Synthesis of 1′-Homo-N-nucleosides from Hexitols

Article abstract of DOI:10.1002/ejoc.200300328

This paper describes a new route for the synthesis of N-(1′ -homo-L-gulitol)nucleosides and amino sugar analogues of N-(1′ -homo-L-gulitol)nucleosides by nucleophilic epoxide ring-opening followed by O-heterocyclization of 1,2:5,6-dianhydro-3,4-di-O-benzy

Full text of DOI:10.1002/ejoc.200300328

FULL PAPER
Synthesis of 1Ј-Homo-N-nucleosides from Hexitols
Raffaele Saladino,*[a] Umberto Ciambecchini,[a] and Stephen Hanessian*[b]
Keywords: Nucleosides / Synthetic design / Heterocycles / Magnesium
This paper describes a new route for the synthesis of N-(1Ј-
homo- -gulitol)nucleosides and amino sugar analogues of
N-(1Ј-homo- -gulitol)nucleosides by nucleophilic epoxide
ring-opening followed by O-heterocyclization of 1,2:5,6-di-
anhydro-3,4-di-O-benzyl- -mannitol and 1,2:5,6-dianhydro-
3,4-diazido-
[Mg(ClO4)2] was found to be the best catalyst for the reaction
of silylated bases, derived from uracil, thymine and adenine,
with these bis(epoxides).
L
L
D
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
-iditol, respectively. Magnesium perchlorate Germany, 2003)
D
Introduction
The design and preparation of novel nucleoside ana-
logues as antiviral and antitumor agents is a well-defined
branch of medicinal chemistry.[1] Modification of the sugar
residue of nucleosides has yielded a large variety of viral
inhibitors against DNA, RNA and retroviruses. These
modified nucleosides include therapeutically useful agents
such as azidothymidine (AZT), dideoxycytidine (ddC), and
dideoxyinosine (ddI),[2Ϫ4] potent antiherpetics in which the
carbohydrate ring is replaced by acyclic side-chains, such as
9-alkylpurine derivatives (Acyclovir, Penciclovir and
Famciclovir),[5] and N-thioxonucleosides such as Lamivud-
ine.[6] During the last decades attention has also been fo-
cused on biologically active cyclopentylnucleosides (carban-
ucleosides),[7] derived from nucleosides by replacement of
the furanose ring oxygen atom by a methylene moiety. Due
to the absence of the natural N-glycosidic bond, these car-
banucleosides possess greater metabolic stability due to
their inertness towards hydrolytic activity of cellular phos-
phorylases. The resistance to enzymatic degradation is the
rational basis for the synthesis of other analogues such as
2Ј,5Ј-anhydro-1Ј-substituted-1Ј-deoxyhexitols (1Ј-homo-N-
nucleosides 1aϪb), in which a methylene group is inserted
between the heterocyclic base and C1Ј of the hexitol residue
(Figure 1).[8] A further incentive for the synthesis and bio-
logical evaluation of these compounds is based on the an-
ticipated interaction of the base moiety with DNA (or
RNA) as base-pair complements.[9]
Figure 1. 1Ј-Homo-N-nucleosides
1Ј-Homo-N-nucleosides 1aϪb are generally prepared by
two main methods.[8] In the first, heterocyclic bases can be
introduced by nucleophilic displacement of a leaving group
at the C-1Ј exocyclic methyl group of the pentofuranose.[10]
In the second method, the nucleobases are constructed from
a C-1Ј pentofuranosyl methylamino derivative.[11] These
methods have been implemented with varying degrees of
success due to side-reactions.
1,2:5,6-Dianhydro-3,4-di-O-protected hexitols have been
widely used for the synthesis of biologically active com-
pounds such as enzyme inhibitors,[12] amino acids,[13] and
aziridines.[14] It has been observed that the selectivity and
efficiency of the nucleophilic ring-opening of the oxiranyl
moieties depend on various experimental factors, such as
the nature of the nucleophile, the reaction solvent, and the
type of 3,4-O-protecting groups used. The newly formed
hydroxy moiety, resulting from the ring-opening process of
one of the epoxides, can attack the second terminal epoxide
to give mainly anhydro derivatives. Thus, enantiomerically
pure amino carboxylic acids or ‘‘pseudo-azadisaccharides’’
have been obtained from C2-symmetric bis(epoxides) on
azidolysis followed by O-ring closure.[15]
[a]
`
Unita INFM, Dipartimento di Agrobiologia ed Agrochimica,
Herein, we describe a novel synthesis of N-(2Ј,5Ј-anhy-
dro-1Ј-deoxy--gulitol)nucleosides by nucleophilic ring
opening of 1,2:5,6-dianhydro-3,4-di-O-benzyl--mannitol
(3) with purine and pyrimidine nucleophiles followed by O-
Via S. Camillo de Lellis snc, 01100 Viterbo, Italy
Fax: (internat.) ϩ 39-0761-357242
E-mail: saladino@unitus.it
[b]
´
´
Department of Chemistry, Universite de Montreal
´
´
C. P. 6128, Montreal, Quebec H3C3J7, Canada
Eur. J. Org. Chem. 2003, 4401Ϫ4405
DOI: 10.1002/ejoc.200300328
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4401

R. Saladino, U. Ciambecchini, S. Hanessian
FULL PAPER
heterocyclization to 2,5-anhydro derivatives. A similar pro- actions of 1,2:5,6-dianhydro-3,4-di-O-isopropyliden--man-
cedure, starting from 1,2:5,6-dianhydro-3,4-diazido--iditol nitols.[23] Accordingly, the condensation of the bis(trime-
(12), is also reported for the synthesis of N-(1Ј-homo--glu- thylsilyl) derivatives of adenine, uracil, and thymine with 3
citol)nucleosides bearing vicinal amino moieties on the hex- was performed in the presence of magnesium perchlorate
itol residue.
[Mg(ClO4)2] at reflux temperature, to give 4, 5, and 6 in
Amino sugar nucleosides, such as polyoxin or puromycin, yields of 51, 54, and 52%, respectively. Finally, catalytic
are known to possess important antibacterial and anti- hydrogenation of 1Ј-homo-3Ј,4Ј-di-O-benzyl--gulitol-N-
tumor properties.[16] Different procedures involving the re- nucleosides 4, 5, and 6 with 10% palladium/charcoal under
duction of the azidosugar analogue,[17] Mitsunobu reactions ambient pressure afforded the corresponding 2,5-anhydro-
or intramolecular neighboring-group-assisted delivery of 1-deoxy-1-(uracil-1-yl)--gulitol (7), 2,5-anhydro-1-deoxy-1-
amine nucleophiles[18] have been reported to obtain the 2Ј- (thymin-1-yl)--gulitol (8) and 2,5-anhydro-1-deoxy-1-(6-
or 3Ј-aminodeoxynucleoside derivatives.[19] To the best of amino-9H-purin-9-yl)--gulitol (9) in high yields.
our knowledge, this is the first synthesis of an aminohexitol
We next turned our attention to the synthesis of N-(1Ј-
derivative of 1Ј-homo-N-nucleoside reported in the litera- homo--hexitol)nucleosides bearing vicinal amino groups
ture (Scheme 2).
in the 2,5-anhydro ring. 1,2:5,6-Dianhydro-3,4-diazido--
iditol (12) was prepared starting from diazidohexitol (10)
under the experimental conditions described in the litera-
ture for cisplatinum analogues of alditol derivatives
(Scheme 2).[24]
Results and Discussion
The route developed to prepare N-(1Ј-homo--gulitol)nu-
cleosides 7Ϫ9 and their precursors 4Ϫ6 is shown in
Scheme 1. The starting material 1,2:5,6-dianhydro-3,4-di-O-
benzyl--mannitol (3) was prepared from -mannitol, ac-
cording to the procedure reported by Zhang.[20] Initially,
the sodium salt of adenine, uracil, or thymine, generated by
the treatment of the nucleic base with sodium hydride
(NaH, 1.2 equiv.) in DMF (5 mL),[21] was condensed with
freshly prepared bis(epoxide) 3 at room temperature.
Under these experimental conditions, 2,5-anhydro-3,4-di-
O-benzyl-1-deoxy-1-(uracil-1-yl)--gulitol (4), 2,5-anhydro-
3,4-di-O-benzyl-1-deoxy-1-(thymin-1-yl)--gulitol (5), and
2,5-anhydro-3,4-di-O-benzyl-1-deoxy-1-(6-amino-9H-
purin-9-yl)--gulitol (6) were obtained in low yields (13, 19,
and 11%, respectively). Improvements in the reaction yields
were obtained using Lewis acids as catalysts under Vor-
bruggen conditions.[22] Typically, the trimethylsilylated nu-
cleobases were prepared from uracil, thymine, and adenine
with N,O-bis(trimethylsilyl)trifluoroacetamide [BSTFA (5.0
equiv.); CH3CN; 50 °C]. The reaction mixture containing
either the trimethylsilylated pyrimidine or purine derivative
Scheme 2. Reagents and conditions: i. CH3SO2Cl, Py, 48 h, Ϫ15
°C; ii. KOH/H2O, Et2O, 3 h, 25 °C; iii. ROH/NaH or adenine/NaH,
DMF, 4 h, 25 °C or adenine/BSTFA, CH3CN, 50 °C then
Mg(ClO4)2, CH3CN, 6 h, 85 °C (R ϭ Ph, PhCH2); iv. H2, Pd/C,
MeOH/H2O, 16 h, 25 °C
Diazido compound 10, which is readily available from -
and the bis(epoxide) 3 was then refluxed in the presence of mannitol,[24] was converted into the desired bis(epoxide) 12
tin() chloride (SnCl4; 1.0 equiv.; in acetonitrile) to afford by treatment of the dimesylate 11 with an ethereal solution
compounds 4, 5, and 6 in 28, 32, and 35% yields, respec- of potassium hydroxide (Scheme 2).
tively. It is known that magnesium perchlorate [Mg(ClO4)2]
The opening of the bis(epoxide) 12 was examined with
is more selective as catalyst than SnCl4 in ring-opening re- different nucleophiles. Firstly, sodium phenoxide, in DMF
Scheme 1. Reagents and conditions: i. BH/NaH, DMF, 4 h, 25 °C or BH/BSTFA, CH3CN, 50 °C then Mg(ClO4)2, CH3CN, 6 h, 85 °C
(BH ϭ Ura, Thy, Ade); ii. H2/PdϪC, MeOH/H2O, 16 h, 25 °C
4402
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Eur. J. Org. Chem. 2003, 4401Ϫ4405

Synthesis of 1Ј-Homo-N-nucleosides from Hexitols
FULL PAPER
General Procedure for the Preparation of Compounds 4؊6: A solu-
tion of 1,2:5,6-dianhydro-3,4-di-O-benzyl--mannitol (3, 100 mg,
0.3 mmol)[20] in dry CH3CN (5 mL) was carefully added to a pre-
viously prepared solution of silylated nucleic base [1.0 mmol of
either adenine, uracil or thymine and 5.0 mmol of bis(trimethylsilyl)
trifluoroacetamide (BSTFA) in dry CH3CN (5.0 mL)] under argon.
The mixture was heated to 85 °C and magnesium perchlorate
[Mg(ClO4)2; 1.0 mmol] was added. After 6 h at 85 °C, the mixture
was cooled, diluted with EtOAc, washed with NaCl (aq.; satd.),
and the solvent evaporated. The crude mixture was purified by
at 25 °C, was used in a model reaction. Regiospecific ring-
opening of one epoxide moiety followed by an O-heterocy-
clization was observed giving 2,5-anhydro-3,4-diazido-1-O-
phenyl--glucitol (13) selectively. Subsequent reduction of
the azido groups led to 2,5-anhydro-3,4-diamino-1-O-phe-
nyl--glucitol (16) in a 40% overall yield (Scheme 2). The
same procedure was repeated using sodium benzylate as the
nucleophile to give 2,5-anhydro-3,4-diamino-1-O-benzyl--
glucitol (17) in 58% yield starting from 12 (Scheme 2).
Application of the same protocol using sodium salts of flash chromatography (EtOAc/hexane, 60:40).
adenine was equally successful. Thus, treatment of 12 with
2,5-Anhydro-3,4-di-O-benzyl-1-deoxy-1-(uracil-1-yl)-
L-gulitol
(4):
adenine and NaH in DMF resulted in a regioselective epox-
ide ring-opening to give 1-(6-amino-9H-purin-9-yl)-2,5-
anhydro-3,4-diazido-1-deoxy--glucitol (15, 32%), as the
only isolated product. It is noteworthy that when the reac-
tion was carried out in the presence of magnesium perchlor-
ate and a trimethylsilylated base in acetonitrile at 85 °C, 15
was obtained in 73% yield (Scheme 2). Catalytic hydrogen-
ation afforded the desired 1-(6-amino-9H-purin-9-yl)-2,5-
Yield: 67 mg (51%; clear oil). 1H NMR (CDCl3): δ ϭ 3.56 (dd, J ϭ
11.70, 4.16 Hz, 2 H, CH2OH), 3.68 (dd, J ϭ 12.90, 6.28 Hz, 2 H,
CH2N), 3.55 (m, 2 H, 3-H and 4-H), 3.84 (m, 1 H, 5-H), 4.51 (s, 4
H, 2 ϫ OCH2Ph), 4.63 (m, 1 H, 2-H), 5.79 (d, J ϭ 7.71 Hz, 1 H,
UraH-5), 6.12 (d, J ϭ 7.71 Hz, 1 H, UraH-6), 7.32 (m, 5 H, Ph),
8.18 (m, 5 H, Ph) ppm. 13C NMR (CDCl3): δ ϭ 44.16 (CH2), 61.88
(CH2), 71.33 (CH), 72.11 (CH2), 72.89 (CH2), 77.56 (CH), 83.22
(CH), 86.45 (CH), 103.12 (CH), 128.90 (CH), 129.42 (CH), 133.71
(C), 135.59 (CH), 144.52 (CH), 151.03 (C), 160.16 (C), 160.86 (C),
164.50 (C) ppm. C24H26N2O6 (438.5): calcd. C 65.74, H 5.98, N
6.39; found C 66.09, H 6.12, N 6.36.
anhydro-3,4-diamino-1-deoxy--glucitol
(18,
86%)
(Scheme 2).
2,5-Anhydro-3,4-di-O-benzyl-1-deoxy-1-(thymin-1-yl)-L-gulitol (5):
1
Yield: 70 mg (54%; clear oil). H NMR (CDCl3): δ ϭ 1.91 (s, 3 H,
CH3), 3.43 (dd, J ϭ 11.87, 4.21 Hz, 2 H, CH2OH), 3.54 (dd, J ϭ
12.54, 5.39 Hz, 2 H, CH2N), 3.62 (m, 2 H, 3-H and 4-H), 3.84 (m,
1 H, 5-H), 4.32 (s, 4 H, 2 ϫ OCH2Ph), 4.68 (m, 1 H, 2-H), 6.54 (s,
1 H, ThyH-6), 7.43 (m, 5 H, Ph), 7.66 (m, 5 H, Ph) ppm. 13C NMR
(CDCl3): δ ϭ 12.22 (CH3), 44.87 (CH2), 59.24 (CH2), 68.72 (CH),
72.31 (CH), 73.56 (CH2), 73.98 (CH2), 74.65 (CH), 77.18 (CH),
111.84 (C), 128.12 (CH), 129.87 (CH), 133.04 (CH), 135.16 (CH),
137.59 (C), 141.34 (C), 151.33 (CH), 162.38 (C), 168.10 (C) ppm.
C25H28N2O6 (452.5): calcd. C 66.36, H 6.24, N 6.19; found C 66.47,
H 6.14, N 6.32.
Conclusion
In summary, this paper describes a new route for the syn-
thesis of N-(1Ј-homo--gulitol)nucleosides and amino sugar
analogues of N-(1Ј-homo--glucitol)nucleosides by nucleo-
philic epoxide ring-opening followed by O-heterocyclization
of 1,2:5,6-dianhydro-3,4-di-O-benzyl--mannitol (3) and
1,2:5,6-dianhydro-3,4-diazido--iditol (12), respectively.
Magnesium perchlorate was found to be the best catalyst
for the reaction of silylated bases derived from uracil, thy-
mine, and adenine with these bis(epoxides). This procedure
was also applied to the synthesis of the corresponding 2Ј,3Ј-
diamino analogues. In contrast, the sodium salt method for
nucleophilic ring opening of epoxides gave modest to ac-
ceptable yields of the corresponding 1Ј-homo-N-nucleos-
ides. The 1Ј-homo-N-nucleosides prepared by the methods
described in this paper will be used as biological probes
to explore RNA binding as well as potential antiviral or
related activities.
1-(6-Amino-9HϪpurin-9-yl)-2,5-anhydro-3,4-di-O-benzyl-1-deoxy-
1
L
-gulitol (6): Yield: 72 mg (52%; clear oil). H NMR (CDCl3): δ ϭ
3.64 (dd, J ϭ 10.76, 4.11 Hz, 2 H, CH2OH), 4.06 (dd, J ϭ 14.03,
6.48 Hz, 2 H, CH2N), 4.44 (s, 4 H, 2 ϫ OCH2Ph), 4.74 (m, 1 H,
5-H), 5.08 (m, 1 H, 3-H), 5.28 (m, 1 H, 4-H), 5.45 (m, 1 H, 2-H),
7.48 (m, 5 H, Ph), 8.07 (m, 5 H, Ph), 8.16 (s, 1 H, AdeH-8), 8.27
(s, 1 H, AdeH-2) ppm. 13C NMR (CDCl3): δ ϭ 44.90 (CH2), 59.24
(CH), 67.13 (CH), 72.11 (CH2), 72.67 (CH2), 74.41 (CH), 84.10
(CH), 86.51 (CH), 118.67 (C), 128.44 (CH), 129.73 (CH), 133.41
(CH), 135.26 (CH), 136.18 (C), 137.19 (C), 144.67 (CH), 155.19
(C), 160.86 (CH), 163.42 (C) ppm. C25H27N5O4 (461.5): calcd. C
65.06, H 5.90, N 15.17; found C 65.21, H 5.83, N 15.34.
Experimental Section
General Procedure for the Preparation of Compounds 7؊9: Com-
pound 4, 5, or 6 (50 mg) was hydrogenated in the presence of a
catalytic amount of Pd/C (10%) in a 8:1 mixture MeOH/H2O. After
16 h, the mixture was filtered through Celite, the catalyst was
washed with MeOH, and the solvent removed by evaporation.
General: All commercially available reagents were used without
further purification. Solvents when necessary were dried prior to
use according to standard procedures. NMR (1H, 13C) spectra were
recorded with a Bruker (200 MHz) spectrometer and are reported
in δ values. Elemental microanalyses were performed with a C.
Erba 1106 analyser. Optical rotations were recorded with a
PerkinϪElmer 241 polarimeter in a 1-dm cell at ambient tempera-
2,5-Anhydro-1-deoxy-1-(uracil-1-yl)-L-gulitol (7): Yield: 26 mg
(88%; brown oil). 1H NMR (CD3OD): δ ϭ 3.69 (dd, J ϭ 10.54,
3.57 Hz, 2 H, CH2OH), 3.84 (dd, J ϭ 12.87, 5.35 Hz, 2 H, CH2N),
ture (ca. 25°C). Thin layer chromatography was carried out using 3.94 (m, 1 H, 4-H), 4.12 (m, 3 H, 2-H, 3-H and 5-H), 6.18 (d, J ϭ
Merck 60 F254 precoated silica gel plates. Visualization was done 7.31 Hz, 1 H, UraH-5), 7.75 (d, J ϭ 7.31 Hz, 1 H, UraH-6) ppm.
by UV light (254 nm), followed by heating with ethanolic phospho- 13C NMR (CD3OD): δ ϭ 45.34 (CH2), 60.63 (CH2), 68.24 (CH),
molybdic acid. Chromatographic purifications were performed on
columns packed with Merck 60 silica gel, 230Ϫ400 mesh, for
flash technique.
70.65 (CH), 73.18 (CH), 83.90 (CH), 103.37 (CH), 144.73 (CH),
151.03 (C), 164.50 (C) ppm. C10H14N2O6 (258.2): calcd. C 46.51,
H 5.46, N 10.85; found C 46.30, H 5.64, N 10.81.
Eur. J. Org. Chem. 2003, 4401Ϫ4405
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R. Saladino, U. Ciambecchini, S. Hanessian
FULL PAPER
2,5-Anhydro-1-deoxy-1-(thymin-1-yl)-
L
-gulitol (8): Yield: 25 mg
fully added to a previously prepared solution of sodium benzylate
(83%; yellow oil). 1H NMR (CD3OD): δ ϭ 1.94 (s, 3 H, CH3), 3.41 [benzyl alcohol (200 mg, 1.8 mmol) treated with NaH (48 mg,
(dd, J ϭ 11.43, 3.36 Hz, 2 H, CH2OH), 3.66 (dd, J ϭ 12.90, 2.0 mmol) in dry DMF (6 mL)] at 0 °C. After 4 h at 25 °C, the
4.15 Hz, 2 H, CH2N), 3.96 (m, 2 H, 4-H and 5-H), 4.16 (m, 2 H,
2-H and 3-H), 7.34 (s, 1 H, ThyH-6) ppm. 13C NMR (CD3OD): and NaCl (aq.; satd.), and the solvent evaporated. The crude mate-
δ ϭ 16.14 (CH3), 43.20 (CH2), 60.23 (CH2), 66.17 (CH), 71.56 rial was purified by flash chromatography (EtOAc/hexane, 50:50)
(CH), 74.88 (CH), 85.26 (CH), 111.43 (C), 141.36 (CH), 151.44 to give product 14 (105 mg, 69%) as a yellow oil. [α]D ϭ Ϫ13.46
mixture was diluted with EtOAc, washed sequentially with H2O
1
(C), 166.64 (C) ppm. C11H16N2O6 (272.3): calcd. C 48.53, H 5.92,
N 10.29; found C 48.51, H 5.86, N 10.23.
(c ϭ 0.92, MeOH). H NMR (CD3OD): δ ϭ 3.48 (dd, J ϭ 10.04,
4.12, 2 H, CH2O), 3.76 (dd, J ϭ 11.22, 4.09, 2 H, CH2OH), 3.88
(m, 2 H, 3-H and 4-H), 4.37 (m, 2 H, 2-H and 5-H), 4.44 (s, 2 H,
OCH2Ph), 7.29 (m, 5 H, phenyl) ppm. 13C NMR (CD3OD): δ ϭ
60.63 (CH2), 60.88 (CH2), 70.94 (CH), 71.34 (CH), 72.25 (CH),
73.40 (CH2), 73.52 (CH), 126.83 (2 ϫ CH), 127.34 (CH), 128.26 (2
ϫ CH), 137.56 (C) ppm. C13H18N6O3 (306.3): calcd. C 50.97, H
5.92, N 27.44; found C 50.92, H 5.88, N 27.33.
(6-Amino-9HϪpurin-9-yl)-2,5-anhydro-1-deoxy-1-
L-gulitol
(9):
1
Yield: 27 mg (89%; brown oil). H NMR (CD3OD): δ ϭ 3.55 (dd,
J ϭ 10.38, 3.69 Hz, 2 H, CH2OH), 3.92 (d, J ϭ 13.65, 7.11 Hz, 2
H, CH2N), 4.15 (m, 2 H, 3-H and 4-H), 4.78 (m, 2 H, 2-H and 5-
H), 7.61 (s, 1 H, AdeH-8), 8.14 (s, 1 H, AdeH-2) ppm. 13C NMR
(CD3OD): δ ϭ 45.81 (CH2), 63.76 (CH2), 67.19 (CH), 70.43 (CH),
74.28 (CH), 85.11 (CH), 120.90 (C), 144.79 (CH), 151.22 (C),
153.47 (CH), 155.19 (C) ppm. C11H15N5O4 (281.3): calcd. C 46.97,
H 5.38, N 24.90; found C 46.91, H 5.23, N 24.93.
1-(6-Amino-9H-purin-9-yl)-2,5-anhydro-3,4-diazido-1-deoxy-L-
glucitol (15). Method A: A solution of compound 12 (100 mg,
0.5 mmol) in dry DMF (4 mL) was carefully added to a previously
prepared solution of sodium adenylate [adenine (200 mg,
1.48 mmol) treated with NaH (40 mg, 1.7 mmol) in dry DMF
(6 mL)] at 0 °C. After 4 h at 25 °C, the mixture was diluted with
EtOAc, washed sequentially with H2O and NaCl (aq.; satd.), dried
and the solvent evaporated. The crude material was purified by
flash chromatography (EtOAc/hexane, 50:50) to give product 15
3,4-Diazido-3,4-dideoxy-1,6-bis(O-mesyl)-D-iditol (11): 3,4-Diazido-
3,4-dideoxy--iditol (10)[24] (600 mg, 2.5 mmol) in dry pyridine
(10 mL) at Ϫ15 °C under argon was treated with methanesulfonyl
chloride (420 µL, 2.1 equiv.). After 48 h, the mixture was diluted
with EtOAc, washed with H2O, and the solvent evaporated (to re-
move also the excess pyridine). The crude mixture was purified by
flash chromatography (EtOAc/hexane, 80:20) to give 906 mg (93%)
of 11 as a clear oil. 1H NMR (CDCl3): δ ϭ 3.12 (s, 6 H, 2 ϫ
CH3SO2), 3.75 (dd, J ϭ 11.30, 5.83 Hz, 4 H, 2 ϫ CH2OMs), 4.18
(m, 2 H, 2 ϫ CHN3), 4.37 (m, 2 H, 2 ϫ CHOH) ppm. 13C NMR
(CDCl3): δ ϭ 35.15 (CH3), 63.10 (CH2), 68.21 (CH), 70.0 (CH)
ppm. C8H18N6O8S2 (390.4): calcd. C 24.61, H 4.65, N 21.53; found
C 24.66, H 4.72, N 21.45.
1
(54 mg, 32%) as a yellow oil. H NMR (CD3OD): δ ϭ 3.68 (m, 4
H, CH2OH and 3-H and 4-H), 3.90 (dd, J ϭ 13.82, 5.09, 2 H,
CH2N), 4.47 (m, 1 H, 5-H), 4.84 (m, 1 H, 2-H), 7.82 (s, 1 H, AdeH-
8), 8.08 (s, 1 H, AdeH-2) ppm. 13C NMR (CDCl3/CD3OD): δ ϭ
47.32 (CH2), 60.90 (CH2), 69.28 (CH), 71.84 (CH), 72.65 (CH),
74.35 (CH), 123.10 (C), 145.02 (CH), 153.18 (CH), 156.65 (C),
159.92 (C) ppm. C11H15N11O2 (333.3): calcd. C 39.64 H, 4.54 N,
46.23; found C 39.37 H, 4.56 N, 46.35. Method B: A solution of
compound 12 (100 mg, 0.5 mmol) in dry CH3CN (5 mL) was added
under argon to a previously prepared solution of silylated adenine
[adenine (1.0 mmol) and BSTFA (5.0 mmol) in dry CH3CN
(5.0 mL)]. The resulting mixture was heated to 85 °C. Magnesium
perchlorate [Mg(ClO4)2, 1.0 mmol] was then added. After 6 h at 85
°C, the mixture was cooled, diluted with EtOAc, washed with NaCl
(aq.; satd.), and the solvent evaporated. The crude product was
purified by flash chromatography (EtOAc/hexane, 60:40) to give 12
(121 mg, 73%) as a yellow oil.
1,2:5,6-Dianhydro-3,4-diazido-D-iditol (12): Compound 11 (585 mg,
1.5 mmol), dissolved in Et2O (15 mL), at 25 °C, was treated with
KOH (336 mg, 6.0 mmol, 4.0 equiv.) as a solution in H2O (6 mL).
After 3 h, the mixture was diluted with EtOAc, washed with NaCl
(aq.; satd.), and the organic solvent removed by evaporation. The
crude mixture was purified by chromatography (EtOAc/hexane,
90:10) to give the product 12 (213 mg, 72%) as a clear oil. [α]D
ϭ
Ϫ77.48 (c ϭ 1.35, MeOH). 1H NMR (CD3OD): δ ϭ 2.75 (dd, J ϭ
4.85, 3.38 Hz, 2 H, CH2O), 2.90 (dd, J ϭ 4.20, 3.38 Hz, 2 H,
CH2O), 3.20 (m, 2 H, 2 ϫ CHO), 3.35 (m, 2 H, 2 ϫ CHN3) ppm.
13C NMR (CD3OD): δ ϭ 45.0 (CH2), 52.10 (CH), 65.0 (CH) ppm.
C6H10N6O2 (198.2): calcd. C 36.36, H 5.09, N 42.41; found C
36.31, H 5.11, N 42.44.
3,4-Diamino-2,5-anhydro-1-O-phenyl-L-glucitol (16): Compound 13
(70 mg, 0.24 mmol) was hydrogenated in the presence of a catalytic
amount of Pd/C (10%) in a 8:1 mixture of MeOH/H2O. After 16 h,
the mixture was filtered through Celite, the catalyst washed with
MeOH, and the organic solvent removed to give product 16 (43 mg,
2,5-Anhydro-3,4-diazido-1-O-phenyl-L-glucitol (13): A solution of
compound 12 (100 mg, 0.5 mmol) in dry DMF (4 mL) was care-
fully added to a previously prepared solution of sodium phenoxide
[phenol (200 mg, 2.1 mmol) treated with NaH (57 mg, 2.4 mmol)
in dry DMF (6 mL)] at 0 °C. After 4 h at 25 °C, the mixture was
diluted with EtOAc, washed with NaCl (aq.; satd.), and the organic
solvent evaporated. The crude material was purified by flash chro-
matography (EtOAc/hexane, 50:50) to give product 13 (76 mg,
52%) as a brown oil. 1H NMR (CD3OD): δ ϭ 3.65 (dd, J ϭ 10.62,
3.77, 2 H, CH2OH), 3.85 (dd, J ϭ 11.07, 3.27, CH2OPh), 4.01 (m,
2 H, 3-H and 4-H), 4.15 (m, 1 H, 5-H), 4.35 (m, 1 H, 2-H) 6.80
(m, 3 H, phenyl), 7.18 (m, 2 H, phenyl) ppm. 13C NMR (CD3OD):
δ ϭ 62.07 (CH2), 63.22 (CH2), 70.94 (CH), 71.43 (CH), 73.43 (CH),
73.67 (CH), 114.10 (2 ϫ CH), 122.11 (CH), 129.10 (2 ϫ CH),
162.12 (C) ppm. C12H16N6O3 (292.3): calcd. C 49.31, H 5.52, N
28.75; found C 49.11, H 5.66, N 28.71.
1
76%) as a yellow oil. [α]D ϭ ϩ12.13 (c ϭ 0.85, MeOH). H NMR
(CD3OD): δ ϭ 3.79 (dd, J ϭ 10.70, 4.19, 2 H, CH2OH), 3.89 (dd,
J ϭ 11.07, 4.91, 2 H, CH2OPh), 4.01 (m, 2 H, 3-H and 4-H), 4.42
(m, 2 H, 2-H and 5-H), 6.79Ϫ7.24 (m, 5 H, phenyl) ppm. 13C NMR
(CD3OD): δ ϭ 52.94 (CH), 55.08 (CH), 61.65 (CH2), 64.04 (CH2),
74.66 (CH), 75.16 (CH), 116.42 (2 ϫ CH), 121.18 (CH), 126.85 (2
ϫ CH), 158.21 (C) ppm. C12H18N2O3 (238.3): calcd. C 60.49, H
7.61, N 11.76; found C 60.65, H 7.32, N 11.74.
3,4-Diamino-2,5-anhydro-1-deoxy-L-glucitol (17): Compound 14
(50 mg, 0.16 mmol) was hydrogenated in the presence of a catalytic
amount of Pd/C (10%) in a 8:1 mixture of MeOH/H2O. After 16 h,
the mixture was filtered through Celite, the catalyst washed with
MeOH, and the solvent removed to give product 17 (21 mg, 84%)
1
as a yellow oil. [α]D ϭ Ϫ2.60 (c ϭ 0.5, MeOH). H NMR (D2O):
2,5-Anhydro-3,4-diazido-1-O-benzyl-
compound 12 (100 mg, 0.5 mmol) in dry DMF (4 mL) was care-
L
-glucitol (14): A solution of
δ ϭ 3.72 (m, 4 H, 2 ϫ CH2OH), 4.02 (m, 2 H, 3-H and 4-H), 4.35
(m, 2 H, 2-H and 5-H), 5.58 (br. s, 2 H, 2 ϫ CH2OH) ppm. 13C
4404
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4401Ϫ4405

Synthesis of 1Ј-Homo-N-nucleosides from Hexitols
FULL PAPER
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4405