A novel seven-membered carbohydrate phostone

Article abstract of DOI:10.1016/j.tetlet.2003.09.187

Treatment of methyl 2,3-di-O-benzyl-4,6-O-benzylidene-α(β)-D- glucopyranoside with triethyl phosphite and trimethylsilyl trifluoromethanesulfonate affords the seven-membered phostone arising from the attack of reagents on the acetal protecting group.

Full text of DOI:10.1016/j.tetlet.2003.09.187

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8797–8800
A novel seven-membered carbohydrate phostone
Jitka Moravcova,a,* Helena Heissigerova,a,b Petr Kocalka,a Anne Imberty,b David Sykorac and
Miroslav Frisa
aDepartment of Chemistry of Natural Compounds, Institute of Chemical Technology, Technicka 5, 166 28 Prague,
Czech Republic
bCentre de Recherches sur les Macromolecules Ve´ge´tales, CNRS, 601 rue de la Chimie, BP 53, 38041 Grenoble cedex 9, France
cDepartment of Analytical Chemistry, Institute of Chemical Technology, Technicka 5, 166 28 Prague, Czech Republic
Received 2 July 2003; revised 15 September 2003; accepted 26 September 2003
Abstract—Treatment of methyl 2,3-di-O-benzyl-4,6-O-benzylidene-a(b)-D-glucopyranoside with triethyl phosphite and
trimethylsilyl trifluoromethanesulfonate affords the seven-membered phostone arising from the attack of reagents on the acetal
protecting group.
© 2003 Elsevier Ltd. All rights reserved.
The specific binding of complex carbohydrates to lectin
type receptors forms the basis of vital intercellular
recognition processes. Thus, the biosynthesis of oligosac-
charides and other glycosylated intracellular metabolites
is of enormous importance, as these compounds are
directly involved in various fundamental biological path-
ways.1 The range of carbohydrate structures present in
a cell wall varies in different tissues reflecting the specifi-
city of glycosyltransferases, enzymes that catalyse the
transfer of a specific monosaccharide from activated
donor (glycosyl nucleotide) into a defined linkage with
a specific acceptor. Replacement of the C1ꢀO linkage in
the donor with a more stable CꢀP bond should provide
non-isosteric but isopolar donor mimetics that are more
resistant to enzymic degradation and therefore have a
greater potential to selective inhibition.
phosphonate 1 modified at the C-4 atom. For the
creation of the CꢀP bond, we decided to follow a
well-established protocol described for the Michaelis–
Arbuzov reaction of benzylated 1-O-acetyl-D-hexo-
pyranoses with triethyl phosphite and trimethylsilyl tri-
fluoromethanesulfonate as catalyst,2 which was applied
successfully later to protected methyl pentofuranosides.3
Employing
methyl
2,3-di-O-benzyl-4,6-O-benzyl-
idene-a- -glucopyranoside 2 as starting compound
D
and hoping to take advantage of both regioselec-
tive deprotection of the OH-4 moiety and a subsequent
SN2 inversion of configuration in an intermediate
glycosylphosphonate 3, the desired phosphonate 1
would be synthesized. The reaction of glucoside 2
with triethyl phosphite in the presence of trimethyl-
silyl trifluoromethanesulfonate afforded smoothly
a major crystalline product but instead of the ex-
pected phosphonate 3, phostone 4 was obtained (Scheme
1).
Continuing our search for galactosyltransferase
inhibitors, we aimed to prepare a-D-galactopyranosyl-C-
Keywords: carbohydrates; phosphonic acid; phostone; acetal group.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.187

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J. Mora6co6a et al. / Tetrahedron Letters 44 (2003) 8797–8800
Scheme 1. Reagents and conditions: (a) P(OEt)3 (2 equiv.), TMSOTf (2 equiv.), CH2Cl2, 0°C to rt, 2 h, 70%; (b) aceton/5% NaOH
(1:2, v/v), 90°C, 2 h, then CH3COOH, 77%; (c) TMSBr (2 equiv.), CCl4, 0°C to rt, 12 h, then H2O, 80%; (d) TMSl (5 equiv.),
CCl4, 0°C to rt, 12 h, then H2O, 30%; (e) EtOH, Pd/C, 2 h, 60%.
Recently, there has been renewed interest in the synthe-
sis of the cyclic phosphonate analogues (phostones) of
pentoses4,5 or hexoses6–9 having the anomeric carbon
atom replaced by a pentacovalent phosphorus. This
type of glycomimetic represents a promising structural
matrix for glycosidase inhibitor construction or for the
generation of new types of catalytic antibodies.10 The
formation of an unexpected sugar-derived phostone has
been previously reported; a Michaelis–Arbuzov reac-
tion performed on a g-iodoalcohol11 or acetylation of
carbohydrate-derived g-hydroxyphosphonic acids12
serve as good examples, however, to our knowledge,
the preparation of a seven-membered phostone is
unprecedented.
chromatography on silica gel with a mobile phase con-
taining 1% of triethylamine. The identification of
product 5 corresponds with a previous finding that
seven-membered 2-ethoxy-[1,2]oxaphosphepane-2-oxide
was decomposed by hydroxyl ions in an alcohol–water
mixture.14 TMSBr treatment of phostone 4 afforded
phosphonic acid triethylamine salt 6 leaving the cyclic
ester group intact. In contrast, treatment with TMSI
led to unprotected acyclic phosphonate 7 in which the
C-6 primary hydroxyl group had been transformed into
a 6-iodo moiety in accord with the mechanism pro-
posed.15 Finally, hydrogenation of 4 with H2 in
methanol in the presence of Pd/charcoal gave the
expected phostone 8 (absolute configuration at the
phosphorus atom was not determined). All products
5–8 (Scheme 1) were identified and characterized by
NMR experiments and MS measurements.13 In the 31P
NMR spectra of phostones 6 and 8, the phosphorus
resonates at 18.01 and 23.67 ppm, respectively, while
the 31P signal in acyclic 5 and 7 appears at 15.96 and
19.14 ppm, respectively, Characteristic vicinal couplings
between the phosphorus atom and carbon C-6 as well
as proton H-6 were observed for both phostones 6 and
8.
Phostone 4 was readily isolated by crystallization (ethyl
acetate) as a single diastereoisomer (absolute configura-
tion at the phosphorus atom was not determined) and
its identity was confirmed in particular from NMR
studies (31P, 1H, 13C, HMQC, COSY, NOESY, and
HMBC).13 In 31P NMR, the ring phosphorus in 4
appears at 23.49 ppm (relative to H3PO4). A character-
istic feature of the phostone 4 is the spin–spin coupling
between 31P and both proton H-6 and carbon C-6.
Furthermore, HMBC showed a cross peak between the
nuclei C-4 and H-7 (and vice versa) being indicative of
O-6 phosphonate unit (see Scheme 1 for numbering).
Irradiation of the signal due to the H-4 proton resulted
in a NOE enhancement of the H-7 proton, which
suggests that the proton H-7 remains axial.
In conclusion, we have synthesized original carbohy-
drate phostones using a simple method based on the
finding that the protecting acetal group can interact
with triethyl phosphite and trimethylsilyl trifluoro-
methanesulfonate.16 Particularly noteworthy is the fact
that readily available phostone 4 can be selectively
cleaved or deprotected and thus it might be an interest-
ing scaffold for the generation of new types of potential
biologically active compounds.
In view of the unique nature of phostone 4 we studied
its reactivity under several conditions. Acid hydrolysis
of phostone 4 failed but alkaline hydrolysis gave exclu-
sively a ring cleavage product isolated as salt 5 by

J. Mora6co6a et al. / Tetrahedron Letters 44 (2003) 8797–8800
8799
3.66–3.72 (m, 3H, OCH2CH3, H-6), 3.59–3.62 (m, 1H,
H-5), 3.53 (dd, 1H, J=3.5, 9.6 Hz, H-2), 3.37 (s, 3H,
OCH3), 3.09 (q, 6H, J=7.3 Hz, NCH2CH3), 1.23 (t, 9H,
J=7.3 Hz, NCH2CH3), 1.09 (t, 3H, J=7.0 Hz,
OCH2CH3). 13C NMR (125 MHz, CD3OD) l 140.65
(aromatic quaternary carbon), 140.34 (aromatic quater-
nary carbon), 139.51 (aromatic quaternary carbon),
128.61–129.35 (aromatic carbons), 99.08 (C-1), 83.93 (C-
3), 81.95 (d, J=154.1 Hz, CHPh), 81.94 (C-2), 77.89
(C-4), 75.58 (CH2Ph), 73.86 (C-6), 72.62 (C-5), 61.99 (d,
J=6.5 Hz, OCH2CH3), 61.58 (CH2Ph), 55.40 (OCH3),
47.54 (NCH2CH3), 17.09 (J=6.4 Hz, OCH2CH3), 9.10
(NCH2CH3). 31P NMR (202 MHz, CD3OD) l 15.96.
HRMS (ESI) for C30H37O9P (anion) calcd 571.2097,
found 571.2112.
Acknowledgements
We thank Dr. Ivan Rosenberg for valuable discussions
and Dr. Hana Dvorakova for NMR measurements.
This work was carried out within the framework of a
project of the Ministry of Education, Youth and Sports
of the Czech Republic No. 223300006 and of the
French Ministry of Foreign Affairs.
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4.05 (m, 2H, H-6, H-5), 3.85 (t, 1H, J=9.3 Hz, H-3), 3.64
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7: 1H NMR (500 MHz, CD3OD) l 7.52–7.25 (m, aro-
matic protons), 4.99 (d, J=13.4 Hz, CHPh), 4.62 (d,
J=3.5 Hz, H-1), 3.82–3.70 (m, 2H), 3.58–3.51 (m, 1H),
3.43 (s, 3H, OCH3), 3.40–3.28 (m, 3H), 3.14 (q, 6H,
J=7.3 Hz, NCH2CH3), 1.28 (t, 9H, J=7.3 Hz,
NCH2CH3). 13C NMR (125 MHz, CD3OD) l 139.15
(aromatic quaternary carbon), 129.61–128.67 (aromatic
carbons), 100.91 (C-1), 83.58 (C-2), 79.10 (d, J=130 Hz,
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(NCH2CH3, 9.23 (NCH2CH3), 8.16 (C-6). 31P NMR (202
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Hz, H-1), 4.49 (ddd, 1H, J=4.6, 12.6, 18.0 Hz, H-6), 4.28
(ddd, 1H, J=6.6, 12.6, 13.6 Hz, H-6), 4.02–4.14 (m, 3H,
OCH2CH3, H-5), 3.87 (t, 1H, J=9.4 Hz, H-3), 3.66 (t,
1H, J=9.5 Hz, H-4), 3.52 (dd, 1H, J=3.4, 9.4 Hz, H-2),
3.41 (s, 3H, OCH3), 1.26 (t, 3H, OCH2CH3). 13C NMR
(125 MHz, CD3OD) l 139.58 (aromatic quaternary car-
bon), 139.49 (aromatic quaternary carbon), 135.87 (aro-
matic quaternary carbon), 128.57–129.71 (aromatic
carbons), 99.69 (C-1), 86.86 (C-4), 82.15 (d, J=121.7 Hz,
CHPh), 80.90 (C-2, C-3), 76.77 (CH2Ph), 74.24 (CH2Ph),
69.95 (C-5), 68.51 (d, J=3.6 Hz, C-6), 64.20 (d, J=6.4
Hz, OCH2CH3), 55.84 (OCH3), 16.68 (J=3.9 Hz,
OCH2CH3). 31P NMR (202 MHz, CD3OD) l 23.49. MS
(EI, 70 eV) m/z 554 (M+), 523, 463, 448, 91 (100). Anal.
calcd for C30H35O8P (554.56): C, 64.97; H, 6.36; P, 5.59;
found: C, 65.16; H, 6.27; P, 5.68.
8: mp 215–217°C, 1H NMR (500 MHz, DMSO-d6) l
7.41–7.29 (m, aromatic protons), 5.11 (d, 1H, J=5.3 Hz,
CHPh), 5.01 (d, 1H, J=5.5 Hz, OH), 4.95 (d, 1H, J=6.5
Hz, OH), 4.59 (d, 1H, J=3.3 Hz, H-1), 4.36 (ddd, 1H,
J=4.1, 12.3, 18.5 Hz, H-6), 4.22 (ddd, 1H, J=6.3, 12.3,
13.0 Hz, H-6), 3.91–4.03 (m, 2H, OCH2CH3), 3.78–3.82
(m, 1H, H-5), 3.50 (m, 1H, H-3), 3.25 (t, J=9.4 Hz, H-4),
3.23–3.28 (m, 4H, OCH3, H-2). 13C NMR (125 MHz,
DMSO-d6)
l 135.3 (aromatic quaternary carbon),
127.49–128.25 (aromatic carbons), 100.22 (C-1), 79.53 (d,
J=150.3 Hz, CHPh), 72.50 (C-2), 71.38 (C-3), 84.97
(C-4), 68.67 (C-5), 66.80 (d, J=4.4 Hz, C-6), 62.27 (d,
J=7.8 Hz, OCH2CH3), 55.05 (OCH3), 16.43 (d, J=4.8
Hz, CH3). 31P NMR (202 MHz, CD3OD) l 23.67.
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(d, 1H, J=10.3 Hz, CHPh), 4.72 (d, 1H, J=3.5 Hz,
H-1), 4.69 (d, 1H, J=11.0 Hz, CH2Ph), 4.60 (s, 2H,
CH2Ph), 4.27 (dd, 1H, J=2.2, 12.7 Hz, H-6), 3.96–4.02
(m, 2H, CH2Ph, H-4), 3.76 (t, 1H, J=9.2 Hz, H-3),

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J. Mora6co6a et al. / Tetrahedron Letters 44 (2003) 8797–8800
on the anomeric configuration of the starting methyl
2,3-di-O-benzyl-4,6-O-benzylidene- -glucopyranoside.
15. Thiem, J.; Meyer, B. Chem. Ber. 1980, 113, 3075–3085.
16. The attack of triethyl phosphite and trimethylsilyl tri-
fluoromethanesulfonate on methyl 2,3-di-O-benzyl-4,6-
D
O-benzylidene-b-
mation of phostone
D
-glucopyranoside resulted in the for-
identified as mixture of
9
a
diastereoisomers in a ratio 2:1. The major isomer 9a was
obtained by crystallization from EtOAc (mp 173–175°C,
[h]2D0=−26.0 (c 1, CH3OH)) and its structure was con-
firmed by NMR measurements. Phostone 9a displays
reactivity analogous to that of a-phostone 4 when sub-
jected to the reagents described above. Thus, the course
of this Michaelis–Arbuzov-type reaction does not depend
In contrast to the
phostones derived from both methyl 2,3-di-O-benzyl-4,6-
O-benzylidene- -galactopyranosides was unsuccessful
probably due to the steric hindrance of cis fused rings.
D-gluco series, an attempt to prepare
D