A dramatic concentration effect on the stereoselectivity of N-glycosylation for the synthesis of 2′-deoxy-β-ribonucleosides

Article abstract of DOI:10.1039/c2cc33155a

A dramatic concentration effect on the stereoselectivity of N-glycosylation, which is attributable to a low-concentration-facilitated remote-participation, has been disclosed, leading to convenient synthesis of the 2′-deoxy-β-ribonucleosides of biological significance. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc33155a

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A dramatic concentration effect on the stereoselectivity of
N-glycosylation for the synthesis of 20-deoxy-b-ribonucleosidesw
Fei Yang, Yugen Zhu and Biao Yu*
Received 2nd May 2012, Accepted 22nd May 2012
DOI: 10.1039/c2cc33155a
A dramatic concentration effect on the stereoselectivity of
N-glycosylation, which is attributable to a low-concentration-
facilitated remote-participation, has been disclosed, leading to
convenient synthesis of the 20-deoxy-b-ribonucleosides of biological
significance.
at C20.6 This problem could be bypassed by synthesis starting
from a natural nucleoside7 or by N-glycosidation of a glycosyl
donor installed with a temporary participating group at C20.8
Obviously, the former synthesis is limited by the availability of
the original structures, while the latter one is plagued by
additional steps required to install and remove the temporary
C20-substituent. With additional steps, a nucleobase could also
be linked to the C50 (or C30) followed by an intramolecular
N-glycosidation to secure the b-selectivity.9 Nevertheless, the
direct and versatile synthesis of 20-deoxynucleosides requires
the stereoselective N-glycosylation of nucleobases with 2-deoxy-
furanosyl donors. This has been realized by SN2 type substitu-
tion of a 2-deoxyfuranosyl a-chloride with nucleobases under
basic conditions.10,11 In fact, the so-called ‘sodium salt method’
developed by Robins and co-workers has been the most successful
method for this purpose.11a In addition, N-glycosylation under the
assistance of a participating group at C3 has also been explored
for the synthesis of 20-deoxy-b-nucleosides.12 However, the stereo-
selectivity, together with the regioselectivity (associated with the
glycosylation of ambident bases) and the coupling yields are highly
dependent on the glycosylation partners.7–13
Only in rare cases, concentration has a dramatic effect on the
stereoselectivity of a reaction. These rare cases involve mainly
pre-assembly of the reactants at a higher concentration.1
Recently, a remarkable concentration effect was observed in
a glycosylation reaction with nitrile as the solvent,2 in which
the formation of a 1,2-cis-glycosyl oxazolinium intermediate
was kinetically favored at a lower concentration to facilitate a
subsequent SN2-like glycosidation.2b In addition, sialylation in
acetonitrile was found to have a nonlinear concentration
dependence, which was attributable to changes of the structures
of the reagents supramers at different concentrations.3 Herein,
we report an unprecedented dramatic concentration effect
on the stereoselectivity of N-glycosylation for the synthesis of
20-deoxy-b-ribonucleosides.4
20-Deoxy-b-D-ribonucleosides of thymine, cytosine, adenine
and guanine, via linear 50 - 30 phosphodiester linkages,
constitute the deoxyribonucleic acid (DNA), which determines
heredity and evolution. The analogues of these 20-deoxy-b-D-
ribonucleosides and their oligomers could interfere with
the native genetic processes and thus be of great biological
significance.5 Remarkably, a number of the 20-deoxynucleosides
have already been used effectively as anticancer and antiviral
drugs, such as cladribine (1) and floxuridine (2). Synthesis of
20-deoxynucleosides has therefore attracted great attention.
Nevertheless, it is associated with a special challenge, besides
others in the context of nucleosides synthesis, that the N-glycosyla-
tion demands stereoselectivity in the absence of a directing group
Recently, we disclosed that the gold(I)-catalyzed glycosylation
with glycosyl ortho-alkynylbenzoates as donors was highly efficient
for the N-glycosylation of nucleobases.14 Especially, complete
regioselectivity was achieved for the glycosylation of purines,
contributing to the mild reaction conditions (cf., the conventional
Vorbruggen-type reaction conditions)15 that allow purines bearing
¨
acid-labile protecting groups (e.g., the N-Boc group) to be used as
the coupling partners. However, the problem of stereoselectivity
for the synthesis of 20-deoxynucleosides remains unsolved.
Thus, the glycosylation of N-Boc-2-amino-6-iodo-purine (4a)
with 3,5-di-O-p-methoxybenzoyl-D-ribofuranosyl ortho-hexynyl-
benzoate (3a) proceeded smoothly in the presence of Ph3PAuNTf2
(0.1 equiv.) in ClCH2CH2Cl at above the temperature of 30 1C,
furnishing nucleoside 5a nearly quantitatively within 6–8 h with
b/a ratios of o3.7. Accidentally, we found that the b/a selectivity
of this coupling reaction was increased remarkably with a decrease
of the reaction concentration (Scheme 1, entries 1–4). Thus, when
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China.
E-mail: byu@mail.sioc.ac.cn; Fax: (0086)-21-64166128
w Electronic supplementary information (ESI) available: Experimental
details, characterization data, and NMR spectra for all new
compounds. The crystallographic data for compounds 5bb (CCDC
865441) and 5db (CCDC 865440) can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc33155a
c
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Chem. Commun., 2012, 48, 7097–7099 7097

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was silylated with BSTFA (N,O-bis(trimethylsilyl)trifluoro-
acetamide) in acetonitrile and then subjected to coupling with 3a
(at 25 mM) in the presence of Ph3PAuNTf2 (0.1 equiv.) at
45 1C. The reaction completed within 10 h to provide the
coupled nucleoside 7a in B85% yield with a b/a ratio of B2.0.
A similar reaction at a low concentration of 1 mM led to a
much lower yield of 7a. We thus evaporated the acetonitrile
after silylation of the base 6a and conducted the coupling
reaction with ClCH2CH2Cl as the solvent. Thus, the coupling
of the silylated base of 6a with 3a in ClCH2CH2Cl (0.1 equiv.
Ph3PAuNTf2, 4 A MS, rt) led to 7a quantitatively with the b/a
ratio of 0.9 at the concentration of 25 mM (Scheme 2, entry 1).
Decreasing the reaction concentration to 10 mM, 2.5 mM and
1 mM, the reaction rate remained, while the b/a ratio of
the coupled 7a was increased dramatically to 4.2, 8.0 and
15.0, respectively (entries 2–4). Similar results were obtained
with thymine (6b) and 5-F-uracil (6c) as the coupling bases
(entries 5–10). In fact, the coupling of 6b and 6c with 3a at the
low concentration of 1 mM led to nucleosides 7b and 7c in the
b-form exclusively (entries 7 and 10). Removal of the 30,50-O-
p-methoxybenzoyl groups on 7cb with MeONa in MeOH
afforded the anticancer drug floxuridine (2).13a,19 Worth
noting is that the present concentration effect was also
observed in the O-glycosylation of alcohols (e.g., n-pentenol,
2-propanol, and 1,2;3,4-di-O-isopropylidene-D-galactose) with
2-deoxyribofuranosyl donor 3a.19
Scheme 1 Low-concentration-facilitated highly b-selective N-glycosyl-
ation of purines (4a–4e) with 2-deoxy-D-ribofuranosyl ortho-hexynyl-
benzoate 3a.
To testify whether the participation of the 3-O-p-methoxy-
benzoyl group (in donor 3a) played a role in the above
b-selective glycosylation, 2-deoxyribofuranosyl ortho-hexynyl-
benzoate 3b, which bears a non-participating 3-O-benzyl
group, was subjected to glycosylation with purine 4a
(Scheme 3). The reactions showed a marginal bias to the
formation of the b- and a-isomers, and the b/a ratios of the
the coupling of 4a (1.0 equiv.) and 3a (1.2 equiv.) was
conducted at a concentration of 25 mM in ClCH2CH2Cl at
45 1C in the presence of 4 A MS and Ph3PAuNTf2 (0.1 equiv.),
the reaction completed within 6 h to give 5a quantitatively with
a b/a ratio of 2.8. A similar reaction at a lower concentration of
10 mM led to 5a quantitatively with an increased b/a ratio of 4.2.
The b/a ratio of 5a was further increased to 9.7, while the yield
remained excellent (97%) when the reaction proceeded at a
concentration of 2.5 mM. At a further diluted concentration of
1 mM, 5a was obtained in 89% yield with the b/a ratio being
increased to 15.0. This dramatic concentration effect was
confirmed with a panel of purines 4b–4e as acceptors to couple
with the 2-deoxyribose donor 3a (entries 5–16). It was also
observed that the reaction rate was not affected considerably
when lowering down the reaction concentration (from 25 mM
to 1 mM).16 In addition, only the N9-glycosylated products
(i.e., 5b–5e) were obtained without detection of the corre-
sponding N7-regioisomers. This should be due to the mild
reaction conditions, which allowed the differentiation of the
slight difference between the nucleophilicity of the N9 and
N7.17 In comparison, the glycosylation of 6-chloropurine 4e
with pentenyl 3,5-di-O-p-toluyl-2-deoxy-ribofuranoside led to a
mixture of the N9- and N7-nucleosides.18 The lower yields at the
low concentration of 1.0 mM when coupling with purines 4a and
4c (89% and 84%, respectively; entries 4 and 10) were due to the
slight cleavage of the N-Boc group. The obtained 2,6-dichloro-
purine b-riboside 5db was readily converted into the clinical drug
cladribine (1) via treatment with NH3 in MeOH.7c,19
The N-glycosylation of pyrimidine nucleobases (6a–6c) with
2-deoxyribofuranosyl ortho-hexynylbenzoate 3a was then
examined (Scheme 2). As a background reaction, uracil (6a)
Scheme 2 Low-concentration-facilitated highly b-selective N-glycosyl-
ation of pyrimidines (6a–c) with 2-deoxyribofuranosyl ortho-hexynyl-
benzoate 3a.
c
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The participation of the 3-O-acyl group in the glycosylation
involves a dioxalenium intermediate, which is formed from the
oxacarbenium species.20 This is an intramolecular process, therefore
is more favoured at lower concentrations, being reminiscent of the
well-performed intramolecular cyclization, which demands the
reaction at low concentration to avoid intermolecular reaction.21
The present finding of the low-concentration-facilitated remote
participation is also attributed to the unique glycosylation system
using glycosyl alkynylbenzoates as the donors, Ph3PAuNTf2
as the promoter and ClCH2CH2Cl as the solvent, in that
neither an electrophilic nor nucleophilic species is present,
which could interfere with the equilibrium of the oxacarbenium
and dioxalenium species under varied concentrations.22 To
extrapolate the present concentration effect to the other reaction
systems shall be a subject of great interest and promise for
organic synthesis.
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We thank the financial support from the Ministry of Science
and Technology of China (2012ZX09502-002) and the National
Natural Science Foundation of China (20932009 and 20921091).
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 7097–7099 7099