New chiral nitrones in the synthesis of modified nucleosides

Article abstract of DOI:10.1055/s-2002-32579

New chiral nitrones 7 and 12, easily prepared from D-xylose by multistep synthetic routes, undergo regioselective 1,3-dipolar cycloadditions with N-vinylated bases (uracil, adenine) giving isoxazolidinyl nucleosides in good yields. Attack of the dipolarophile on the Z-configuration of the nitrone through exo and endo transition states from the si face of nitrone (C-1′/C-3 erythro) affords C-3/C-5 cis (exo) and C-3/C-5 trans (endo) isoxazolidines as two major isomers.

Full text of DOI:10.1055/s-2002-32579

LETTER
1113
New Chiral Nitrones in the Synthesis of Modified Nucleosides
New
C
hiral Nitro
ó
nes inthe Sy
b
nthesis of
M
e
odifiedN
u
r
c
leosidest Fischer,a Alexandra Drucková,a Lubor Fišera,*a Alfonz Rybár,b Christian Hametner,c Micha K. Cyra skid
a
Department of Organic Chemistry, Slovak University of Technology, 812 37 Bratislava, Slovak Republic
E-mail: fisera@cvt.stuba.sk
b
c
d
Institute of Chemistry, Slovak Academy of Sciences, 842 38 Bratislava, Slovak Republic
Institute of Applied Synthetic Chemistry, University of Technology, 1060 Vienna, Austria
Department of Chemistry, University Warsaw, 02 093 Warsaw, Poland
Received 18 April 2002
azanucleosides possessing an ethylene bridge between the
anomeric carbon and nitrogen (Scheme 1), we focused
our attention on the preparation of new sugar-derived
nitrones possessing structures suitable for building pyr-
Abstract: New chiral nitrones 7 and 12, easily prepared from D-xy-
lose by multistep synthetic routes, undergo regioselective 1,3-dipo-
lar cycloadditions with N-vinylated bases (uracil, adenine) giving
isoxazolidinyl nucleosides in good yields. Attack of the dipolaro-
phile on the Z-configuration of the nitrone through exo and endo rolidine rings and their 1,3-dipolar cycloadditions with
transition states from the si face of nitrone (C-1 /C-3 erythro) af-
N-vinylated bases 3, 4a and 4b (Figure).
fords C-3/C-5 cis (exo) and C-3/C-5 trans (endo) isoxazolidines as
two major isomers.
Key words: chiral, dipolar cycloadditions, nitrones, isoxazolidines,
modified nucleosides
R
N
OR1 LG
B
B
OR4
O
O
N
OR2
R
O
O
The discovery of AZT (azidothymidine) promoted rapid
and productive investigations in the field of modified nu-
cleosides.1 The potential activity of a variety of the struc-
tures against viral infections or tumor diseases stimulated
great interest for the preparation of different types of mod-
ifications of glycone and aglycone moieties.2 In this con-
text, exciting biological results have been achieved from
the generation of nucleoside analogues in which a second
heteroatom has been inserted into the furanosyl ring.3
Uracil, thymine, cytosine and adenine nucleosides pos-
sessing an isoxazolidinyl moiety 14,5 as well as azanucle-
osides and their homoanalogues 2 are very valuable for
their biological activity against HIV, HBV and HSV in-
fections and also in anticancer therapy.4c,6
LG - leaving group
B - base
B
OR2
OR2
R
R4O
N
O
R4O
O
OR3 OR1
OR3 OR1
Scheme 1
R1
N
R1
O
N
R
HO
B
N
N
HN
R
B
N
The first example of an isoxazolidinyl nucleoside was
synthesized in 1992 by Tronchet.7 Since this time many
modified nucleosides possessing an isoxazolidinyl moiety
have been created by a wide range of synthetic pathways,
including Michael additions of hydroxylamines to , -un-
saturated esters,5,8 additions of ketene acetals to ni-
trones,5,9 and 1,3-dipolar cycloadditions of nitrones to
vinyl acetate5,7,10 with the subsequent transformation of
the isoxazolidines thus formed. On the other hand, 1,3-di-
polar cycloaddition reactions of nitrones with N-vinylated
bases afford modified isoxazolidinyl nucleosides direct-
ly.4,10b,11
N
O
O
N
N
R
HO
OH
3
4a,b
1
2
Figure 4a) R1 = H, 4b) R1 = Ms
The chiral nitrone 7 was prepared from D-xylose in four
steps (Scheme 2).13 Thus, D-xylose was converted into D-
xylose diisopropyldithioacetal by treatment with 2-mer-
captopropane in 92% yield. Reaction of the corresponding
dithioacetal with acetone in the presence of a catalytic
quantity of sulfuric acid gave protected dithioacetal 5 in
52% yield. Deprotection of the thiol group with HgCl2/
HgO afforded aldehyde 6,14 which in turn reacted with N-
benzylhydroxylamine according to the method of
Dondoni15 to give nitrone 7 in 42% yield over two steps.
With our continuing efforts to utilize chiral 1,3-dipolar
cycloadditions12 and the goal of developing a simple route
to the synthesis of isoxazolidinyl nucleosides with the
possibility of subsequent transformation toward novel
Chiral nitrone 12 (Scheme 1), an alternative suitable for
building the pyrrolidine moiety in azanucleosides, was
Synlett 2002, No. 7, Print: 01 07 2002.
Art Id.1437-2096,E;2002,0,07,1113,1117,ftx,en;D08602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1114
R. Fischer et al.
LETTER
S-i-Pr
O
HO
5
1
O
2
4
OH
S-i-Pr
3
a)
b)
O
O
O
HO
D-xylose
OH
5
O
O
1
5
1
5
2
4
2
c)
4
d)
Bn
3
O
O
3
O
N
O
O
O
O
O
6
7
Scheme 2 (a) i-PrSH, HCl, r.t., 2 h, 92%; (b) acetone, H2SO4, r.t., 8 h, 52%; (c) acetone, H2O, HgCl2/HgO, 56 °C, 2 h; (d) BnNHOH, CH2Cl2,
MgSO4, r.t., 4 h, 42% in two steps.
prepared in five steps (Scheme 3).13 Selective removal of Cycloadditions of nitrones 7 and 12 to N-vinylated bases
the primary acetonide of 5 with ethanol/water/HCl gave 3, 4a and 4b16 proceeded regioselectively and led to the
diol 8 in 62% yield. Silylation of the primary alcohol isoxazolidines as a mixture of four diastereoisomers in all
group with TBDPSCl/imidazole in CH2Cl2 (92%) fol- cases (Table).17,18 Purification by flash chromatography
lowed by benzoylation with benzoyl chloride/pyridine in allowed the isolation of pure exo-adducts 13a, 14a, 15a
CH2Cl2 afforded the protected dithioacetal 10 in 90% and endo-adduct 15b,19 identified by spectroscopic analy-
yield. Subsequent deprotection of the thiol group (HgCl2/ sis, particularly NOE difference experiments, and subse-
HgO) and condensation of aldehyde 11 with N-benzylhy- quently confirmed by X-ray-crystallographic analysis in
droxylamine gave chiral nitrone 12 in 63% yield over two the case of 13a (Scheme 4).20
steps.13
O
S-i-Pr
O
S-i-Pr
5
5
1
1
2
2
4
4
b)
S-i-Pr
a)
HO
S-i-Pr
3
3
O
O
O
OH
O
5
8
O
S-i-Pr
O
S-i-Pr
5
5
1
1
2
2
4
4
c)
TBDPSO
S-i-Pr
TBDPSO
S-i-Pr
3
3
OH
O
BzO
O
9
10
O
O
1
1
5
5
2
4
2
4
d)
e)
Bn
TBDPSO
3
TBDPSO
O
3
N
O
BzO
O
BzO
O
11
12
Scheme 3 (a) EtOH/H2O (80%), HCl, 40 °C, 4 h, 62%; (b) TBDPSCl, imidazole, CH2Cl2, 0 °C to r.t., 30 min, 92%; (c) BzCl, pyridine,
CH2Cl2, reflux, 24 h, 90%; (d) HgCl2/HgO, acetone, H2O, 56 °C, 2 h; (e) BnNHOH, CH2Cl2, MgSO4, r.t., 4 h, 63% in two steps.
Synlett 2002, No. 7, 1113–1117 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
New Chiral Nitrones in the Synthesis of Modified Nucleosides
1115
Scheme 4
Table 1,3-Dipolar Cycloadditions of Nitrones 7 and 12 to N-Viny-
lated Bases
15a. Fortunately, in this case we obtained two adenosines
15a and 15b in pure form.19
Entry Nitrone Dipolaro- Total yield Adduct
a:b:c:da
X-ray analysis of 13a reveals a C-1 /C-3 erythro and C-3/
C-5 cis stereochemistry and therefore indicates that cyc-
loaddition arises from the more sterically accessible si
face of the Z-nitrone 7, via an exo-transition state for 13a
and via an endo transition state for 13b (Scheme 5).
phile
(%)
75
86
83
77
95
1
2
3
4
5
7
7
3
13
63:17:15:5
39:34:20:7
73:13:9:5
4a
4b
3
7
15
14
H
O
O
N
2''
12
12
59:24:11:6
45:30:19:6
O
O
3''
4''
5''
4
1''
exo
N
5
2'
O
3
4a
R1
R2
1'
3'
R1=base
R2=H
6''
4'
a Ratios were determined by 1H NMR and 13C NMR (400 MHz) from
crude reaction mixture.
O
N
O
1
2
Bn
O
O
O
O H
O
N
13a 1´,3-erythro-3,5-cis
H
Bn
In the case of cycloadditions of nitrones 7 and 12 with 9-
vinyladenine (4a, Table, entry 2 and 5) we were not able
to obtain the adenosine diastereoisomers in the pure form.
To improve separation we decided to protect the free ami-
no group of the adenine moiety. Cycloaddition of nitrone
7 with N,N-dimesylated 9-vinyladenine (4b, Table, entry
3) afforded a mixture of four diastereoisomers and pro-
ceeded with better selectivity in favour of major isomer
H
N
3''
O
O
2''
O
O
endo
4''
5''
4
1''
N
5
2'
O
3
R1=H
1'
3'
6''
4'
R2=base
O
N
O
1
2
Bn
13b 1´,3-erythro-3,5-trans
Scheme 5
Synlett 2002, No. 7, 1113–1117 ISSN 0936-5214 © Thieme Stuttgart · New York

1116
R. Fischer et al.
LETTER
(13) Selected Data: (Z)-N-(1-Deoxy-2,3:4,5-di-O-
Acknowledgement
isopropylidene-D-xylo-1-ylidene)-benzylamine-N-
oxide(7): Colorless solid, mp 95–97 °C (crystalized from
hexanes); total yield 20%; [ ]D = +41.3 (CHCl3, c 0.22); 1H
NMR (400 MHz, CDCl3): = 1.36, 1.38, 1.43, 1.48 [4 s, 4
3 H, C(CH3)2], 3.73 (dd, 1 H, J4,5a = 6.8 Hz, J5a,5b = 8.6 Hz,
H-5a), 3.95 (dd, 1 H, J2,3 = 5.9 Hz, J3,4 = 6.7 Hz, H-3), 4.09
(dd, 1 H, J4,5b = 6.7 Hz, J5a,5b = 8.8 Hz, H-5b), 4.40 (q, 1 H,
J3,4 = 6.7 Hz, J4,5a = J4,5b = 6.7 Hz, H-4), 4.89 (s, 2 H,
NCH2Ph), 5.07 (dd, 1 H, J1,2 = J2,3 = 6.2 Hz, H-2), 6.81 (d, 1
The authors are grateful to the Slovak Grant Agency (No. 1/7314/
20), M.K.C. is supported by the Polityka weekly and PKN Orlen
S.A. (2001/2002).
References
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H, J1,2 = 6.0 Hz, H-1), 7.41–4.42 (br s, 5 H, NCH2Ph); 13
C
NMR (125 MHz, CDCl3): = 25.8, 26.8, 27.0, 27.4
[C(CH3)2], 66.1 (C-5), 70.1 (NCH2Ph), 73.6 (C-2), 76.8 (C-
4), 81.1 (C-3), 110.1, 111.3 [C(CH3)2], 129.4, 129.5, 129.7,
129.8, 130.0, 132.5 (NCH2Ph), 137.4 (C-1). (Z)-N-(1-
Deoxy-2,3-O-isopropylidene-4-O-benzoyl-5-O-tert-
butyldiphenylsilyl-D-xylo-1-ylidene)-benzylamine-N-
oxide(12): Colorless oil, total yield 15%; [ ]D = +9.5
(CHCl3, c 0.22); 1H NMR (400 MHz, CDCl3): = 1.04 [s, 9
H, OSiC(CH3)3], 1.39, 1.50 [2 s, 2 3 H, C(CH3)2], 3.99
(dd, 1 H, J4,5a = 5.7 Hz, J5a,5b = 10.4 Hz, H-5a), 4.10 (dd, 1 H,
H-5b, J4,5b = 6.1 Hz, J5a,5b = 10.2 Hz, H-5b), 4.50 (dd, 1 H,
J2,3 = 6.7 Hz, J3,4 = 3.8 Hz, H-3), 4.86 (s, 2 H, NCH2Ph),
5.23 (dd, 1 H, J1,2 = J2,3 = 6.3 Hz, H-2), 5.68 (dt, 1 H,
J3,4 = 3.8 Hz, J4,5a = J4,5b = 5.8 Hz, H-4), 6.79 (d, 1 H,
J
1,2 = 5.6 Hz, H-1), 7.28–8.11 (m, 20 H, NCH2Ph, OSiPh2);
13C NMR (125 MHz, CDCl3): = 19.6 [OSiC(CH3)3], 27.0
[C(CH3)2], 27.2 [OSiC(CH3)3], 27.3 [C(CH3)2], 62.9 (C-5),
69.9 (NCH2Ph), 72.9 (C-2), 74.0 (C-4), 78.6 (C-3), 111.0
[C(CH3)2], 128.0–136.1 (NCH2Ph, OSiPh2), 136.9 (C-1),
166.0 (COPh).
(5) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org.
Chem. 2000, 65, 5575.
(14) Kochetkov, N. K.; Dmitriev, B. A. Tetrahedron 1965, 21,
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(6) Yokoyama, M.; Momotake, A. Synthesis 1999, 1541.
(7) (a) Tronchet, J. M. J.; Iznaden, M.; Barbalat-Rey, F.;
Dhimane, H.; Ricca, A.; Balzarini, J.; DeClercq, E. Eur. J.
Med. Chem. 1992, 27, 555. (b) Tronchet, J. M. J.; Iznaden,
M.; Barbalat-Rey, F.; Komaromi, I.; Dolatshahi, N.;
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(15) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.;
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11305.
(17) Typical Experimental Procedure: A mixture of nitrone
and N-vinylated base was stirred in toluene for 12–24 h
under reflux. When starting nitrone had been consumed
(TLC), the toluene was evaporated under vacuum and the
mixture of isomers was separated by flash column
chromatography (silica gel, CHCl3:MeOH = 95: 5).
(18) Yields of cycloadditions depended on the numbers of
equivalents of the dipolarophiles employed, presumably due
to the nitrone’s instability. Nitrone 7 in the absence of
dipolarophile was completely decomposed after 24 h in
toluene at 110 °C.
(19) Selected Data: 1-{(3S,5R)-2-Benzyl-3-[1,2:3,4-di-O-
isopropylidene-D-xylo]isoxazolidine-5-yl}uracil(13a):
Colorless solid, mp 187–189 °C (from toluene); yield 33%;
[ ]D = –52.7 (MeOH, c 0.12); 1H NMR (400 MHz, CDCl3):
= 1.38, 1.40, 1.41, 1.44 [4 s, 4 3 H, C(CH3)2], 2.60
(ddd, 1 H, J3,4b = 7.3 Hz, J4a,4b = 13.7 Hz, J4b,5 = 3.2 Hz, H-
4b), 2.91 (dt, 1 H, J3,4a = 8.5 Hz, J4a,4b = 14.3 Hz, J4a,5 = 8.5
Hz, H-4a), 3.19 (ddd, 1 H, J1 ,3 = 2.9 Hz, J3,4a = 6.9 Hz,
J3,4b = 8.9 Hz, H-3), 3.64 (dd, 1 H, J1 ,2 and J2 ,3 = 3.4 Hz and
8.6 Hz, H-2 ), 3.87 (t, 1 H, J3 ,4 a = J4 a,4 b = 7.9 Hz, H-4 a),
4.00 (dd; 1 H, J3 ,4 b = 6.7 Hz, J4 a,4 b = 8.2 Hz, H-4 b), 4.04 (d,
1 H, NCH2Ph, J = 14.3 Hz), 4.08–4.13 (m, 2 H, H-1 , H-3 ),
4.24 (d, 1 H; NCH2Ph, J = 14.0 Hz), 5.70 (dd, 1 H,
J5 ,6 = 8.2 Hz, J5 ,NH = 2.1 Hz, H-5 ), 6.28 (dd, 1 H,
(9) (a) Merino, P.; Del Alamo, E. M.; Bona, M.; Franco, S.;
Merchan, F. L.; Tejero, T.; Vieceli, O. Tetrahedron Lett.
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D.; Piperno, A.; Rescifina, A.; Romeo, R.; Romeo, G.
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Romeo, G.; Romeo, R. Tetrahedron: Asymmetry 2000, 11,
2045. (b) Merino, P.; Del Alamo, E. M.; Franco, S.;
Merchan, F. L.; Simon, A.; Tejero, T. Tetrahedron:
Asymmetry 2000, 11, 1543.
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Procopio, A.; Siciliano, C.; Sindona, G. J. Chem. Soc.,
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Fišera, L.; Ertl, P.; Goljer, I.; Prónayová, N. Monatsh. Chem.
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Blanáriková, I.; Fengler-Veith, M.; Jäger, V.; Fišera, L.
Chem. Papers 1998, 52, 780. (e) Blanáriková, I.; Dugovi ,
B.; Fišera, L.; Hametner, C. ARKIVOC 2001, 2, 1091.
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Prónayová, N. Synlett 2001, 1866.
J4a,5 = 7.9 Hz, J4b,5 = 2.9 Hz, H-5), 7.30–7.40 (m, 5 H,
NCH2Ph), 7.96 (d, 1 H, J5 ,6 = 8.2 Hz, H-6 ), 8.81 (s, 1 H,
NH); 13C NMR (125 MHz, CDCl3): = 25.9, 26.5, 27.3,
Synlett 2002, No. 7, 1113–1117 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
New Chiral Nitrones in the Synthesis of Modified Nucleosides
1117
27.4 [C(CH3)2], 37.3 (C-4), 61.6 (NCH2Ph), 65.3 (C-3), 66.0
J4 a,4 b = 8.0 Hz, H-4 a), 3.89 [s, 6 H, N(SO2CH3)2], 4.01 (dd;
1 H, J3 ,4 b = 6.8 Hz, J4 a,4 b = 8.0 Hz, H-4 b), 4.08 (dt, 1 H,
J2 ,3 = 3.6 Hz, J3 ,4 a and J3 ,4 b = 6.8 Hz, H-3 ) 4.16 (d, 1 H,
NCH2Ph, J = 14.0 Hz), 4.17 (dd, 1 H, J1 ,3 = 2.4 Hz,
(C-4 ), 74.7, 75.1 (C-1 , C-3 ), 78.6 (C-2 ), 83.3 (C-5), 102.1
(C-5 ), 110.2, 110.5 [C(CH3)2], 128.4, 128.9, 129.1, 129.6,
135.9 (NCH2Ph), 141.7 (C-6 ), 151.0, 163.8 (CO). 1-
{(3S,5R)-2-Benzyl-3-[1,2-O-isopropylidene-3-O-benzoyl-
4-O-tert-butyldiphenylsilyl-D-xylo]isoxazolidine-5-
yl}uracil(14a): Colorless solid, mp 57–60 °C (purified by
column chromatography); yield 40%; [ ]D = –30.9 (CHCl3,
c 0.13); 1H NMR (400 MHz, CDCl3): = 1.04 [s, 9 H,
OSiC(CH3)3], 1.32, 1.37 [2 s, 2 3 H, C(CH3)2], 2.61 (ddd,
1 H, J3,4b = 7.0 Hz, J4a,4b = 14.0 Hz, J4b,5 = 3.0 Hz, H-4b),
2.91 (ddd, 1 H, J3,4a = 9.2 Hz, J4a,4b = 14.0 Hz, J4a,5 = 8.0 Hz,
H-4a), 3.27 (ddd, 1 H, J1 ,3 = 2.4 Hz, J3,4a = 9.4 Hz, J3,4b = 7.0
Hz, H-3), 3.84 (dd, 1 H, J1 ,2 = 8.6 Hz, J1 ,3 = 2.6 Hz, H-1 ),
3.94 (dd, 1 H, J3 ,4 a = 6.0 Hz, J4 a,4 b = 2.4 Hz, H-4 a), 3.99–
4.02 (m; 2 H, H-2 , H-4 b), 4.01 (d, 1 H, NCH2Ph, J = 14.8
Hz), 4.10 (d, 1 H, NCH2Ph, J = 14.0 Hz), 5.35 (dt, 1 H,
J3 ,4 a = 6.0 Hz, J3 ,4 b = 2.7 Hz, H-3 )5.62 (dd, 1 H, J5 ,6 = 8.4
Hz, J5 ,NH = 2.4 Hz, H-5 ), 6.28 (dd, 1 H, J4a,5 = 7.8 Hz,
J1 ,2 = 8.4 Hz, H-1 ), 4.30 (d, 1 H, NCH2Ph, J = 14.0 Hz),
6.61 (dd, 1 H, J4a,5 = 8.0 Hz, J4b,5 = 2.4 Hz, H-5), 7.35–7.36
(m, 5 H, NCH2Ph), 8.88, 8.91 (2 s, 2 1 H, H-adenine); 13
NMR (125 MHz, CDCl3): = 25.9, 26.5, 27.2, 27.4
C
[C(CH3)2], 36.9 (C-4), 45.4 [N(SO2CH3)2], 60.7 (NCH2Ph),
64.9 (C-3), 66.0 (C-4 ), 74.5 (C-1 , C-3 ), 78.6 (C-2 ), 81.0
(C-5), 110.2, 110.6 [C(CH3)2], 128.4, 128.9, 130.0, 130.9,
135.6, 146.5, 154.2 (NCH2Ph, C-adenine), 146.3, 152.3
(CH-adenine). 9-{(3S,5S)-2-Benzyl-3-[1,2:3,4-di-O-
isopropylidene-D-xylo]isoxazolidine-5-yl}adenine(15b):
Colorless solid, mp 67–70 °C (purified by column
chromatography); yield 10%; [ ]D = +13.8 (CHCl3, c 0.05);
1H NMR (400 MHz, CDCl3): = 1.42, 1.43, 1.45, 1.47 [4
s, 4 3 H, C(CH3)2], 3.23 (ddd, 1 H, J3,4a = 4.0 Hz,
J4a,4b = 13.6 Hz, J4a,5 = 7.6 Hz, H-4a), 3.48 (m, 1 H, H-4b),
J
4b,5 = 3.0 Hz, H-5), 7.20–7.70 and 8.07–8.09 (m, 20 H,
3.60 (dd, 1 H, J = 4.2 Hz, J = 7.4 Hz, H-2 ), 3.68 (m, 1 H, H-
3), 3.90 [s, 6 H, N(SO2CH3)2], 3.86–3.93 (m, 1 H, H-4a ),
4.00 (dd, 1 H, J3 ,4 b = 6.6 Hz, J4 a,4 b = 8.2 Hz, H-4 b) 4.18–
4.23 (m, 2 H, H-1 , H-3 ), 4.19 (d, 1 H, NCH2Ph, J = 12.4
Hz), 4.26 (d, 1 H; NCH2Ph, J = 12.8 Hz), 6.40 (dd, 1 H,
J4a,5 = 7.6 Hz, J4b,5 = 5.2 Hz, H-5), 7.27–7.31 (m, 5 H,
NCH2Ph), 8.27, 8.92 (2 s, 2 1 H, H-adenine); 13C NMR
(75 MHz, CDCl3): = 25.7, 26.3, 27.0, 27.4 [C(CH3)2], 35.1
(C-4), 45.0 [N(SO2CH3)2], 61.9 (NCH2Ph), 65.4 (C-3), 65.7
(C-4 ), 75.6 (C-1 , C-3 ), 79.6 (C-2 ), 86.0 (C-5), 109.8,
110.3 [C(CH3)2], 128.2–131.5 (NCH2Ph, C-adenine), 146.8,
153.1 (CH-adenine).
NCH2Ph, COPh, OSiPh2), 7.99 (d, 1 H, J5 ,6 = 8.4 Hz, H-
6 ), 9.03 (d, 1 H, J5 ,NH = 1.6 Hz, NH); 13C NMR (125 MHz,
CDCl3): = 19.5 [OSiC(CH3)3], 27.1, 27.3 [C(CH3)2,
OSiC(CH3)3], 37.5 (C-4), 61.7 (NCH2Ph), 63.3 (C-4 ), 65.7
(C-3), 72.1 (C-3 ), 74.5 (C-1 ), 77.8 (C-2 ), 83.3 (C-5), 102.0
(C-5 ), 110.3 [C(CH3)2], 128.2-141.9 (NCH2Ph, COPh,
OSiPh2), 151.0 (C-6 ), 163.8, 166.5 (CO). 9-{(3S,5R)-2-
Benzyl-3-[1,2:3,4-di-O-isopropylidene-D-
xylo]isoxazolidine-5-yl}adenine(15a): Colorless solid, mp
59–62 °C (purified by column chromatography); yield 59%;
[ ]D = –69.4 (CHCl3, c 0.16); 1H NMR (400 MHz, CDCl3):
= 1.31, 1.39, 1.42, 1.46 [4 s, 4 3 H, C(CH3)2], 2.95
(ddd, 1 H, J3,4b = 6.8 Hz, J4a,4b = 13.6 Hz, J4b,5 = 2.4 Hz, H-
4b), 3.04 (ddd, 1 H, J3,4a = 9.2 Hz, J4a,4b = 13.6 Hz, J4a,5 = 8.0
Hz, H-4a), 3.25 (ddd, 1 H, J1 ,3 = 2.4 Hz, J3,4a = 9.2 Hz,
(20) Crystallographic data for the structure 13a have been
deposited with the Cambridge Crystallographic Data Centre;
reference number CCDC 178867(13a). Copies of the data
can be obtained on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (email:
J3,4b = 6.8 Hz, H-3), 3.64 (dd, 1 H, J1 ,2 = 8.8 Hz and
J2 ,3 = 3.2 Hz, H-2 ), 3.87 (dd, 1 H, J3 ,4 a = 7.2 Hz,
deposit@ccdc.cam.ac.uk).
Synlett 2002, No. 7, 1113–1117 ISSN 0936-5214 © Thieme Stuttgart · New York