3, 149.1, 140.4, 119.5, 88.6, 87.9, 71.3,
62.4, 59.4, 55.5, 38.3, 23.6, 14.7, 10.7; HRMS-FAB m/z
[M+H+] calcd for C16H25N7O4: 380.205; found: 380.209.
Anal. Calcd for C16H25N7O4: C, 50.65; H, 6.64; N, 25.84.
Found: C, 50.61; H, 6.73; N, 25.73.
4.3.7. 20-(N-a-Acetyl-N-u-benzyloxycarbonyl-L-lysinyl)-
amino-20-deoxyadenosine (5g). Using general procedure
B, 176 mg of 6g afforded 111 mg (88%) of 7g as a white
solid, [a]2D0 ꢁ71.0 (c 0.1, MeOH); nmax (KBr)/cmꢁ1 3420,
1701, 1684, 1650, 1542, 1260, 1094, 733, 698, 646; dH
(400 MHz, CD3OD) 8.20 (1H, s), 8.17 (1H, s), 7.33–7.26
(5H, m), 5.98 (1H, d, J¼8.3 Hz), 5.14 (1H, dd, J¼8.3,
5.5 Hz), 5.05 (2H, s), 4.38 (1H, d, J¼5.5 Hz), 4.23–4.19
(2H, m), 3.88 (1H, dd, J¼12.6, 2.6 Hz), 3.76 (1H, dd,
J¼12.6, 2.4 Hz), 3.07 (2H, t, J¼7.0 Hz), 1.91 (3H, s),
1.67–1.40 (4H, 3ꢂm), 1.32–1.19 (2H, m); dC (100 MHz,
CD3OD) 173.3, 172.1, 157.6, 156.2, 152.1, 148.9, 140.4,
137.1, 128.1, 127.6, 127.4, 119.6, 88.6, 88.5, 71.1, 66.0,
62.4, 55.7, 53.5, 40.1, 30.9, 29.2, 22.6, 21.0; HRMS-FAB
m/z [M+H+] calcd for C26H34N8O7: 570.263; found:
570.262.
4.4.3. 20-(L-Threoninyl)-amino-20-deoxyadenosine (8c).
Using general procedure C, 45 mg of 7c and 19 mg 10%
Pd on C afforded 32 mg (97%) of 8c as a white powder,
[a]2D0 ꢁ56.4 (c 0.01, MeOH); nmax (KBr)/cmꢁ1 3339,
1653, 1603, 1479, 1425, 1376, 1334, 1303, 1251, 1093,
900, 797, 645; dH (400 MHz, CD3OD) 8.26 (1H, s), 8.17
(1H, s), 6.01 (1H, d, J¼8.4 Hz), 5.16 (1H, dd, J¼8.0,
5.5 Hz), 4.41 (1H, dd, J¼5.5, 1.1 Hz), 4.24–4.19 (1H, m),
3.89 (1H, dd, J(AB)¼12.5, 2.9 Hz, H50), 3.85–3.81 (1H,
m, HOCH2CHCH3), 3.77 (1H, dd, J(AB)¼12.5, 2.6 Hz,
H50), 3.17–3.11 (2H, m, HOCH2CHCH3), 1.10 (3H, d,
J¼6.24 Hz, CH3); 13C NMR 174.0, 156.2, 152.2, 148.9,
140.5, 119.6, 88.5, 71.3, 67.9, 62.4, 60.1, 55.7, 18.5;
HRMS-FAB m/z [M+H+] calcd for C15H23N7O5: 380.205;
found: 380.209.
4.3.8. 20-(N-a-Benzyloxycarbonyl-L-IlePhe)-amino-20-de-
oxyadenosine (10). Using general procedure B, 242 mg of 9
afforded 117 mg of 10 as a white solid, [a]2D0 ꢁ115.8 (c 0.01,
MeOH); nmax (KBr)/cmꢁ1 3320, 1648, 1599; dH (400 MHz,
CD3OD) 8.25 (1H, s), 8.13 (1H, s), 7.34–7.11 (10H, m), 5.96
(1H, d, J¼8.1 Hz), 5.71 (1H, d, J¼4.4 Hz), 5.54 (1H, dd,
J¼4.4, 7.0 Hz), 5.11–5.06 (1H, m), 5.06–4.97 (2H, m),
4.57–4.52 (1H, m), 4.24 (1H, t, J¼2.8 Hz), 4.05 (1H, s),
3.79 (1H, t, J¼8.4 Hz), 3.70–3.66 (1H, m), 3.60–3.54 (1H,
m), 2.92 (1H, dd, J¼4.8, 13.9 Hz), 2.73 (1H, dd, J¼9.5,
13.9 Hz), 1.57–1.51 (1H, m), 1.27–1.20 (1H, m), 0.98–
0.91 (1H, m), 0.70 (3H, t, J¼7.3 Hz), 0.55 (3H, t,
J¼7.0 Hz); dC (100 MHz, CD3OD) 171.7, 171.5, 156.7,
156.4, 152.9, 149.9, 140.2, 138.1, 137.6, 129.7, 128.9,
128.5, 128.3, 128.2, 126.7, 199.9, 87.9, 86.7, 71.1, 65.9,
62.4, 59.7, 55.2, 54.1, 49.2, 37.9, 36.9, 24.8, 15.6, 11.3;
HRMS-FAB m/z [M+H+] calcd for C33H40N8O7: 661.310;
found: 661.311.
4.4.4. 20-(L-Asparaginyl)-amino-20-deoxyadenosine (8d).
Using general procedure C, 38 mg of 7d and 20 mg 10%
Pd on C afforded 27 mg (96%) of 8d as a white powder,
[a]2D0 ꢁ90.3 (c 0.01, MeOH); nmax (KBr)/cmꢁ1 3341,
2931, 2362, 2342, 1653, 1603, 1578, 1560, 1541, 1522,
1508, 1580, 1422, 1377, 1335, 1302, 1253, 1092, 1064,
896, 867, 797, 728, 668, 645; dH (400 MHz, DMSO-d6)
8.28 (1H, s), 8.17 (1H, s), 7.37 (1H, br s), 6.88 (1H, br s),
5.98 (1H, d, J¼8.1 Hz), 5.86 (1H, d, J¼4.4 Hz), 5.74 (1H,
dd, J¼7.7, 4.0 Hz), 5.04 (1H, m), 4.29 (1H, t, J¼4.8 Hz),
4.09–4.11 (1H, m), 3.68–3.73 (1H, m), 3.60–3.66 (1H, m),
2.34 (1H, dd, J¼14.7, 3.7 Hz), 2.04 (1H, dd, J¼15.0,
9.5 Hz); dC (100 MHz, CD3OD) 175.3, 174.4, 156.2,
152.2, 148.9, 140.7, 119.7, 88.5, 88.4, 71.4, 62.5, 55.9,
51.8, 39.5; HRMS-FAB m/z [M+H+] calcd for
C14H20N8O5: 381.163; found: 381.164. Anal. Calcd for
4.4. Removal of the N-Cbz protecting group
(general procedure C)
The N-Cbz protected compounds 7a–g (1 equiv) was sus-
pended in methanol (6 mL), 10% palladium on carbon was
added and the mixture was stirred at room temperature under
balloon pressure of hydrogen gas until TLC analysis (9:1
CH2Cl2/MeOH) indicated that there was no starting material
left. The catalyst was filtered off through a pad of CeliteÒ
and washed well with methanol. The solvent was removed
under reduced pressure affording the product as a white
powder.

G. O’Mahony et al. / Tetrahedron 63 (2007) 6901–6908
6907
C14H20N8O5: C, 44.21; H, 5.30; N, 29.46. Found: C, 44.08;
H, 5.38; N, 29.41.
J¼2.1, 10.3 Hz), 3.02–2.95 (1H, m), 2.86–2.81 (1H, m),
1.55–1.47 (1H, m), 1.19–1.11 (1H, m), 0.96–0.88 (1H, m),
0.74 (3H, t, J¼7.3 Hz), 0.67 (3H, d, J¼7.0 Hz); dC
(100 MHz, CD3OD) 175.7, 172.4, 156.2, 152.1, 149.0,
140.5, 136.9, 128.9, 128.2, 126.5, 119.7, 88.6, 88.2, 71.2,
64.1, 62.4, 55.6, 54.5, 37.8, 37.4, 23.8, 14.6, 10.5; HRMS-
FAB m/z [M+H+] calcd for C25H34N8O5: 527.273; found:
527.273.
4.4.5. 20-(L-Phenylalaninyl)-amino-20-deoxyadenosine
(8e). Using general procedure C, 90 mg of 7e and 25 mg
10% Pd on C afforded 55 mg (81%) of 8e as a white powder,
[a]D20 ꢁ94.1 (c 0.01, MeOH); nmax (KBr)/cmꢁ1 3308, 3166,
2916, 2359, 1676, 1644, 1603, 1519, 1477, 1301, 1096,
987, 867, 797, 700, 648, 534, 488; dH (400 MHz, CD3OD)
8.31 (1H, s), 8.15 (1H, s), 7.36 (2H, s), 7.12 (2H, d,
J¼1.8 Hz), 6.99 (1H, t, J¼3.2 Hz), 5.93 (1H, d, J¼8.4 Hz),
5.88 (1H, s), 5.63 (1H, s), 5.06 (1H, d, J¼4.4 Hz), 4.22
(1H, d, J¼3.3 Hz), 4.06 (1H, s), 3.71–3.69 (1H, m), 3.61–
3.58 (1H, m), 3.38 (1H, t, J¼4.8 Hz), 2.73 (1H, dd, J¼4.4,
13.2 Hz), 2.54 (1H, dd, J¼8.1, 13.6 Hz, CHCHHPh); dC
(100 MHz, CD3OD) 174.9, 156.7, 152.9, 149.9, 140.4,
138.7, 129.7, 128.6, 119.9, 88.1, 87.1, 71.4, 62.5, 56.4, 54.8,
40.8; HRMS-FAB m/z [M+H+] calcd for C19H23N7O4:
414.189; found: 414.189. Anal. Calcd for C19H23N7O4: C,
55.20; H, 5.61; N, 23.72. Found: C, 55.08; H, 5.69; N, 23.65.
Acknowledgements
We thank the Knut and Alice Wallenberg Foundation and
€
Goteborg University for financial assistance.
Supplementary data
1H NMR spectra of compounds 7f, 8g, 10 and 11, and 13C
NMR spectra for compounds 7c, 7e, 8a, 8c, 8f and 10. Sup-
plementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2007.04.038.
4.4.6. 20-(L-Prolinyl)-amino-20-deoxyadenosine (8f). Us-
ing general procedure C, 110 mg of 7f and 32 mg 10% Pd
on C afforded 80 mg (99%) of 8f as a white powder, [a]D20
ꢁ112.4 (c 0.01, MeOH); nmax (KBr)/cmꢁ1 3303, 3164,
2912, 2341, 1679, 1631, 1606, 1526, 1478, 1421, 1302,
1242, 1100, 983, 871, 798, 692, 668; dH (400 MHz,
CD3OD) 8.29 (1H, s), 8.10 (1H, s), 5.91 (1H, d, J¼8.4 Hz),
4.93–4.87 (1H, m), 4.20 (1H, d, J¼4.8 Hz), 4.09 (1H, s),
3.71 (1H, d, J¼10.8 Hz), 3.61 (1H, d, J¼10.8 Hz), 3.44
(1H, dd, J¼5.2, 9.2 Hz), 2.86–2.80 (1H, m), 2.72–2.66
(1H, m), 1.78–1.70 (1H, m), 1.49–1.34 (2H, m), 1.31–1.24
(1H, m); dC (100 MHz, CD3OD) 175.0, 156.6, 152.8,
149.7, 140.1, 119.8, 88.4, 87.6, 71.5, 62.5, 60.6, 55.2,
47.1, 30.9, 26.1; HRMS-FAB: m/z [M+H+] calcd for
C15H21N7O4: 364.173; found: 364.173. Anal. Calcd for
C15H21N7O4: C, 49.58; H, 5.83; N, 26.98. Found: C, 49.46;
H, 5.83; N, 26.86.
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