Diastereoselective synthesis of 2′,3′-dideoxy- β-C- glucopyranosides as intermediates for the synthesis of 2′,3′- dideoxy-β-D-glucopyranosyl-C-nucleosides

Article abstract of DOI:10.1080/15257770701508695

An extension of the Vorbrueggen method of nucleotide synthesis for the synthesis of C-glucopyranosides, as intermediates for C-nucleosides, is described. It could be shown that the diastereoselectivity of the reaction can be tuned by a simple change of protecting groups. Copyright Taylor & Francis Group, LLC.

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Diastereoselective Synthesis of 2′,3′-
Dideoxy- β-C- Glucopyranosides as
Intermediates for the Synthesis of
2′,3′-Dideoxy-β-D-Glucopyranosyl-C-
Nucleosides
Michael Löpfe a & Jay S. Siegel a
a Institute of Organic Chemistry, University of Zurich , Zurich,
Switzerland
Published online: 10 Dec 2007.
To cite this article: Michael Löpfe & Jay S. Siegel (2007) Diastereoselective Synthesis of 2′,3′-
Dideoxy- β-C- Glucopyranosides as Intermediates for the Synthesis of 2′,3′-Dideoxy-β-D-
Glucopyranosyl-C-Nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 26:8-9, 1029-1035, DOI:
10.1080/15257770701508695
To link to this article: http://dx.doi.org/10.1080/15257770701508695
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1029–1035, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701508695
DIASTEREOSELECTIVE SYNTHESIS OF 2ꢀ,3ꢀ-DIDEOXY-β-C-
GLUCOPYRANOSIDES AS INTERMEDIATES FOR THE SYNTHESIS
OF 2ꢀ,3ꢀ-DIDEOXY-β-D-GLUCOPYRANOSYL-C-NUCLEOSIDES
Michael Lo¨ pfe and Jay S. Siegel
Institute of Organic Chemistry, University
2
of Zurich, Zurich, Switzerland
An extension of the Vorbru¨ggen method of nucleotide synthesis for the synthesis of C-
2
glucopyranosides, as intermediates for C-nucleosides, is described. It could be shown that the di-
astereoselectivity of the reaction can be tuned by a simple change of protecting groups.
Keywords C-glycosides; C-nucleosides
INTRODUCTION
C-glycosides serve as glycomimetics,[1] as well as important intermediates
for the synthesis of C-nucleosides.[2]
Most of the methods available for the synthesis of C-glycosides are more
suited for the synthesis of α-C-glycosides than for β-C-glycosides.[3] More-
over, the diastereoselectivity of the typically used methods for the synthe-
sis of β-C-glycosides are dependent on the influence of the neighbouring
group at 2-O-position and are therefore ineffective for the diastereoselective
prepartion of 2-deoxy sugar β-C-glycosides.[4] This limitation motivated the
developement of methods to epimerize the α- to the β-anomer.[5] As part of
our ongoing studies towards the synthesis of C-nucleosides, especially 2ꢁ,3ꢁ-
dideoxy-β-D-glucopyranosyl-C-nucleosides (homo-DNA-C-nucleosides) 1,
we developped an extension of the Hilbert-Johnson method[6] of nucleoside
synthesis, modified by Vorbru¨ggen et al.[7] to form C-glycosides 2–4 as a key-
intermediates. This new method allowed us to tune the β/α ratio according
to the protecting group at the OC(4) and OC(6) positions and, with the ben-
zyl protecting group, gave direct access (without additional epimerisation)
to the desired 2ꢁ, 3ꢁ-dideoxy-β-C-glycoside, which was used to synthesize 1.
The Vorbru¨ggen method of nucleoside synthesis forms the glycosidic
bond between the sugar and the persilylated heterocyclic base under Lewis
Address correspondence to Jay S. Siegel, Institute of Organic Chemistry, University of Zurich, Win-
terthurerstrasse 190, CH-8057 Zurich, Switzerland. E-mail: jssi@oci.uzh.ch
1029

1030
M. Lo¨pfe and J. S. Siegel
FIGURE 1 Homo-DNA-C-nucleoside (1), key intermediates (2–4) and typical example of a Vorbru¨ggen-
coupling.
acid catalysis. This method possesses two advantages: First, no activation of
C(1) in the sugar is necessary and second, the persilylated heterocyclic base
is produced in situ in the reaction mixture and does not need to be isolated
(Figure 1). The first advantage is critical for the synthesis of C-glycosides, the
in situ generation of the silylenolether (versus the isolation of the silyleno-
lether) offers preparatively no benefits.
RESULTS AND DISCUSSION
Commercially available 3,4,6-tri-O-acetyl-D-glucal 5 was converted, ac-
cording to a procedure by Ferrier and Prasad,[8] to methyl-4,6-di-O-acetyl-
β-D-erythro-hex-2-enopyranoside (6) (6α/6β = 8:1). The following hydro-
genation resulted in pyranoside 7. C(1) activation of pyranoside 7 under
strongly acidic conditions gave access to 1,4,6-tri-O-acetyl-pyranoside 8 in
76% yield and with a diastereomeric ratio α/β 5:1 (Scheme 1).
Eschenmoser et al.[9] reported that, for the product distributions and
the yields of the classical Vorbru¨ggen coupling, the configuration at the
anomeric center of the starting material had no influence. Under the cou-
pling conditions for C-glycoside 2, a diastereomeric mixture (2α/2β 66:34)
was obtained. Although a separation of the two diastereomers 2α/2β was
possible on preparative column chromatography, the unfavourable α/β ra-
tio was a synthetic challenge. Inspired by the Vorbru¨ggen method for the
synthesis of nucleosides, the coupling also was carried out without C(1) ac-
tivation, resulting in a diastereomeric ratio 2α/2β 47:53 with a yield of 49%
(Scheme 2).
Recent results from Woerpel et al.,[10] studying systematically the C-
glycolsylation reactions of mannose and other pyranoses, have shown that
the alkoxy groups at C-2, C-3, and C-4 exert powerful influences on the

2ꢁ,3ꢁ-Dideoxy-β-C-Glucopyranosides
1031
SCHEME 1 Synthesis of intermediates 8–11. i) MeOH, BF3∗OEt2, toluene; ii) Pd(C), H2, MeOH/AcOH
100:1; iii) H2SO4, AcOH, Ac2O; iv) 2N NaOH, THF/MeOH/H2O 5:4:1 resp. amberlite IRA 400, MeOH;
v) BzCl, pyridine resp. NaH, BnBr, Bu4NI, THF.
diastereoselectivity. This effect led us to investigate the influence of the
protecting groups at OC(4) and OC(6) on the diastereoselectivity of the
C-glycolsylation. The benzoyl-protected derivative 10 was prepared from
pyranoside 7 by a deprotection with the strongly basic anion exchange
resin amberlite IRA 400, followed by an esterification with benzoyl-chloride.
The benzyl-protected pyranoside 11 was accessible from the 4,6-dihydroxy-
pyranoside 9 by an ether formation with benzyl bromide.
SCHEME 2 Vorbru¨ggen-coupling reactions and synthesis of β-C-nucleosides 1, 14 from
i) tBuOCH(NMe2)2, toluene; ii) guanidine-sulfate, NaOEt, EtOH.
4

1032

2ꢁ,3ꢁ-Dideoxy-β-C-Glucopyranosides
1033
The diastereomeric ratio of the reaction product was inverted by a pro-
tecting group change from benzoyl (10) to benzyl (11). Under the coupling
conditions (25◦C, 6 hours for 7, 10, 11, respectively −78◦C, 1.5 hours for
8), the following effect was observed: the benzoyl-protected derivative 10 re-
sulted in a diastereomeric ratio 3α/3β 77:23, compared to a diastereomeric
ratio 4α/4β 18:82 with 4,6-O-benzyl-pyranoside 11. A reduction of the re-
action time with 11 (2 hours) resulted in a ratio 4α/4β 43:57 during an
increase of the reaction time to 2 hours gave a 4α/4β 8:92 ratio, indicating
a rearrangement from 4α to the thermodynamically more stabile 4β (Fig-
ure 2). The diastereoselectivity can be explained by a complexation of the
SnIV with the ester protecting groups in 7, 8, and 10 protecting these com-
pounds from the rearrangement. The two diastereomers 4α/4β were sepa-
rable on preperative column chromatography. With this synthetic strategy,
the desired diastereomer 4β was accessible and was converted with Bredereck’s
reagent to the regioisomeric enaminoketones 12 and 13. Condensation un-
der basic conditions with guanidine-sulfate resulted in a 3:1 mixture (1:14)
of the C-nucleosides 1, 14 which were separated on column chromatography
(cf. Scheme 2).
CONCLUSION
It was shown that 2ꢁ,3ꢁ-dideoxy-β-C-glucopyranosides, as intermediates
for the synthesis of homo-DNA-C-nucleosides, can be synthesised based on
an extension of the Vorbru¨ggen method for the synthesis of nucleosides,
particularly without C(1) activation of the sugar in acceptable yields (44–
56%) and that the diastereoselectivity of the reaction can be varied by a
simple change of protecting groups.
EXPERIMENTAL DATA OF FINAL COMPOUNDS
Rf (SiO2; Et2O/hexane 2:1) 0.22 (Ce(SO4)2).
IR (film): 3410w, 3087w, 3062m, 3030m, 2934s, 2864vs, 1954w, 1876w,
1812w, 1714vs (CO), 1605w 1586w, 1496m, 1453s, 1437m, 1418m, 1367s,
1330m, 1315m, 1285m, 1206m, 1161s, 1091br. vs, 1028s, 999s, 931w, 908m,
874w, 818w, 846w, 737vs, 698vs, 649w, 609w, 566w, 466w.
1H-NMR (600 MHz, CDCl3): 7.34–7.21 (m, arom. H); 4.63–4.39 (m,
benz. H); 3.78 (dddd, J = 12.9, 7.4, 5.6, 2.0, HC(1)); 3.71 (dd, J = 10.7,
1.2, 1H from H2C(6)); 3.67 (dd, J = 10.7, 4.4, 1H from H2C(6)); 3.42–3.39
(m, HC(4), HC(5)); 2.75 (dd, J = 15.9, 7.1, 1H from C(1)CH2CO); 2.46

1034
M. Lo¨pfe and J. S. Siegel
(dd, J = 15.9, 5.6, 1H from C(1)CH2CO); 2.29–2.23 (m, HC(3)eq); 1.83–1.76
(m, HC(2)eq); 1.56–1.43 (m, HC(3)ax); 1.35 (dddd, J = 17.3, 13.4, 11.2, 3.9,
HC(2)ax).
13C-NMR: (75 MHz, CDC13): 207.0 (s, CO); 138.4, 138.3 (2s, arom.
Cquart.); 128.23, 128.19, 127.7, 127.6, 127.5, 127.4 (6d, arom. C); 80.5, 73.8,
72.9 (3d, C(1), C(4), C(5)); 73.3, 70.9, 69.6 (3t, 2 OCH2-arom., C(6)); 49.4
(t, C(1)CH2CO); 30.9 (q, Me); 30.5, 29.1 (2t, C(2), C(3)).
CI-MS: 386 (100, [M+NH4]+), 369 (15, [M+H]+), 277 (9, [M-C7H7]+),
206 (7), 189 (5), 91 (6, [C7H7]+).
Anal. calc. for C23H28O4 (368.47) : C 74.97, H 7.66; found C 74.95, H
7.62.
Rf (Al2O3; EtOAc/hexane 2:1) 0.25 (UV254, Ce(SO4)2).
IR (film): 3337vs (br.), 3063m, 3030m, 2935m, 2863m, 2079w, 1955w,
1812w, 1631vs, 1578vs, 1495m, 1459s, 1369m, 1341m, 1315w, 1265w, 1205m,
1100s, 1027m, 1001w, 907w, 880w, 800w, 781w, 736s, 698s, 646w, 607w.
1H-NMR (CDC13, 600 MHz) δ 8.11 (d, 1H, J = 5.1 Hz, NCHarom.), 7.33–
7.21 (m, 10H, arom. H), 6.64 (d, J = 5.1 Hz, NCHCHarom), 5.29 (br. s, NH2),
4.63–4.40 (m, 4H, benz. H), 3.76–3.71 (m, 1H from H2C(6), HC(1)), 3.66
(dd, J = 10.8, 4.8 Hz, 1H from H2C(6)), 3.44–3.39 (m, HC(4), HC(5)),
2.88 (dd, J = 14.0, 7.6 Hz, 1H from HC(1)CH2-arom.), 2.68 (dd, J = 14.0,
5.1 Hz, 1H from HC(1)CH2-arom.), 2.29–2.26 (m, HC(3)eq.), 1.79–1.76 (m,
HC(2)eq.), 1.50–1.40 (m, HC(3)ax).
13C-NMR (CDC13, 150 MHz): 169.1 (s, C(1)CH2Carom); 162.1 (s,
H2NCarom); 157.3 (d, NCHarom); 138.5, 138.4 (2s, 2 OCH2Carom); 128.4,
128.3, 127.7, 127.6, 127.5 (5d, 5 Carom); 111.9 (d, NCHCHarom); 80.7 (d,
C(5)); 76.3 (d, C(1)); 73.3 (t, 1 OCH2-arom); 73.1 (d, C(4)); 71.0 (t, 1 OCH2-
arom); 69.8 (t, C(6)); 43.8 (t, C(1)CH2-arom); 30.6 (t, C(2)); 29.2 (t, C(3)).
ESI-MS: 458.1 (5, [M+K]+), 442.2 (6, [M+Na]+), 420.3 (100,
[M+H]+).
HR-ESI-MS: calc. for C25H30N3O3 ([m+H]+) 420.2287; found 420.2287.
Anal. calc. for C25H29N3O3 (419.52) C 71.57 H 6.97; found C 71.62 H
6.94.
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