Synthesis of 5-methylamino-2′-deoxyuridine derivatives

Article abstract of DOI:10.1081/NCN-100107194

Reductive amination of 3′,5′ -O-(tetraisopropyldisilyloxane-1,3-diyl)-2′-deoxy-5-formyluridine with several aliphatic and aromatic amines, in various solvents, is described. In the case of aliphatic amines, the expected C-5 substituted methylamino pyrimid

Full text of DOI:10.1081/NCN-100107194

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SYNTHESIS OF 5-METHYLAMINO-2′-DEOXYURIDINE
DERIVATIVES
Bruno Catalanotti a , Aldo Galeone a , Luciano Mayol b , Giorgia Oliviero a , Daniela Rigano a
& Michela Varra a
a Dipartimento di Chimica delle Sostanze Naturali , Università degli Studi di Napoli “Federico
II” , Via D. Montesano 49, Napoli, I-80131, Italy
b Dipartimento di Chimica delle Sostanze Naturali , Università degli Studi di Napoli “Federico
II” , Via D. Montesano 49, Napoli, I-80131, Italy
Published online: 19 Aug 2006.
To cite this article: Bruno Catalanotti , Aldo Galeone , Luciano Mayol , Giorgia Oliviero , Daniela Rigano & Michela Varra
(2001) SYNTHESIS OF 5-METHYLAMINO-2′-DEOXYURIDINE DERIVATIVES, Nucleosides, Nucleotides and Nucleic Acids, 20:10-11,
1831-1841, DOI: 10.1081/NCN-100107194
To link to this article: http://dx.doi.org/10.1081/NCN-100107194
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(10&11), 1831–1841 (2001)
SYNTHESIS OF 5-METHYLAMINO-
20-DEOXYURIDINE DERIVATIVES
Bruno Catalanotti, Aldo Galeone, Luciano Mayol,* Giorgia Oliviero,
Daniela Rigano, andMichela Varra
Dipartimento di Chimica delle Sostanze Naturali, Universita degli
Studi di Napoli ‘‘Federico II’’, Via D.Montesano 49,
I-80131 Napoli, Italy
ABSTRACT
Reductive amination of 30,50-O-(tetraisopropyldisilyloxane-1,3-diyl)-
20-deoxy-5-formyluridine with several aliphatic and aromatic amines, in
various solvents, is described.In the case of aliphatic amines, the ex-
pected C-5 substituted methylamino pyrimidine nucleosides are formed
along with by-products deriving from opening of the pyrimidine ring.
Relative amounts of the by-products depend upon the polarity of the
solvent employed.
INTRODUCTION
Pyrimidine nucleoside analogues, variously modified at C-5 of the base
moiety, have great potential as drugs for treatment of viral diseases and
cancer1–9.5-(2-Chloroethyl)- and (2-fluoroethyl)-2 -deoxyuridine, for an ex-
0
ample, interfere with herpes simplex virus type 1 (HSV 1) and varicella zoster
virus (VZV) replication10,11 whereas a number of 5-methylamino derivatives
have been found to be potent inhibitors of thymidylate synthetase12 (TS) and
thymidine kinase13.Incorporation of such compounds may also cause
favourable variations of physico-chemical and=or biological properties in
*Corresponding author.Fax: +39 81 678552; E-mail: mayoll@uninai.t
1831
Copyright # 2001 by Marcel Dekker, Inc.
www.dekker.com

1832
CATALANOTTI ET AL.
synthetic oligonucleotides14–18, consequently improving their performance as
antisense or antigene agents19–21.Particularly, substitution of 5-(propyn-
1-yl)-20-deoxyuridine for thymidine leads to DNA fragments characterized by
an increased stability of both double and triple helix structures, when com-
pared with their natural counterparts19,21.A further possibility to exploit C-5
position of pyrimidines to obtain new compounds with selected biological
properties is offered by the conjugation with intercalating or metal com-
plexing molecules capable of cleaving abasic sites in DNA22.
It follows from the above that there is a great deal of interest in new C-5
modified pyrimidine nucleosides, thus justifying the considerable efforts so
far fulfilled, aimed at developing new synthetic routes towards compounds of
this type.
In this paper, we report the synthesis and structural characterization
of a number of C-5 substituted methylamino pyrimidine nucleosides, pre-
pared by reductive amination of 5-formyl-30,50-O-(tetraisopropylsilyloxy)-20-
deoxyuridine with a set of primary amines in various experimental condi-
tions.This reaction is useful to obtain new derivatives which may turn out
to be of biological interest on their own or as intermediates for the con-
struction of other C-5 conjugated derivatives.A competitive opening of
the pyrimidine ring, promoted by NaBH3CN in polar solvents, is also
described.
RESULTS AND DISCUSSION
The first step of this work was to select a practical synthetic procedure
to secure a large amount of the synthone, namely 30,50-O-(tetra-
isopropyldisiloxane-1,3-diyl)-5-formyl-20-deoxyuridine (3, fdU scheme).
Among the several routes reported in the literature, photochemical oxidation
of thymidine23 was ruled out, due to the disadvantage of not being suitable
24
2
for a scale up of the process.Oxidation with MnO
was also judged not
convenient, since it requires a preliminary preparation of 5-hydroxymethyl-
20-deoxyurine, followed by a further synthetic step.Finally, oxidation of
thymidine by peroxodisulphate ion, as reported by Itahara and co-
workers25,26 was adopted with minor modifications, which led to formation
of fdU in good yields.A nucleoside protected at the sugar moiety was used
since, in some cases, the product of the following reductive amination was
to be used for further modification.For this purpose, the tetra-
isopropyldisilyloxane group appeared to be the most suitable.Oxidation
of the 5-methyl group of the protected nucleoside 2 with sodium per-
oxodisulfate in phosphate buffer at pH 7.0 gave 30,50-O-(tetra-
isopropyldisilyloxane-1,3-diyl)-20-deoxy-5-formyluridine 3 (62% yield) along
with the product of partial oxidation, namely, 30,50-O-(tetra-
isopropildisilyloxane-1,3-diyl)-20-deoxy-5-hydroxymethyluridine (23% yield).

5-METHYLAMINO-20-DEOXYURIDINE DERIVATIVES
1833
Reductive amination of aldehyde 3 was initially carried out following
the procedure described by Mattson and coworkers27, which required tita-
nium (IV) isopropoxide [Ti(O-Pri)4] as a mild Lewis acid catalyst.According
to this methodology, however, the solvent and the reducing agent must be
added only after 1 h, to allow an intermediate titanium=aldehyde=amine
adduct to form.Since in our cases mostly solid amines (b–f, scheme) were to
be used, these were dissolved in the solvent along with aldehyde 3 and Ti(O-
Pri)4.After 1 h, sodium cyanoborohydride was added.We have evaluated the
influence of the catalyst performing the reactions in the absence of Ti(O-Pri)4.
In any case, we did not observe such differences in the yields and rates be-
tween the reactions performed with or without Ti(O-Pri)4 to justify the use of
the catalyst.Similarly, the direct addition of NaBH 3CN to the initial solution
did not seem to significantly affect the outcome of the reaction and, therefore,
the one pot procedure described in the experimental section was adopted.
The above reaction, performed on amines a–d, afforded, besides the
expected product of reductive amination, a by-product derived from opening
of the pyrimidine ring (5a^f).The amount of by-product was dependent
upon the polarity of the starting amine as well as that of the solvent em-
ployed, as summarized in the Table.Particularly, it could be observed that,
for a given amine, yields of the target product (4a^d) decreased by increasing
the polarity of the solvent.On the other hand, solvent being equal, the higher
the number of hydroxyl groups on the amine, the lower the yields of 4a^d.
Consequently, when 30,50-O-(tetraisopropyldisilyloxane-1,3-diyl)-20-deoxy-5-
formyluridine (3) was reacted with 2-amino-1,3-propanediol (c) or R-(þ)-
1-amino-2,3-propanediol (d) in anydrous DMF, only products deriving from
opening of the pyrimidine ring (5c and 5d, respectively) could be detected.
Interestingly, no by-products were observed in the reductive amination with
the two aromatic amines, p-toluidine (e) and 1,4-diaminobenzene (f ), in any
solvent.It is also noteworthy that the opening of the pyrimidine ring, most
likely involving a nucleophilic attack to C-6, did not occur in the absence of
NaBH3CN.
Table. Reaction Yields of Compound 4 and 5 for Amines a–f in Several Solvents
Yield of 4 (%)
Yield of 5 (%)
Amine
CH2Cl2
THF
DMF
CH2Cl2
THF
DMF
NH2(CH2)3CH3 (a)
NH2(CH2)5OH (b)
NH2CH(CH2OH)2 (c)
NH2CH2CH(OH)CH2OH (d)
NH2C6H4NH2 (e)
88
85
76
78
99
91
70
60
45
49
86
72
50
8
0
0
90
85
< 5
10
16
20
0
10
35
41
40
0
35
42
70
82
0
NH2C6H4CH3 (f)
0
0
0

1834
CATALANOTTI ET AL.
In conclusion, we have described a reductive amination of 30,50-O-
(tetra isopropyldisilyloxane-1,3-diyl)-20-deoxy-5-formyluridine, as a con-
venient synthetic approach to obtain C-5 substituted methylamino pyrimidine
nucleosides.Particularly, we have shown that, when an aliphatic amine is
employed, the target molecule is always accompanied by a side product, de-
rived from opening of pyrimidine ring.By-product formation can be mini-
mized by the usage of dry CH2Cl2 as a solvent.Furthermore, we have found
that, in this case, addition of Ti(O-Pri)4, a catalyst commonly used according
to Mattson’s procedure, does not improve either reaction rate or yields of the
target product.The obtained products, particularly those containing an
aromatic moiety, will be tested for their potential activities against TS.
EXPERIMENTAL
General Methods
1H- and 13C-NMR spectra were recorded in CDCl3 on a Bruker WM 500
spectrometer.Residual proton and carbon signals of the solvent (CDCl
3
d ¼ 7.24 and 77.5, respectively) were used as internal references. NMR signals
1
were assigned to the pertinent nuclei through two-dimensional H-1H and
1H-13C COSY experiments.TLC was performed on silica gel plates
20620 cm, 0.25 mm (MERCK). Mass spectra were registered by a Finnigan
MAT instrument.UV spectra were recorded on a Jasco V-530 spectro-
25ꢀ
photometer. ½aŠ values were measured by a Perkin-Elmer 243 B polarimeter.
D
General reagents and solvents were purchased from Sigma-Aldrich-Fluka.
30,50-O-(Tetraisopropyldisiloxane-1,3-diyl)-20-deoxythymidine (2)
10 g (40 mmol) of 20-deoxythymidine (1) and 12.5 g of imidazole
(182 mmol) were co-evaporated in anhydrous DMF and then dissolved in
60 ml of the same solvent.To the ice-cooled solution, 12 mL of 1,3-dichloro-
1,1,3,3-tetraisopropyldisiloxane (44 mmol) in dry CH2Cl2 (8 mL) were added
dropwise, in 20 min under stirring.After 4 h, the reaction was quenched with
CH3OH and the solvent evaporated invacuo.The residue, dissolved in CHCl 3
(300 mL), was washed with a 1M aqueous sodium bicarbonate solution
(360.5 L). The organic phase was dried over anhydrous sodium sulphate,
filtered and evaporated in vacuo.After repeated additions and evaporations
of toluene (361 L) in vacuo, 49.9 g of 2 were obtained and identified by
comparison of spectral data with those reported in the literature28.
30,50-O-(Tetraisopropyldisiloxane-1,3-diyl)-5-formyl-20-deoxyuridine (3)
Compound 2 (10.0 g, 20 mmol) was dissolved in CH3CN (125 mL) and,
then, 7.4 g (70 mmol) of 2,6-lutidine and 25 mL of an aqueous solution of

5-METHYLAMINO-20-DEOXYURIDINE DERIVATIVES
1835
K2S2O8 (10.8 g, 40 mmol) and CuSO465H2O (2.0 g, 8 mmol) were added.
The mixture was kept at 65 ꢀC for 4.5 h under stirring, cooled and filtered and
the resulting solution dried in vacuo.The crude material was dissolved in
ethyl acetate (0.5 L), washed with H2O (361 L) and then with an aqueous
solution of EDTA (261 L).The organic phase was dried over anhydrous
sodium sulphate, filtered and evaporated in vacuo.The product was purified
on a silica gel column (800 g 30064 cm) eluted with increasing concentrations
of CH3OH in CHCl3 (0 to 2%).Fractions eluted with 2% CH 3OH in CHCl3
gave pure 3 (6.2 g, 62% yield). 1H NMR d 9.97 (1H, s, CHO); 8.5 (1H, s, H-
6); 6.0 (1H, dd, H-10); 4.43 (1H, m, H-30); 4.1 (2H, m, H-50a and H-50b); 3,82
(1H, m, H-40) 2.55 (1H, m, H-20a); 2.30 (1H, m, H-20b); 1.15-0.9 [28H,
4CH(CH3)2]. 13C NMR d 187.5 (CHO); 163.0 (C-4); 151.2 (C-2); 149.8 (C-6);
112.5 (C-5); 89.8 (C-40); 89.3 (C-10); 70.22 (C-30); 62.5 (C-50); 42.5 (C-20); 13.7-
12.8 ½4CHðCH3Þ Š; 17.7-17.2 ½4CHðCH3Þ Š.MS ESI ( þ) ¼ 499.UV (CHCl )
3
2
2
25ꢀ
D
lmax ¼ 290 nm (e ¼ 14000). ½aŠ (CHCl3) ¼ ꢁ 48.6.
General Procedure for Reductive Amination
Compound 3 (1 g, 2.0 mmol), dried by addition and evaporation of dry
CH2Cl2 in vacuo (63), was dissolved in the same solvent (150 mL) and
40 mmol of amine (a–f) and 0.5 g of NaBH3CN (1.02 mmol) were added to
the solution, under stirring.After 24 h, silica gel TLC in n-hexane=ethyl
acetate 1:1 (v=v) showed the complete consumption of 3.The mixture was
washed with H2O (360.5 L), dried over anhydrous sodium sulphate, filtered
and evaporated in vacuo, thus giving a solid residue which was chromato-
graphed as specified below.The same conditions of reaction, analytical TLC
and purification were applied when reductive amination of product 3 was
performed in dry DMF or dry THF.The yields of the reactions are sum-
marised in the Table.
30,50-O-(Tetraisopropyldisiloxane-1,3-diyl)-5-[(N-butyl)aminomethyl]-20-de-
oxyuridine (4a)
The crude product from reductive amination of 3 with amine a was
analysed by TLC (CHCl3=CH3OH 85:15 v=v), which showed the presence of
two spots at Rf 0.5 (4a) and Rf 0.75 (5a), and chromatographed on a silica gel
column (200 g, 15062.5 cm), eluted with increasing amounts (from 0 to 15%)
of CH3OH in CHCl3.Fractions eluted with 4% CH OH in CHCl3, gave 5a
3
(0.045 g, 4%) while fractions eluted with 12% CH3OH in CHCl3, gave 4a
(0.98 g, 88%). 4a: 1H NMR d 7.55 (1H, s, H-6); 6.05 (1H, m, H-10); 4.50 (1H, m,
H-30); 4.07 (2H, m, H-50a and H-50b); 3.75 (1H, m, H-40); 3.50 [2H, m,
CH2NH(CH2)3CH3]; 2.60 [2H, m, CH2NHCH2(CH2)2CH3]; 2.45 (1H, m,

1836
CATALANOTTI ET AL.
H-20a); 2.35 (1H, m, H-20b); 1.50 (2H, m, NHCH2CH2CH2CH3); 1.35 (2H, m,
NH(CH2)2CH2CH3); 1.10-0.90 [28H, 4CH(CH3)2]; 0.85 [3H, t, CH2NH
(CH2)3CH3]; 13C NMR d 163.6 (C-4); 150.2 (C-2); 137.5 (C-6); 112.3 (C-5); 85.3
(C-40); 84.3 (C-10); 68.9 (C-30); 61.1 (C-50); 49.1 [CH2NH(CH2)3CH3]; 46.7
[CH2NHCH2(CH2)2CH3]; 40.0 (C-20); 32.0 (CH2NHCH2CH2CH2CH3); 20.7
[CH2NH(CH2)2CH2CH3]; 17.77-17.1 [4CH(CH3)2]; 14.2 [CH2NH(CH2)3
CH3]; 13.6-12.7 [4CH(CH3)2].MS ESI( þ) ¼ 556.UV (CHCl 3) lmax ¼ 268 nm
25ꢀ
D
(e ¼ 22000). ½aŠ (CH3OH) ¼ ꢁ 4.63; 5a: 1H NMR d 11.0 (1H, s, NH-3); 9,96
(1H, m, NH-1); 8.96 (1H, s, CHO); 8.84 (1H, d, NH-7); 7.72 (1H, d, H-6); 5.82
(1H, m, H-10), 4.02 (1H, dd, H-50a); 3.80 (2H, m, H-50b and H-40); 4.44 [2H, m,
NHCH2(CH2)2CH3]; 2.33 (1H, m, H-20a); 2.10 (1H, m, H-20b); 1.62 (2H, m,
NHCH2CH2CH2CH3); 1.41 [2H, m, NH(CH2)2CH2CH3]; 1.00 [3H, t,
NH(CH2)3CH3]; 1.12-0.80 [28H, 4CH(CH3)2]. 13C NMR d 183.9 (CHO); 159.7
(C-4); 146.3 (C-2); 144.5 (C-6); 122.4 (C-5); 85.3 (C-40); 75.7 (C-10); 68.9 (C-30);
61.1 (C-50); 50.1 [NHCH2(CH2)2CH3]; 42.1 (C-20); 31.9 (NHCH2CH2CH2
CH3); 22.3 [NH(CH2)2CH2CH3]; 18.1-17.1 [8C, 4CH(CH3)2]; 14.0 [NH(CH2)3
CH3]; 13.4-12.5 [4C, 4CH(CH3)2]; MS ESI (þ) ¼ 572.
30,50-O-(Tetraisopropyldisiloxane-1,3-diyl)-5-[N-(5-hydroxypentyl)aminome-
thyl]-20-deoxyuridine (4b)
The crude product from reductive amination of 3 with amine b was
analysed by TLC (CHCl3=CH3OH 8:2 v=v), which showed the presence of
two spots at Rf 0.4 (4b) and Rf 0.6 (5b), and chromatographed on a silica gel
column (200 g, 15062.5 cm), eluted with increasing amounts (from 0 to 25%)
of CH3OH in CHCl3.Fractions eluted with 10% of CH 3OH gave 5b (0.12 g,
10%) while fractions eluted with 12% of CH3OH gave 4b (1.0 g, 88%).
1
4b: H NMR d 7.55 (1H, s, H-6); 6.02 (1H, m, H-10); 4.45 (1H, m, H-30);
4.00 (2H, m, H-50a and H-50b); 3.75 (3H, m, H-40); 3.62 [2H, t,
CH2NHCH2(CH2)3CH2OH]; 3.5 [2H, dd, CH2NHCH2(CH2)3CH2OH] 2.60
[2H, m, CH2NHCH2(CH2)3CH2OH]; 2.45 (1H, m, H-20a); 2.25 (1H, m, H-
20b); 1.55 (4H, m, CH2NHCH2CH2CH2CH2CH2OH); 1.40 [2H, m,
CH2NHCH2CH2CH2CH2CH2OH]; 1.10-0.80 [28H, 4CH(CH3)2]; 13C NMR
d 163.6 (C-4); 149.8 (C-2); 137.4 (C-6); 111.6 (C-5); 85.0 (C-40); 84.0 (C-10);
68.4 (C-30); 62.5 [CH2NHCH2(CH2)3CH2OH]; 60.7 (C-50); 48.8
[CH2NHCH2(CH2)3CH2OH]; 46.5 [CH2NHCH2(CH2)3CH2OH]; 39.7 (C-20);
32.2 [CH2NHCH2(CH2)2CH2CH2OH]; 29.0 [CH2NHCH2CH2(CH2)2
CH2OH]; 23.2 (CH2NHCH2CH2CH2CH2CH2OH); 17.4-13.4 [4CH(CH3)2];
13.4-12.4 [4CH(CH3)2]; MS ESI(þ) ¼ 586; UV (CHCl3) ¼ lmax ¼ 268 nm
25ꢀ
1
(e ¼ 28000); ½aŠ (CH3OH) ¼ ꢁ 8.27; 5b: H NMR d 11.0 (1H, s, NH-3);
D
10.0 (1H, m, NH-7); 8.98 (1H, s, CHO); 8.84 (1H, d, NH-1); 7.30 (1H, d, H-
6); 5.80 (1H, m, H-10), 4.48 (1H, m, H-30); 4.02 (2H, m, H-50a and H-50b);
3.80 (1H, m, H-40); 3.65 [2H, t, NHCH2(CH2)3CH2OH]; 3.40 [2H, m,

5-METHYLAMINO-20-DEOXYURIDINE DERIVATIVES
1837
NHCH2(CH2)3CH2OH]; 2.30 (1H, m, H-20a); 2.10 (1H, m, H-20b); 1.55 (4H,
m, NHCH2CH2CH2CH2CH2OH); 1.40 (2H, m, NHCH2CH2H2CH2CH2
OH); 1.03-0.80 [28H, 4CH(CH3)2]; 13C NMR d 189.3 (CHO); 162.1(C-4);
149.9 (C-2); 145.8 (C-6); 125.6 (C-5); 84.5 (C-40); 73.6 (C-10); 68.9 (C-30); 61.0
[C-50 and NHCH2(CH2)3CH2OH]; 44.5 [NHCH2(CH2)3CH2OH]; 39.6 (C-20);
33.2 [NHCH2(CH2)2CH2CH2OH]; 29.0 [NHCH2CH2(CH2)2CH2OH]; 23.5
(NHCH2CH2CH2CH2CH2OH); 17.4-13.4 [4CH(CH3)2]; 13.4-12.4 [4CH
(CH3)2]; MS ESI(þ) ¼ 602.
30,50-O-(Tetraisopropyldisiloxane-1,3-diyl)-5-[N-(1,3-dihydroxy-1-propyl)-
aminomethyl]-20-deoxyuridine (4c)
The crude product from reductive amination of 3 with amine c was
analysed by TLC (CHCl3=CH3OH 75:25 v=v), which showed the presence of
two spots at Rf 0.45 (4c) and Rf 0.70 (5c), and chromatographed on a silica
gel column (200 g, 15062.5 cm), eluted with increasing amounts (from 0 to
30%) of CH3OH in CHCl3.Fractions eluted with 15% CH OH in CHCl3
gave 5c (0.18 g, 16%) while fractions eluted with 30% CH3OH in CHCl3,
3
1
gave 4c (0.87 g, 76%). 4c: H NMR d 7.61 (1H, s, H-6); 6.02 (1H, m, H-10);
4.45 (1H, m, H-30); 4.08 [4H, m, CH2NHCH(CH2OH)2]; 3.65 (3H, m, H-40,
H-50a and H-50b); 3.58 [2H, m, CH2NHCH(CH2OH)2]; 2.75 [1H, m,
CH2NHCH (CH2OH)2]; 2.55 (1H, m, H-20a); 2.35 (1H, m, H-20b); 1.10-0.90
[28H, 4CH(CH3)2]; 13C NMR d 164.3 (C-4); 150.1(C-2); 137.5 (C-6); 111.6
(C-5); 85.0 (C-40); 84.1 (C-10); 68.0 (C-30); 61.4 [CH2NHCH(CH2OH)2]; 62.0
[CH2NHCH(CH2OH)2]; 62.4 (C-50); 45.0 [CH2NHCH(CH2OH)2]; 39.7 (C-
20); 17.3-6.9 [4CH(CH3)2]; 13.3-12.3 [4CH(CH3)2]; MS ESI(þ) ¼ 574; UV
25ꢀ
1
(CHCl3) lmax ¼ 266 nm (e ¼ 11000); ½aŠ (CH3OH) ¼ ꢁ 6.80; 5c: H NMR d
D
11.0 (1H, s, NH-3); 10.2 (1H, m, NH-7); 8.85 (1H, s, CHO); 8.84 [1H, d,
NHCH(CH2OH)2]; 7.50 (1H, d, H-6); 5.78 (1H, m, H-10), 4.48 (1H, m, H-30);
4.02 (2H, m, H-50b and H-40); 3.75 (1H, m, H-50a); 3.90 [4H, m,
NHCH(CH2OH)2]; 3.55 [1H, m, NHCH (CH2OH)2] 2.25 (1H, m, H-20a);
2.05 (1H, m, H-20b); 1.03-0.80 [28H, 4CH(CH3)2]; 13C NMR d 184.6 (CHO);
160.5 (C-4); 145.9 (C-2); 143.8 (C-6); 122.6 (C-5); 84.7 (C-40); 76.3 (C-10); 68.9
(C-30); 61.0 (C-50); 60.6 [NHCH(CH2OH)2]; 48.7 [NHCH(CH2OH)2]; 43.1
(C-20); 13.9 ꢁ 12.6 [4CH(CH3)2]; MS ESI(þ) ¼ 590.
30,50-O-(Tetraisopropyldisiloxane-1,3-diyl)-5-[N-(2R,3-dihydroxy-1-propyl)-
aminomethyl]-20-deoxyuridine (4d)
The crude product from reductive amination of 3 with amine d was
analysed by TLC (CHCl3=CH3OH 75:25 v=v), which showed the presence of
two spots at Rf 0.55 (4d) and Rf 0.75 (5d), and chromatographed on a silica

1838
CATALANOTTI ET AL.
gel column (200 g, 15062.5 cm), eluted with increasing amounts (from 0 to
35%) of CH3OH in CHCl3.Fractions eluted with 15% CH OH in CHCl3,
3
gave 5d (0.24 g, 20%) while fractions eluted with 35% of CH3OH gave 4d
(0.89 g, 78%). 4d: 1H NMR d 7.58 (1H, s, H-6); 6.08 (1H, dd, H-10); 4.46 (1H,
m, H-30); 4.05 (2H, m, H-50a and H-50b); 3.75 (1H, m, H-40); 3.71-3.40 [5H,
m, CH2NHCH2CH(OH)CH2OH]; 2.76 [2H, m, CH2NHCH2CH(OH)-
CH2OH]; 2.45 (1H, m, H-20a); 2.28 (1H, m, H-20b); 1.10-0.90 [28H,
4CH(CH3)2]; 13C NMR d 164.9 (C-4); 150.7 (C-2); 139.2 (C-6); 109.8 (C-5);
85.5 (C-40); 84.6 (C-10); 69.6 (C-30); 69.0 [CH2NHCH2CH(OH)CH2OH]; 65.2
[CH2NHCH2CH(OH)CH2OH]; 61.2 (C-50); 51.0 [CH2NHCH2CH(OH)-
CH2OH]; 46.3 [CH2NHCH2CH(OH)CH2OH]; 40.0 (C-20); 17.3-6.9
[4CH(CH3)2]; 13.3-12.3 [4CH(CH3)2]; MS ESI(þ) ¼ 574; UV (CHCl3)
25ꢀ
1
lmax ¼ 266 nm (e ¼ 24000); ½aŠ (CH3OH) ¼ ꢁ 3.72; 5d: H NMR d 11.0
D
(1H, s, NH-3); 10.2 (1H, m, NH-7); 9.0 (1H, s, CHO); 8.84 (1H, d, NH-1);
7.78 (1H, d, H-6); 5.75 (1H, m, H-10); 4.60 (1H, m, H-30); 4.48 [1H, m,
NHCH2CH(OH)CH2OH]; 4.03 (1H, dd, H-50b); 3.90 (1H, dd, H-50a); 3.85
(1H, m, H-40); 3.72 [2H, m, NHCH2CH(OH)CH2OH]; 3.60 [2H, m,
NHCH2CH(OH)CH2OH]; 2.35 (1H, m, H-20a); 2.20 (1H, m, H-20b); 1.03-
0.80 [28H, 4CH(CH3)2]; 13C NMR d 185.8 (CHO); 163.4 (C-4); 147.6 (C-2);
145.8 (C-6); 123.4 (C-5); 84.9 (C-40); 75.3 (C-10); 69.8 (C-30); 69.3
[NHCH2CH(OH)CH2OH]; 67.2 [NHCH2CH(OH)CH2OH]; 62.1 (C-50); 48.3
[NHCH2CH(OH)CH2OH]; 41.5 (C-20); 17.3-6.9 [4CH(CH3)2]; 13.3-12.3
[4CH(CH3)2]; MS ESI(þ) ¼ 590.
30,50-O-(Tetraisopropyldisiloxane-1,3-diyl)-5-[N-(4-methylphenyl)aminome-
thyl]-20-deoxyuridine (4e)
The crude product from reductive amination of 3 with amine e was
analysed by TLC (CHCl3=CH3OH 7:3 v=v), which showed the presence of a
single spot at Rf 0.65 (4e), and chromatographed on a silica gel column
(200 g, 15062.5 cm), eluted with increasing amounts (from 0 to 35%) of
CH3OH in CHCl3.Fractions eluted with 30% CH OH in CHCl3, gave 4e
3
(1.17 g, 99%). 4e: 1H NMR d 7.48 (1H, s, H-6); 6.98 (2H, d, H-2 tolyl and H-
6 tolyl); 6.50 (2H, d, H-3 tolyl and H-5 tolyl); 6.02 (1H, dd, H-10); 4.45 (1H,
dd, H-30); 4.03 (4H, m, H-50a, H-50b and CH2NHC6H4CH3); 3.70 (1H, m, H-
40); 2.45 (1H, m, H-20a); 2.20 (3H, s, CH3 tolyl); 2.15 (1H, m, H-20b); 1.08-
0.90 [28H, 4CH(CH3)2]; 13C NMR d 163.0 (C-4); 149.6 (C-2); 145.0 (C-1
tolyl); 136.7 (C-6); 129.6 (C-2 tolyl and C-6 tolyl); 127.3 (C-4 tolyl); 113.5
(C-3 tolyl and C-5 tolyl); 111.5 (C-5); 84.8 (C-40); 83.7 (C-10); 68.7 (C-30); 60.9
(C-50); 41.5 (CH2NHC6H4CH3); 39.6 (C-20); 20.7 (CH3 tolyl); 17.3 ꢁ 16.9
[4CH(CH3)2]; 13.3-12.3 [4CH(CH3)2]; MS ESI(þ) ¼ 590; UV (CHCl3)
25ꢀ
lmax ¼ 254 nm (e ¼ 19000); ½aŠ (CH3OH) ¼ ꢁ 9.12.
D

5-METHYLAMINO-20-DEOXYURIDINE DERIVATIVES
1839
30,50-O-(Tetraisopropyldisiloxane-1,3-diyl)-5-[N-(4-aminophenyl)aminome-
thyl]-20-deoxyuridine (4f)
The crude product from reductive amination of 3 with amine f was
analysed by TLC (CHCl3=CH3OH 7:3 v=v), which showed the presence of a
single spot at Rf 0.45 (4f), and chromatographed on a silica gel column
(200 g, 15062.5 cm), eluted with increasing amounts (from 0 to 35%) of
CH3OH in CHCl3.Fractions eluted with 35% CH OH in CHCl3, gave 4f
3
1
(1.07 g, 91%). 4f: H NMR d 7.44 (1H, s, H-6); 6.55 (2H, d, H-2 amino-
phenyl and H-6 aminophenyl); 6.45 (2H, d, H-3 aminophenyl and H-5
aminophenyl); 6.00 (1H, dd, H-10); 4.45 (1H, dd, H-30); 3.98 (4H, m, H-50a,
H-50b and, CH2NHC6H4NH2); 3.72 (1H, m, H-40); 2.42 (1H, m, H-20a); 2.13
(1H, m, H-20b); 1.08-0.90 [28H, 4CH(CH3)2]; 13C NMR d 163.7 (C-4); 150.3
(C-2); 140.5 (C-1 aminophenyl); 137.1 (C-6); 117.0 (C-2 aminophenyl and C-
6 aminophenyl); 138.6 (C-4 aminophenyl); 115.7 (C-3 aminophenyl and C-5
aminophenyl); 112.1 (C-5); 85.2 (C-40); 84.1 (C-10); 69.0 (C-30); 61.2 (C-50);
42.8 (CH2NHC6H4NH2); 40.0 (C-20); 17.7-17.1 [4CH(CH3)2]; 13.7-12.7
[4CH(CH3)2]; MS ESI(þ) ¼ 591; UV (CHCl3) lmax ¼ 258 nm (e ¼ 25000);
25ꢀ
½aŠ (CH3OH) ¼ ꢁ 14.8.
D
ACKNOWLEDGMENTS
This work is supported by Italian M.U.R.S.T. and C.N.R. The authors are
grateful to ‘‘Centro Ricerche Interdipartimentale di Analisi Strumentale’’,
C.R.I.A.S., for supplying NMR facilities.
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Received February 19, 2001
Accepted June 12, 2001