New and efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides

Article abstract of DOI:10.1016/S0040-4039(02)02514-5

A short, efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides 1 has been developed through the diastereoselective addition of methylmagnesium bromide or methyllithium to an intermediate tert-butylsulfinimide.

Full text of DOI:10.1016/S0040-4039(02)02514-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 293–297
New and efficient synthesis of
5%-amino-5%-(S)-methyl-2%,5%-dideoxynucleosides
Pierre M. J. Jung,* Renaud Beaudegnies, Alain De Mesmaeker and Sebastian Wendeborn
Syngenta Crop Protection AG, CH-4002 Basel, Switzerland
Received 27 September 2002; revised 7 November 2002; accepted 8 November 2002
Abstract—A short, efficient synthesis of 5%-amino-5%-(S)-methyl-2%,5%-dideoxynucleosides 1 has been developed through the
diastereoselective addition of methylmagnesium bromide or methyllithium to an intermediate tert-butylsulfinimide. © 2002
Elsevier Science Ltd. All rights reserved.
Modified oligonucleotides and their analogs offer the
possibility of designing compounds with potential ther-
apeutic and diagnostic applications. Antisense or anti-
gene technology requires modified oligonucleotides that
bind strongly and specifically to defined RNA or DNA
target sequences, respectively.1 Replacement of the
phosphodiester moiety in natural oligonucleotides
(wild-type) with an amide moiety leads to modified
oligonucleotides (amide modification) displaying higher
affinity for an RNA target and greatly improved resis-
tance toward nucleases (Fig. 1).2 Further work demon-
strated that the introduction of an S-methyl group
within the amide backbone (S-methyl amide modifica-
tion) further improved the binding affinity towards
single stranded RNA and DNA.3
Our initial approach towards the synthesis of S-methyl
amide backbone relied on the non-selective Grignard
addition to 5%-aldehydo-2%-deoxynucleoside which led to
a 1:1 mixture of diastereomeric alcohols which could be
transformed to the corresponding amine 1 via the
nucleophilic displacement of a C5% mesylate by an azide
followed by the reduction of the latter to the amine.
This synthesis provided compound 1 in eight steps and
10% overall yield starting from 2%-deoxynucleoside and
is not suitable for large-scale preparation (Scheme 1).3
In the context of a recent program directed toward the
synthesis of modified oligonucleotides with improved
biophysical properties, we became interested in devel-
oping a more practical synthesis of 1 that could serve as
a general route to amide-modified oligonucleotides.
Initial studies demonstrated that the nucleophilic addi-
tion of an organometallic to a 5%-oxime or a 5%-hydra-
zone derivatives of a protected thymine gave none or
only trace amounts of the desired product along with
products derived from the addition of the organometal-
lic on C4 followed by dehydration.
For example, the reaction of hydrazone 2 in the pres-
ence of methyllithium in tetrahydrofuran at −78°C gave
a mixture of 4 and 5. The desired compound 3 could
not be detected (Scheme 2). When the nucleic base was
not protected by a BOM group, only the compound
resulting from the nucleophilic addition of the C6 posi-
tion of the nucleic base on the hydrazone bond was
isolated.
Figure 1.
Keywords: 5%-amino-5%-(S)-methyl-2%, 5%-dideoxynucleosides; tert-
butylsulfinamide; nucleophilic addition.
* Corresponding author. Tel.: +41-613236904; fax: +41-613238529;
e-mail: pierre.jung@syngenta.com
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02514-5

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P. M. J. Jung et al. / Tetrahedron Letters 44 (2003) 293–297
Scheme 1. Eight steps, 10% overall.
Scheme 2.
ether gave as the major product the sulfinamide which
possesses the S configuration at C5% (entry 1) with a
selectivity of 5:1 in favor of the diastereomer 8 (com-
bined yield 91%). Other solvents, like tetrahydrofuran
or dichloromethane decreased the selectivity and the
yield of the reaction. In contrast, the use of methyl-
lithium in tetrahydrofuran gave the sulfinamide 9 with
the R configuration at C5%, as the major product (entry
4).7
In order to avoid these side reactions, we turned our
attention to the more reactive imine derived from sulfin-
amide.4 The required aldehyde 6 was synthesized from
thymidine in four steps in 66% overall yield,5 and
reacted with S-tert-butylsulfinamide providing 7 in 74%
yield (Scheme 3).6
Reaction of methylmagnesium bromide or methyl-
lithium with 7 in different solvents gave exclusively the
desired addition to the imine bond. Even when an
excess of organometallic was used, no side reaction was
observed with the nucleic base, protected or not.
While the reaction is not completely diastereoselective,
the separation of the two diastereoisomers, 8 and 9, was
easily accomplished chromatographically. This is in
strong contrast to the separation of the diastereoiso-
meric mixture of 1 obtained by the nucleophilic dis-
placement of C5% mesylate by sodium azide followed by
the reduction of the azide to the amine3 where the
separation was tedious.
Detailed investigation (Table 1, Scheme 4) of this reac-
tion showed that the reaction is strongly counter-ion
and solvent dependent. For example, the reaction of 7
in the presence of methylmagnesium bromide in diethyl

P. M. J. Jung et al. / Tetrahedron Letters 44 (2003) 293–297
295
the diastereoselectivity of the reaction could be
explained by the model advanced by Davis et al.7b
where the sulfinyl oxygen is proposed to coordinate to
one equivalent of the organometallic and sterically
shields the Re face of the imine to give the Cram
product (Scheme 5 (A)).
In contrast, the predominant diastereoisomer
obtained with the use of methyllithium could be pre-
9
dicted by Ellman’s model, which involved a six-mem-
bered chair transition state (Scheme
5
(B)).
Nevertheless, the results show that the ratio between 8
and 9 are a function of the nature of the solvent and
of the organometallic reagent used. In addition, these
results are likely strongly influenced by the het-
eroatoms of the nucleoside.8
Treatment of 8 or 9 with a mixture of hydrogen chlo-
ride and methanol gave the desired amines 10 and 11
in 92% and quantitative yield, respectively (Scheme 6).
The configuration at C5% was determined by compari-
son of the NMR data of 10 and 11 with those of
original product.3,9
Scheme 3. Reagents and conditions: (I) TrCl, pyridine, 81%
yield; (II) Ph2tBuSiCl, DMF, imidazole, 87% yield; (III)
AcOH, H2O, 98% yield; (IV) DCC, DMSO, TFA·pyr, 96%
yield; (V) S-tert-butylsulfinamide, benzene.
In conclusion, we have shown that the 5%-tert-butyl-
sulfinamide group could be used as activating and
directing group for the preparation of 5%-amino-5%-
methyl-2%,5%-dideoxynucleoside. Compounds 10 and 11
were synthesized in seven steps in 34 and 32% yield,
respectively. Their incorporation into oligonucleotides
for antisense and antigene applications is currently
underway.
The derivatives obtained with the corresponding R- or
racemic tert-butylsulfinamide led to mixtures that were
inseparable on silica gel.
In the case of methylmagnesium bromide, the predom-
inant diastereoisomer 8 is the opposite to that pre-
dicted by the model proposed by Ellman.7a However,
Table 1.
Entry
RM*
Solvent
Temperature
8 (%)
9 (%)
Yield (%)
Ratio 8/9***
1
2
3
4
MeMgBr
MeMgBr
MeMgBr
MeLi
Et2O
THF
CH2Cl2
THF
−48°C to rt
−48°C to rt
−48°C to rt
−48°C
76
47
43
30
15
24
12
65
91
71
55**
95
5/1
2/1
3.5/1
1/2
* 3 equiv.
** 36% of starting material was recovered.
*** Isolated and NMR.
Scheme 4.

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P. M. J. Jung et al. / Tetrahedron Letters 44 (2003) 293–297
Scheme 5.
Scheme 6.
References
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(1H, t, H-1%, 6 Hz); 4.32 (1H, m, H-3%); 3.69 (1H, m, H-4%),
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