Novel observation concerning the nitrobenzenesulfonamide protecting group

Article abstract of DOI:10.1016/j.tetlet.2006.01.110

In an ongoing work directed towards the synthesis of nucleoside derivatives containing an l-alanine residue, we report herein a novel observation concerning the Ns-protecting group: the epimerization of the α-hydrogen in acylation conditions.

Full text of DOI:10.1016/j.tetlet.2006.01.110

Tetrahedron Letters 47 (2006) 2191–2195
Novel observation concerning the
nitrobenzenesulfonamide protecting group
*
´
´
Estelle Vallee, Freddy Loemba, Melanie Etheve-Quelquejeu and Jean-Marc Valery
`
´
Synthese, Structure et Fonction de Molecules Bioactives—UMR CNRS 7613, Equipe ‘Chimie des Glucides’,
Universite´ Pierre et Marie Curie, 4 place Jussieu, Case 179, 75252 Paris Cedex 05, France
Received 4 October 2005; revised 20 January 2006; accepted 23 January 2006
Abstract—In an ongoing work directed towards the synthesis of nucleoside derivatives containing an L-alanine residue, we report
herein a novel observation concerning the Ns-protecting group: the epimerization of the a-hydrogen in acylation conditions.
ꢀ 2006 Elsevier Ltd. All rights reserved.
NO2
1. Introduction
Ns OMe
Ns
N
a
c
c
N
O
COOH
As a part of an ongoing programme directed to the syn-
thesis of a modified adenosine bearing a 20,30-cyclized
peptidic moiety,1 we needed to prepare compounds 5.
As depicted in Scheme 1 this required the acylation of
the 30-O by a N-protected L-alanyl residue suitably N-
alkylated.
4a 68%
3a 80%
SO2 OMe
HN
O
Ns OMe
Ns
b
N
O
n
N
n
COOH
OH
n
n = 2 3b 99%
n = 3 3c 63%
n = 4 3d 95%
n = 2 4b 56%
n = 3 4c 66%
n = 4 4d 62%
Such functionalized amino acids can be readily obtained
using the methodology recently developed by Fukuyama
and co-workers,2 according to Scheme 2.
Scheme 2. Reagents and conditions: (a) allylbromide, K2CO3; (b)
DEAD, P(Ph)3; (c) (i) LiOH, (ii) HCl.
It is important to notice that racemization was never
observed during the alkylation step.3
presence of DMAP in refluxing dichloromethane
(Scheme 3).
2. Results and discussion
Surprisingly NMR analysis of the so obtained deriva-
tives revealed the presence of two compounds, which
could not be separated by column chromatography.
The final acylation step at 30-O of the protected
adenosine 1 was first conducted using EDCI in the
NHBz
NHBz
NH2
N
N
N
N
N
N
N
TBDMSO
TBDMSO
O
HO
N
N
N
N
O
O
N
O
R
HO
O
O
O
n
N
CO2H
HO OH
n
adenosine
N
R
1
5
Scheme 1.
*
Corresponding author. Tel.: +33 1 44 27 58 93; e-mail: quelque@ccr.jussieu.fr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.110

2192
E. Vallee et al. / Tetrahedron Letters 47 (2006) 2191–2195
NHBz
NHBz
N
N
N
N
N
N
N
TBDMSO
TBDMSO
N
O
Ns
N
O
COOH
a
+
n
O
N
O
O
HO
O
1
4a n=1
4b n=2
4c n=3
n
p-Ns
ratio of
isomers
Ns
5a n=1 81 %
5b n=2 64 %
5c n=3 85 %
5e n=1 61%
74/26
85/15
53/47
o-Ns
4e n = 1 o-Ns
p-Ns
Scheme 3. Reagents and conditions: (a) EDCI, DMAP, CH2Cl2, D.
SOCl2, CH2Cl2,
, 1 h
For 5a and 5b mass spectrometry showed a single peak
at m/z = 822.4 and 836.4, respectively, although in H
pNs
N
X
pNs
1
∆
N
COOH
NMR, two characteristic doublets appear for H10 (this
differentiation was used to quantify the two isomers
and the ratio was done in Scheme 3 for each compound).
For compound 5e (protected by the ortho-nitrobenzene-
sulfonamide group o-Ns) the two signals corresponding
to the H10 overlap, but the result seems comparable to
that obtained for compound 5a (about 20% in condi-
tions of Table 1, entry 1). All those facts suggest the par-
tial epimerization of the chiral centre on the amino acid
moiety. To reduce this side effect, many acylation condi-
tions were tested and described in Table 1. We observed
that an excess of EDCI (Table 1, entry 2) increased the
epimerization and a shortened reaction time decreased
the epimerization. Unfortunately, the yield appeared
very low in the latter (Table 1, entry 3). This method
(EDCI, DMAP) is known to be problematic,4 so a vari-
ety of coupling reagents were tested.
O
or
F
N
N
X = Cl, 6a 92%
X= F, 7a 83%
4a
F
N
F
CH2Cl2, pyr., −15°C, 1 h
Scheme 4.
but the yield was dramatically low (24%) and if we run
the condensation by refluxing in CH2Cl2, the percentage
of epimerization increased. With the method developed
by Carpino et al.7 (Table 1, entry 9) using acid fluoride
as intermediate (the acid fluoride was obtained under
mild nonacidic conditions by reaction of the carboxylic
acid with cyanuric fluoride and pyridine, Scheme 4), the
result was not any better.
At this stage, it seems that the presence of Ns-protecting
group increases the acidity of the a-hydrogen in the ami-
no acid moiety, and in many conditions of acylation,
substantial epimerization was observed at the chiral cen-
tre of the amino acid part. To be sure that the presence
of Ns-protecting group is responsible for this side reac-
tion, the acylation was done with the NCbz L-alanine
derivative 88 and the desired product 9 was obtained
without epimerization9 (Scheme 5).
The phosphonium reagent: ‘BOP reagent’5 (Table 1,
entry 7) known as a racemization suppressant, gave no
acylation product. With additives like HOAt (1-hydro-
xy-7-azabenzotriazole) in the presence of carbodiimide
reagent, or HBTU (Table 1, entries 4 and 5) the percent-
age of epimerization is very high. It is known that the
highly reactive aminoacyl chloride protected at the
nitrogen atom by an arene or heteroarenesulfonyl group
can be used for peptide coupling and can avoid the risk
of racemization.6 In our case, the lower percentage of
epimerization was obtained from the corresponding
amino acid chloride 6a (Table 1, entry 8; Scheme 4),
In conclusion, even if the use of Ns-strategy presents a
lot of advantages, the organic chemist has to be aware
that during the acylation process, the presence of this
protecting group could induce unfavourable side effects.
Table 1. Coupling of optically pure 4a under different conditions
Entry
Yield (%)
Ratio of isomers 5a
1
2
3
4
5
6
7
8
9
EDCI (1.2 equiv), DMAP (1.2 equiv)a
EDCI (1.7 equiv), DMAP (1.2 equiv)a
EDCI (1.1 equiv), DMAP (1.2 equiv)b
EDCI (1.1 equiv), HOAt (0.9 equiv), NMM (1 equiv)c
HBTU (0.9 equiv), DIPEA (1 equiv)c
‘Bop reagent’
81
78
32
32
32
—
24
40
25
50
74/26
54/46
86/14
51/49
60/40
—
99/01
95/05
89/11
76/24
Acid chloride, pyr. (1.1 equiv)c
Acid chloride, pyr. (1.1 equiv)a
Acid fluoride, pyr.a
10
Symmetrical anhydride
a D, 18 h.
b D, 2 h.
c Room temperature, 2 h.

E. Vallee et al. / Tetrahedron Letters 47 (2006) 2191–2195
2193
NHBz
NHBz
N
N
N
N
N
N
TBDMSO
TBDMSO
O
N
N
O
O
Cbz
N
COOH
+
a
HO
O
O
O
N
1
8
9
Cbz
Scheme 5. No epimerization observed during the acylation step. Reagents and conditions: (a) EDCI, DMAP, CH2Cl2, D.
1
In our particular case, new strategies have to be devel-
oped to prepare adenosine derivatives 5.
yield. [a]D ꢀ31.3 (c 1.03, CH2Cl2). H NMR (CDCl3,
250 MHz): d = 1.51 (d, 3H, J = 7,4 Hz, CH3); 2.22–
2.61 (2 m, 2H, CH2bN); 3.07–3.41 (m, 2H, CH2aN);
4.63 (m, 1H, CH); 5.07 (m, 2H, CH2@); 5.68 (m, 1H,
CH@); 7.97–8.06 (m, 2H, 2 · CHAr); 8.30–8.38 (m,
2H, 2 · CHAr); 9.77 (br s, 1H, CO2H) ppm 13C NMR
(CDCl3, 63 MHz): d = 16.7 (CH3); 35.2 (CH2bN); 45.9
(CH2aN); 55.6 (CH); 117.5 (CH2@); 124.1; 128.5
(4 · CHAr); 133.9 (CH@); 145.3; 150.0 (2 · CqAr);
176.8 (CO) ppm. Ms (IC NH3+): 346 (M+NH4+).
3. Experimental
3.1. General methods
1H and 13C NMR spectra were recorded in CDCl3 solu-
tion. All assignments were confirmed by 2D experiments
and Dept 135. Moisture-sensitive reactions were con-
ducted under argon in oven-dried glassware. All chemi-
cal reagents were purchased from Aldrich Chemical Co.
and used without further purification. THF was distilled
over sodium and benzophenone. Dichloromethane was
distilled over P2O5. Column chromatography was per-
formed on E. Merck Silica gel 60 (230–400 mesh). Ana-
lytical thin layer chromatography was performed on E.
Merck aluminium plates of Silica Gel 60F-254 with
detection by UV and by spraying with 6 N H2SO4 and
heating for about 1 min at 300 ꢁC.
3.2.3. (S)-2[Pent-4-enyl-(4-nitro-benzenesulfonyl)-amino]-
propionic acid 4c. Preparation as described in the
general procedure afforded 4c as a yellowish solid in
66% yield. [a]D ꢀ31 (c 0.93, CH2Cl2). 1H NMR
(CDCl3, 250 MHz): d = 1.48 (d, 3H, J = 7.2 Hz,
CH3); 1.56–1.97 (2m, 2H, CH2bN); 2.07 (m, 2H,
CH2cN); 3.02–3.36 (2m, 2H, CH2aN); 4.63 (q, 1H,
J = 7.5 Hz, CH); 4.97–5.20 (m, 3H, CH2@, CO2H);
5.73 (m, 1H, CH@); 7.97–8.02 (m, 2H, 2 · CHAr);
8.29–8.34 (m, 2H, 2 · CHAr) ppm 13C NMR (CDCl3,
63 MHz): d = 17.0 (CH3); 30.1 (CH2bN); 31.0
(CH2cN); 46.1 (CH2aN); 55.7 (CH); 115.8 (CH2@);
124.3; 128.7 (4 · CHAr); 137.2 (CH@); 145.7; 150.1
(2 · CqAr); 175.2 (CO) ppm. Ms (IC NH3+): 360
(M+NH4+).
3.2. General procedure for hydrolysis of esters
To a solution of 3 (2 mmol) in THF (10 mL) was added
LiOH 0.5 M (4 mmol). The reaction mixture was stirred
at room temperature for 30 min. and concentrated
under reduced pressure. Ether and saturated aqueous
NaHCO3 were added. The layers were separated, and
the ether layer was washed with saturated aqueous
NaHCO3. The combined aqueous layer was acidified
with concentrated HCl and extracted with Ether. The
organic phase was dried (MgSO4) and concentrated
under reduced pressure to give acid 4.
3.2.4. (S)-2-[Hex-5-enyl-(4-nitro-benzenesulfonyl)-amino]-
propionic acid 4d. Preparation as described in the
general procedure afforded 4d as a yellowish solid in
1
62% yield. H NMR (CDCl3, 250 MHz): d = 1.38 (m,
2H, CH2cN); 1.49 (d, 3H, J = 7,5 Hz, CH3); 1.50–
1.84 (2m, 2H, CH2bN); 2.02 (m, 2H, CH2dN); 3.05–
3.35 (2m, 2H, CH2aN); 4.62 (q, 1H, J = 7,5 Hz, CH);
4.92–5.01 (m, 2H, CH2@); 5.50–5.81 (m, 2H, CH@,
CO2H); 7.97–8.02 (m, 2H, 2 · CHAr); 8.29–8.34 (m,
2H, 2 · CHAr) ppm 13C NMR (CDCl3, 63 MHz):
d = 16.9 (CH3); 26.1 (CH2cN); 30.4 (CH2bN); 33.2
(CH2dN); 46.6 (CH2aN); 55.7 (CH); 115.1 (CH2@);
124.2; 128.6 (4 · CHAr); 138.2 (CH@); 145.7; 150.1
(2 · CqAr); 175.4 (CO) ppm. MS (IC NH3+): 374
(M+NH4+).
3.2.1. (S)-2-[Allyl-(4-nitro-benzenesulfonyl)-amino]-pro-
pionic acid 4a. Preparation as described in the general
procedure afforded 4a as a yellowish solid in 68% yield.
[a]D ꢀ24.4 (c 1.25, CH2Cl2). Mp 100 ꢁC. 1H NMR
(CDCl3, 250 MHz): d = 1.48 (d, 3H, J = 7.2 Hz, CH3);
3.75–4.05 (m, 2H, CH2); 4.65 (m, 1H, CH); 5.13–5.26
(m, 2H, CH2@); 5.68–5.82 (m, 1H, CH@); 7.98–8.03
(m, 2H, HAr); 8.29–8.35 (m, 2H, HAr); 8.80 (br s, 1H,
CO2H) ppm. 13C NMR (CDCl3, 63 MHz): d = 15.5
(CH3); 47.7 (CH2); 54.5 (CH); 117.8 (CH2@); 123.1;
127.6 (4 · CHAr); 132.9 (CH@); 144.7; 149.0
(2 · CqAr); 175.8 (CO) ppm. MS (IC NH3+): 332
(M+NH4+).
3.2.5. (S)-2-[Allyl-(2-nitro-benzenesulfonyl)-amino]-pro-
pionic acid 4e. Preparation as described in the general
procedure afforded 4e as a yellowish solid in 91% yield.
1H NMR (CDCl3, 250 MHz): d = 1.53 (d, 3H,
J = 7.5 Hz, CH3); 3.44–4.17 (m, 2H, CH2); 4.82 (q,
1H, CH); 5.06–5.22 (m, 2H, CH2@); 5.82 (m, 1H,
CH@); 7.68 (m, 3H, HAr); 8.06 (m, 1H, HAr) ppm.
13C NMR (CDCl3, 63 MHz): d = 15.5 (CH3); 47.7
(CH2); 54.5 (CH); 117.8 (CH2@); 123.1; 127.6
3.2.2. (S)-2-[But-3-enyl-(4-nitro-benzenesulfonyl)-amino]-
propionic acid 4b. Preparation as described in the gen-
eral procedure afforded 4b as a yellowish oil in 56%

2194
E. Vallee et al. / Tetrahedron Letters 47 (2006) 2191–2195
(4 · CHAr); 132.9 (CH@); 144.7; 149.0 (2 · CqAr);
3.3.3. 6-N-Benzoyl-9-{20-O-allyl-30-O-[1-oxo-2-[(4-penten-
yl),(4-nitrobenzenesulfonyl)]amino]propyl-50-O-(tert-
butyldimethylsilyl)-b-D-ribofuranosyl}adenine 5c. Prepa-
ration as described in the general procedure afforded 5c
as a white powder in 85% yield. Spectroscopic data of
the major isomer 1H NMR (CDCl3, 250 MHz):
d = 0.13 (s, 6H, 2 · CH3–Si); 0.94 (s, 9H, t-Bu); 1.58
(d, 3H, J = 7.2 Hz, CH3); 1.65–1.98 (m, 2H, NCH2b);
2.05 (m, 2H, NCH2c); 3.08–3.50 (m, 2H, NCH2a);
3.75–4.22 (m, 5H, H-40, 2H-50, OCH2); 4.60 (m, 1H,
H-20); 4.76 (m, 1H, CH); 4.98–5.11 (m, 4H, 2 · CH2@);
5.37 (s, 1H, H-30); 5.50–5.85 (m, 2H, 2 · CH@); 6.04
(d, 1H, J = 6.7 Hz, H-10); 7.50–7.62 (m, 3H, HBz);
8.03–8.11 (m, 4H, HBz, 2 · CHAr); 8.30–8.40 (m, 3H,
2 · CHAr, H-2 or H-8); 8.83 (s, 1H, H-2 or H-8); 9.11
(br s, 1H, NH) ppm 13C NMR (CDCl3, 63 MHz):
d = ꢀ5.2 (CH3–Si); 17.5 (CH3); 18.5 (Cq/t-Bu); 26.1
(CH3/t-Bu); 30.0 (NCH2b); 31.1 (NCH2c); 46.1
(NCH2a); 56.0 (CH); 63.2 (C-50); 72.2 (OCH2); 72.9
(C-30); 79.9 (C-40); 83.5 (C-20); 85.6 (C-10); 115.9; 118.9
(CH2@); 124.5 (CHAr); 128.0 (CHBz); 128.6 (CHAr);
129.0; 133.0 (CHBz); 133.7; 137.1 (CH@); 141.2 (C-2
ou C-8); 146.5; 149.6 (CqAr); 150.2; 152.3 (CqBz);
153.0 (C-2 or C-8); 164.6; 170.4 (CO) ppm.
175.8 (CO) ppm.
3.3. General procedure for the acylation step
Acid 4 (0.55 mmol) was dissolved in DCM (3 mL) and
cooled to 0 ꢁC, at which point DMAP (68 mg,
0.55 mmol) and EDCI (106 mg, 0.55 mmol) were added.
After stirring the reaction mixture at 0 ꢁC for 15 min,
alcohol 1 (242 mg, 0.46 mmol) was added. The cooling
bath was removed and the solution was heated to
40 ꢁC for 12 h. The crude reaction was concentrated in
vacuo and purified using silica gel chromatography
(EtOAc/cyclohexane).
3.3.1. 6-N-Benzoyl-9-{20-O-allyl-30-O-[1-oxo-2-[allyl,(4-
nitrobenzenesulfonyl)]amino]propyl-50-O-(tert-butyldi-
methylsilyl)-b-D-ribofuranosyl}adenine 5a. Preparation
as described in the general procedure afforded 5a as a
white powder in 81% yield. Spectroscopic data of the
major isomer 1H NMR (CDCl3, 250 MHz): d = 0.11
(s, 6H, 2 · CH3–Si); 0.92 (s, 9H, t-Bu); 1.56 (d, 3H,
J = 7.2 Hz, CH3); 3.77–4.24 (m, 7H, 2 · CH2, 2H-50,
H-40); 4.62 (m, 1H, H-20); 4.78 (m, 1H, CH); 5.05–5.27
(m, 4H, 2 · CH2@); 5.39 (m, 1H, H-30); 5.53–5.90 (2m,
2H, 2 · CH@); 6.08 (d, 1H, J = 6.7 Hz, H-10); 7.50–
7.62 (m, 3H, HBz); 8.02–8.12 (m, 4H, HBz, 2 · CHAr);
8.31–8.40 (m, 3H, 2 · CHAr, H-2 or H-8); 8.83 (s, 1H,
H-2 or H-8); 9.08 (br s, 1H, NH) ppm 13C NMR (CDCl3,
63 MHz): d = ꢀ5.2 (2 · CH3–Si); 17.2 (CH3); 18.5 (Cq/
t-Bu); 26.1 (3 · CH3/t-Bu); 49.1 (NCH2); 56.2 (CH);
63.1 (C-50); 72.1 (OCH2); 72.8 (C-30); 79.9 (C-20); 83.5
(C-40); 85.6 (C-10); 118.7; 119.1 (CH2@); 124.4 (CHAr);
128.0 (CHBz); 128.7 (CHAr); 128.9; 132.9 (CHBz);
133.7; 134.4 (CH@); 141.0 (C-2 or C-8); 146.2; 149.7
(CqAr); 150.1; 152.1 (CqBz); 153.0 (C-2 or C-8); 164.8;
170.3 (CO) ppm. MS (IC NH3+): 822 (M+H+).
3.3.4. 6-N-Benzoyl-9-{20-O-allyl-30-O-[1-oxo-2-[allyl,(2-
nitrobenzenesulfonyl)]amino]propyl-50-O-(tert-butyldi-
methylsilyl)-b-D-ribofuranosyl}adenine 5e. Preparation
as described in the general procedure afforded 5a as a
white powder in 61% yield. Spectroscopic data of the
major isomer 1H NMR (CDCl3, 250 MHz): d = 0.09
(s, 6H, 2 · CH3–Si); 0.91 (s, 9H, t-Bu); 1.57 (d, 3H,
J = 7.5 Hz, CH3); 3.80–4.11 (m, 7H, 4 · CH2, 2H-50,
H-40); 4.63 (t, 1H, H-20); 4.93 (q, 1H, CH); 5.02–5.19
(m, 4H, 2 · CH2@); 5.41 (m, 1H, H-30); 5.57–5.85 (2m,
2H, 2 · CH@); 6.11 (d, 1H, J = 6,5 Hz, H-10); 7.71–
7.47 (m, 6H, HBz, CHAr); 8.0–8.12 (m, 3H, HBz,
CHAr); 8.31 (s, 1H, H-2 or H-8), 8.80 (s, 1H, H-2 or
H-8); 9.3 (br s, 1H, NH) ppm 13C NMR (CDCl3,
63 MHz): d = ꢀ4.95 (2 · CH3–Si); 17.08 (CH3); 18.8
(Cq/t-Bu); 26.3 (3 · CH3/t-Bu); 49.3 (NCH2); 56.8
(CH); 63.2 (C-50); 72.4 (OCH2); 72.6 (C-30); 80.1 (C-
20); 83.7 (C-40); 86.3 (C-10); 118.5; 119.3 (CH2@); 124.6
(CHAr); 128.3 (CHBz); 129.4 (CHAr); 131.8; 132.4,
133.5, 134.06 (CHBz); 135; 134.4 (CH@); 141.6 (C-2
or C-8); 148.2; 149.9, 152.3 (CqAr–CqBz); 153.1 (C-2
or C-8); 165; 171.1 (CO) ppm. MS (IC NH3+): 822
(M+H+).
3.3.2. 6-N-Benzoyl-9-{20-O-allyl-30-O-[1-oxo-2-[(3-buten-
yl),(4-nitrobenzenesulfonyl)]amino]propyl-50-O-(tert-butyl-
dimethylsilyl)-b-D-ribofuranosyl}adenine 5b. Prepara-
tion as described in the general procedure afforded 5b
as a white powder in 64% yield. Spectroscopic data of
the major isomer 1H NMR (CDCl3, 250 MHz):
d = 0.12 (s, 6H, 2 · CH3–Si); 0.93 (s, 9H, t-Bu); 1.58
(d, 3H, J = 7.2 Hz, CH3); 2.26–2.61 (m, 2H, NCH2b);
3.13–3.27 (m, 1H, NCH2a); 3.40–3.68 (m, 2H, NCH2a,
OCH2); 3.72–4.02 (m, 4H, H-40, 2H-50, OCH2); 4.58
(dd, 1H, J = 6.8; 5.2 Hz, H-20); 4.78 (q, 1H, J =
7.4 Hz, CH); 5.02–5.10 (m, 4H, 2 · CH2@); 5.37 (dd,
1H, J = 4.9; 2.1 Hz, H-30); 5.49–5.78 (m, 2H, 2 · CH@);
6.03 (d, 1H, J = 6.8 Hz, H-10); 7.49–7.61 (m, 3H,
HBz); 8.01–8.11 (m, 4H, HBz, 2 · CHAr); 8.28–8.38
(m, 3H, 2 · CHAr, H-2 or H-8); 8.83 (s, 1H, H-2 or
H-8); 9.11 (br s, 1H, NH) ppm 13C NMR (CDCl3,
63 MHz): d = ꢀ5.2 (2 · CH3–Si); 17.5 (CH3); 18.5 (Cq/
t-Bu); 26.1 (CH3/t-Bu); 35.3 (NCH2b); 46.3 (NCH2a);
56.4 (CH); 63.1 (C-50); 72.2 (OCH2); 72.9 (C-30); 79.9
(C-40); 83.4 (C-20); 85.6 (C-10); 117.5; 119.2 (CH2@);
124.5 (CHAr); 128.0 (CHBz); 128.6 (CHAr); 129.0;
132.9 (CHBz); 133.7; 134.2 (CH@); 141.0 (C-2 or C-8);
146.0; 149.7 (CqAr); 150.2; 152.1 (CqBz); 153.0 (C-2 or
C-8); 170.3 (CO) ppm. MS (FAB): 836 (M+H+).
3.3.5.
6-N-Benzoyl-9-{20-O-allyl-30-O-[1-oxo-2-[allyl-
benzyloxycarbonyl-amino]]propyl-50-O-(tert-butyldimeth-
ylsilyl)-b-D-ribofuranosyl}adenine 9. Preparation as de-
scribed in the general procedure (using acid 8 instead of
4) afforded 9 as a white powder in 67% yield. [a]D ꢀ15 (c
1
1.2, CH2Cl2); H NMR (CDCl3, 250 MHz): d = 0.08 (s,
6H, 2 · CH3–Si); 0.89 (s, 9H, t-Bu); 1.50 (d, 3H,
J = 7.5 Hz, CH3); 3.65–4.20 (m, 7H, H-40, 2H-50,
OCH2, NCH2); 4.29 (m, 1H, H-20); 4.62 (m, 1H, CH);
5.04–5.23 (m, 6H, 2 · CH2@, CH2); 5.43 (br s, 1H, H-
30); 5.62 (m, 1H, CH@); 5.90 (m, 1H, CH@); 6.19 (br
d, 1H, H-10); 7.29 (s, 5H, HAr); 7.47–7.52 (m, 3H,
HBz); 7.99 (m, 2H, HBz); 8.29 (br s, 1H, H-2 or H-8);
8.77 (s, 1H, H-2 or H-8); 9.13 (br s, 1H, NH) ppm 13C

E. Vallee et al. / Tetrahedron Letters 47 (2006) 2191–2195
2195
Org. Chem. 2000, 2335–2344; (e) Reichwein, J. F.; Liskamp,
R. M. J. Tetrahedron Lett. 1998, 39, 1243–1246; (f)
Hoffmann, T.; Waibel, R.; Gmeiner, P. J. Org. Chem.
2003, 68, 62–69.
NMR (CDCl3, 63 MHz): d = ꢀ4.9 (CH3–Si); 18.8
(CH3); 26.4 (CH3/t-Bu); 30.1 (Cq/t-Bu); 48.4 (NCH2);
54.2 (CH); 61.9 (C-50); 66.45 (CH2); 70.8 and 70.9 (C-
30, OCH2); 78.8 (C-20); 82.8 (C-40); 84.8 (C-10); 115.7
(NCH2@); 117.6 (OCH2@); 126.9, 127.4, 127.8 (CHAr);
131.7 (CH@); 132.3 (CHAr); 133.6 (CH@); 135.3
(CHAr); 140.0 (C-2 or C-8); 148.5; 151.0 (CqHAr);
151.8 (C-2 or C-8);154.98 (CO); 158.15 (CqAr); 163.6;
170.3 (CO) ppm. MS (IC NH3+): 771 (M+H+).
3. Di Gioia, M. L.; Leggio, A.; Le Pera, A.; Liguori, A.;
Napoli, A.; Siciliano, C.; Sindona, G. J. Org. Chem. 2003,
68, 7416–7421.
4. Atherton, E.; Benoiton, N. L.; Brown, E.; Sheppard, R. C.;
Williams, B. J. J. Chem. Soc., Chem. Commun. 1981, 336–
337.
5. For a recent review concerning the coupling reagents, see:
Han, S. Y.; Kim, Y. A. Tetrahedron 2004, 60, 2447–2467.
6. (a) Di Gioia, M. L.; Leggio, A.; Liguori, A. J. Org. Chem.
2005, 70, 3892–3897; (b) Vedejs, E.; Lin, S.; Klapars, A.;
Wang, J. J. Am. Chem. Soc. 1996, 118, 9796–9797.
7. Carpino, L. A.; Mansour, E. M. E.; Sadat-Aalaee, D.
J. Org. Chem. 1991, 56, 2611–2614.
Acknowledgements
`
We thank the Ministere de la Recherche et des Nou-
velles Technologies (MRNT), for financial support.
8. Pitzele, B. S.; Hamilton, R. W.; Kudla, K. D.; Tsymbalov,
S.; Stapelfeld, A.; Savage, M. A.; Clare, M.; Hammond, D.
L.; Hansen, D. W. J. Med. Chem. 1994, 37, 888–896.
9. A verification was done by reacting nucleoside 1 with a
racemic mixture of NCbz D–L alanine 8 and the NMR
spectrum of stereoisomers 9 showed two characteristic
signals in 13C NMR for the CH2@ of the O-allyl group and
two characteristic signals in 13C NMR for the CH2@ of the
N-allyl group. This was not observed in the NMR spectrum
of compound 9 after the acylation step with the optically
pure L-alanine derivative 8.
References and notes
`
1. Busca, P.; Etheve-Quelquejeu, M.; Valery, J.-M. Tetra-
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