Selectivity in C-alkylation of dianions of protected 6-methyluridine

Article abstract of DOI:10.3762/bjoc.7.143

A regioselective synthesis of 6-ω-alkenyluridines 3, precursors of potent antiviral and antitumor cyclonucleosides 5, is described. While ω-alkenyl halides do not alkylate 6-lithiouridine, compounds 3 were prepared in a regioselective manner by sequential treatment of 6-methyluridine 2 with LTMP or LDA (4 equiv) in THF at ?30 °C followed by alkylation with ω-alkenyl bromides.

Full text of DOI:10.3762/bjoc.7.143

Selectivity in C-alkylation of dianions of
protected 6-methyluridine
Ngoc Hoa Nguyen1, Christophe Len2, Anne-Sophie Castanet*1
and Jacques Mortier*1,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1228–1233.
1Université du Maine and CNRS, Unité de chimie organique
moléculaire et macromoléculaire (UMR 6011), Faculté des sciences,
avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France and
2Université de technologie de Compiègne, Transformations intégrées
de la matière renouvelable, EA 4297 UTC/ESCOM, 1 allée du réseau
Jean-Marie Buckmaster, 60200 Compiègne, France
doi:10.3762/bjoc.7.143
Received: 22 March 2011
Accepted: 16 June 2011
Published: 06 September 2011
This article is part of the Thematic Series "Directed aromatic
functionalization"
Email:
Ngoc Hoa Nguyen - bexiuhn@yahoo.com;
Christophe Len - christophe.len@utc.fr;
Anne-Sophie Castanet* - anne-sophie.castanet@univ-lemans.fr;
Jacques Mortier* - jacques.mortier@univ-lemans.fr
Guest Editor: V. Snieckus
© 2011 Nguyen et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
§ Fax: +33 (0) 243 83 39 02
Keywords:
C6-alkylation; cyclonucleosides; lithiations; 6-ω-alkenyluridines
Abstract
A regioselective synthesis of 6-ω-alkenyluridines 3, precursors of potent antiviral and antitumor cyclonucleosides 5, is described.
While ω-alkenyl halides do not alkylate 6-lithiouridine, compounds 3 were prepared in a regioselective manner by sequential treat-
ment of 6-methyluridine 2 with LTMP or LDA (4 equiv) in THF at −30 °C followed by alkylation with ω-alkenyl bromides.
Introduction
Conformationally restricted C–C bridged cyclonucleosides As part of an ongoing program directed by one of us (C. L.)
bearing a linkage between the sugar moiety and the nucleobase, toward the synthesis and development of new cyclonucleosides
exhibit a broad spectrum of antiviral and antitumor activities 5 [5,6], we envisioned that the general transformation outlined
[1-4]. Cyclonucleosides are excellent tools for studying the role in Scheme 1 might afford a facile entry to 5 from dialkenyl
of the conformational parameters that are critical for the design precursors 4 by ring-closing metathesis [10-12]. The strategy
of new nucleoside drug candidates [4-8]. These cyclic com- relies on the preparation of unknown 6-ω-alkenyluridine key
pounds are expected to have a beneficial biological impact intermediates 3. We report herein that sequential ring lithiation/
especially toward enzymatic repair processes [9].
methylation of the simple protected uridine 1 leading to 2 fol-
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Beilstein J. Org. Chem. 2011, 7, 1228–1233.
Scheme 1: Synthesis of potent antiviral and antitumor cyclonucleo-
sides 5.
Figure 1: Lithiation of 2',3'-O-isopropylideneuridine (6).
lowed by lateral lithiation/alkylation with ω-alkenyl bromides Consequently, lateral lithiations were examined. Lateral lithia-
provides a useful regioselective chain-extension procedure and tion of benzenoid aromatics requires a stabilizing group capable
an efficient route to 3.
of either delocalizing negative charge or stabilizing an organo-
lithium by coordination [19,20]. Primary, allylic, and benzylic
halides usually give good yields of laterally alkylated products.
Results and Discussion
Most methods for the construction of C-substituted nucleosides Secondary and acetylenic halides have been used in several
are based on ring lithiation of nucleoside derivatives followed instances. Successful reaction with these substrates is note-
by their reaction with appropriate electrophiles. Thus, sequen- worthy since many aryllithiums arising from ortho-lithiation
tial lithiation of 2',3'-O-isopropylideneuridine (6) with LDA in reactions do not alkylate, or give poor yields, with any halides
THF (Figure 1) and electrophilic quenching with n-bromobu-
tane was reported to give 6-n-butyl-2',3'-O-isopropylideneuri-
dine (8) in a regiospecific manner (60%) [13]. It seems likely
that the reaction proceeds via trianion 7 where the 5'-OLi group
can easily participate in the stabilization of the 6-lithio inter-
mediate. ω-Alkenyl bromides are known to be poor elec-
trophiles toward organolithiums [14], and indeed, 7 failed to
react, in our experiments, with 4-bromo-but-1-ene to give 9.
We then turned our attention to the metalation of the 5'-O-
TBDMS protected nucleoside 10 (Figure 2). Treatment with
LDA (5 equiv) in THF at −70 °C followed by addition of D2O
provided 12 in 82% yield (evaluated by NMR) with exclusive
deuterium incorporation at the C6 position. However, almost
complete recovery of the starting material was observed when
dianion 11 was allowed to react with 4-bromobut-1-ene [15].
Lithium–copper transmetallation was also attempted. Unfortu-
nately, addition of 0.25 equiv of Li2CuCl4 [16-18] to 11 fol-
lowed by quenching with 4-bromobut-1-ene failed to
Figure 2: Metalation of 5'-O-TMDMS protected nucleoside 10.
produce 3a.
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Beilstein J. Org. Chem. 2011, 7, 1228–1233.
other than iodomethane [21-24]. Competing base-induced elim- Having these precedents in mind, we decided to investigate the
ination reactions are presumably observed with iodoethane and preparation of 6-ω-alkenyluridines 3 by lithiation of 6-methyl-
higher homologues [19,20,25,26]. It has also been proposed that uridine derivative 2. Miyasaka et al. observed concomitant for-
poor reactivity of lithiated carbanions toward alkyl halides may mation of 6-ethyl derivative alongside the expected 6-methyl
result from steric hindrance [24,27]. Recently, the lateral lithia- derivative when 2',3'-O-isopropylideneuridine (6) was allowed
tion of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid to react with LDA and treated with MeI [13]. We found simi-
was applied to the regioselective efficient construction of a larly that 10 in the presence of LDA (2.5 equiv) followed by
series of 5,5'-didesisopropyl-5,5'-dialkylapogossypol deriva- addition of MeI (3.3 equiv) at −78 °C gave a mixture of
tives that are potent pan-active inhibitors of anti-apoptotic Bcl-2 6-methyluridine 2 (44%) and 6-ethyluridine 17 (17%)
family proteins [28].
(Scheme 2). By slow addition of the preformed dianion 11 to a
THF solution of MeI (reverse-addition mode) [30,31], 2 was
Literature furnishes little information regarding lateral lithia- produced in satisfactory yield (72%) while formation of 6-ethyl-
tions in the nucleoside field and the data, scarce as they are, uridine 17 was reduced to <5%. Apparently LDA does not co-
even appear to be inconsistent at first sight. Treatment of ordinate with the substrate in this transformation [32].
2',3',5'-tri-O-benzoyl-3,6-dimethyluridine (13) with chloroace- 6-Methyluridine can also be synthesized from 5'-O-(tert-butyl-
tone or 2-chloroacetophenone in the presence of LDA dimethylsilyl)-6-iodo-2',3'-O-isopropylideneuridine via palla-
(1.2 equiv, THF, −78 °C) afforded 6-(oxiranylmethyl)uridine dium-catalyzed cross-coupling with Me4Sn [33].
derivatives 14 exclusively (Figure 3) [29]. With 5-chloro-2-
pentanone, the reaction led to a mixture of 5- and 6-substituted
uridine regioisomers 15 and 16 in 47% and 28% yield, respect-
ively. It was suggested that the N-1 sugar moiety in the syn
orientation of the nucleoside might affect the access of a very
sterically demanding electrophile, such as 5-chloro-2-
pentanone, to the 6-position. This hypothesis was confirmed by
a probe experiment where an even more sterically hindered
racemic 3-bromocamphor was used as an electrophile. The
corresponding C5-alkylated uridine derivative was obtained as
the only recovered product, in low yield (23%), besides the
Scheme 2: Preparation of 2',3'-O-isopropylidene-5'-O-(tert-butyl-
dimethylsilyl)-6-methyluridine (2).
unreacted substrate.
We have then embarked on a detailed investigation of the lithia-
tion/alkylation of 6-methyluridine 2, varying the base, metala-
tion temperature, and exposure times (Scheme 3). We were
concerned with the question of relative acidity of the methyl
(C7) and the C5 centers that can compete through 18A or 18B
[34-36]. In fact the two negative charges at N3 and C5/C7 are
delocalized through the O2-C2-N3-C4-O4-C5-C6-C7 bond
system rather than being localized dianions: All these forms are
resonance structures of the same extended dianionic enolate 18
[37].
In the past, the regioselectivity of reactions of allyl anions have
sometimes been explained using the HSAB theory [34]. In the
present case, soft electrophiles (ω-alkenyl bromides) are used in
the alkylation reaction. However, it is not straightforward to
predict the softest center of 18. In the literature, the regioselec-
tivity of lithiation of allyl anions substituted by one nitrogen at
the central carbon (C=C(N)–C) has scarcely been studied [38-
Figure 3: Lithiation/alkylation of 2',3',5'-tri-O-benzoyl-3,6-dimethyluri-
dine (13) using LDA.
40]. Deprotonation of simple enamines or allylamines
employing n-BuLi and t-BuLi/t-BuOK produced nitrogen-
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Beilstein J. Org. Chem. 2011, 7, 1228–1233.
Scheme 3: Lateral lithiation/alkylation of 6-methyluridine 2.
substituted allylic anions which undergo protonation, alkylation, presumed to be 18, as a yellow solution. The colour faded when
trimethylsilylation and reaction with carbonyl compounds and allyl bromide (8 equiv/ −70 °C → rt/12 h) was introduced,
epoxides either exclusively or predominantly at the γ-position providing a mixture of regioisomers 3a and 19a which were
[41-43]. Previous work also showed that cyclic enaminoke- separated by chromatography (entry 1, 58% and 10% yield, res-
tones, esters and nitriles were converted into their enolate with pectively). With LTMP, the delivery of a less acidic conjugated
n-BuLi and alkylated with a variety of alkylating agents, amine (TMP) in the reaction medium could be expected to
affording the product of an exclusive γ-alkylation [42-45]. prevent protonation of lithiated intermediates and thus to allow
more efficient trapping by an electrophile [46,47]. Indeed,
The results are summarized in Table 1. An excess of LDA LTMP gave a better yield, but a slight decrease in the regiose-
(4 equiv) at −70 °C produced a dilithium reagent, which was lectivity was observed (3a/19a 65:20). The 1H NMR spectrum
Table 1: Lateral lithiation/alkylation of 6-methyluridine 2.
entry
base
n
3a,b (%)
19a,b (%)
others (%)
1
2
3
4
5
6
LDA
LTMP
2
2
3
3
2
3
58
65
44
56
0
10
20
0
—
—
LDA
—
LTMP
0
—
20 (40), 21 (18)
—
LiHMDS
s-BuLi/TMEDA
0
38
0
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Beilstein J. Org. Chem. 2011, 7, 1228–1233.
of 19a displayed a singlet at 2.31 ppm, attributed to the
C7-methyl group, and the disappearance of the H5 signal
at 5.57 ppm. 4-Bromobut-1-ene underwent exclusive
C7-carbanion alkylation to 3b in good yield, with no indication
of products resulting from C5-alkylation (entries 3 and 4).
Supporting Information
Supporting Information File 1
Experimental section (preparation and spectral data of
compounds).
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-143-S1.pdf]
Allyl bromide is a good electrophile that can react with both
mesomeric forms 18A and 18B to give 3a and 19a. Apparently
dianion 18B is not nucleophilic enough to react with
4-bromobut-1-ene to give 19b, and 3b is formed exclusively.
The lateral alkylation of uridine enolate 18 was best accom-
plished through use of LDA or LTMP as the carbanion gener-
ating species, rather than LiHMDS or s-BuLi/TMEDA. The bis-
allylated products 20 and 21 (Figure 4) were obtained in 40%
and 18% yield, respectively with LiHMDS at −70 °C and
quenched with allyl bromide (entry 5). This result suggests the
remetalation of 3a is faster than the destruction of LiHMDS by
the excess of allyl bromide. Structure of 20 was confirmed by
1H NMR and a two-dimensional COSY experiment, which
allowed the assignment of the proton–proton correlations of H7
and the allylic methylene groups. Metalation with s-BuLi/
TMEDA complex was less efficient although the reaction did
not lead to degradation products (entry 6). Ring/internal lithia-
tions of uridine derivatives with s-BuLi/TMEDA are usually
performed with fully TBDMS-protected ribofuranose nucleo-
sides to allow better regiochemical control and to prevent nucle-
ophilic attack of the base on the sugar moiety [48].
Acknowledgements
This research was supported by the CNRS and Université du
Maine.
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