First synthesis of P-aryl-phosphinosugars, organophosphorus analogues of C-arylglycosides

Article abstract of DOI:10.1016/j.tetlet.2005.03.148

The synthesis and X-ray crystal structure of the first example of arylphosphinosugar are reported. The protected polyhydroxylated 1,2-oxaphosphinane is prepared by a two steps sequence (phenylphosphinate addition on protected mannofuranose followed by int

Full text of DOI:10.1016/j.tetlet.2005.03.148

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3741–3744
First synthesis of P-aryl-phosphinosugars,
organophosphorus analogues of C-arylglycosides
*
´ ˆ
Henri-Jean Cristau, Jerome Monbrun, Julie Schleiss, David Virieux and Jean-Luc Pirat
*
´
Laboratoire de Chimie Organique, UMR 5076 CNRS, Ecole Nationale Superieure de Chimie de Montpellier,
8 Rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France
Received 9 February 2005; revised 18 March 2005; accepted 21 March 2005
Available online 8 April 2005
Abstract—The synthesis and X-ray crystal structure of the first example of arylphosphinosugar are reported. The protected poly-
hydroxylated 1,2-oxaphosphinane is prepared by a two steps sequence (phenylphosphinate addition on protected mannofuranose
followed by intramolecular transesterification) on gram scale. Deprotection of the di-isopropylidene derivative using acidic
cation-exchange resin affords the free hydroxy organophosphorus heterocycle analogous to C-arylglycosides.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
So, several phosphinosugars (phostones) were synthe-
sized. The presence of a phosphorus atom in place of
the anomeric carbon (Fig. 2a–c)4 and their similarity to
natural carbohydrates suggest that they should have
interesting and potentially useful biological properties.
Indeed, for instance these compounds may mimic the
transition state involved in glycosidase-catalyzed hydro-
lytic reactions. Surprisingly, despite the well known bio-
logical activity of various phosphinic derivatives,5
phosphinosugars are still relatively unexplored (Fig. 2d).6
Carbohydrates are an ubiquitous class of biomolecules,
with a great array of diversity, both in structure and bio-
logical function. Analogues of the natural and common
sugars have the potential to modify many biological
events.
Due to their increased stability towards hydrolysis as
well as their presence in a number of interesting natural
products, C-glycosides have received a great deal of
attention from the synthesis and medicinal chemistry
community.1 Indeed, various examples were described
exhibiting biological activity (Fig. 1).2
Combining C-arylglycosides and phosphonosugars in
the same molecule would lead to cyclic polyhydroxy-
lated P-aryl-oxaphosphinanes for which, to the best of
our knowledge, no example of synthesis is described in
the literature.
Moreover, sugars analogues containing phosphorus
have received continuous attention in the literature.
Numerous modified cyclic sugars in which a phosphorus
atom replaces the ring oxygen were prepared.3
We report herein the first synthesis of 2-phenyl-1,2-oxa-
phosphinanes and their complete deprotection to afford
OR
OR
OR
O
O
P
O
Ar
O
Ar
O
OR
OR
P
RO
OR
RO
OR
RO
OR
OR
OR
Aryl-Phosphinosugars
C-Aryl Glycosides
Phosphonosugars
Keywords: Phostone; Sugar analogues; Arylphosphinic; Polyhydroxylated.
*
Corresponding authors. Tel.: +33 467 144314; fax: +33 467 144319; e-mail: cristau@cit.enscm.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.148

3742
H.-J. Cristau et al. / Tetrahedron Letters 46 (2005) 3741–3744
MeO
O
OH
MeO
O
OH
MeO
O
OH
OH
CO2H
O
CO2H
O
HO
OH
O
HO
OH
HO
OH
HO
OH
OH
OH
OH
OH
O
a
b
c
d
Figure 1. Some biological active synthetic C-arylglycosides.
OH
OH
O
P
O
P
HO
OH
O
OMe
OTs
O
HO
HO
NHCH3
OH
O
P
O
P
O
OMe
O
BnO
HO
HO
PO(OEt)2
AcHN
OH
OH
BnO
OAc
OH
a
b
c
d
Figure 2. Several examples of phosphono- and phosphino-sugars.
the free hydroxyl organophosphorus heterocyclic com-
pound (R = H).
by filtration. The two others can be separated by column
chromatography and the total yield reaches 85%.
Suitable crystals for X-ray analysis were obtained in
DMSO for compound 4a. According to the ORTEP
structure, we were able to assign the absolute configur-
ation of the new created asymmetric centers of the
diastereoisomer 4a (d = 31.1 ppm) (Fig. 3).
2. Results and discussion
Starting material is the low-cost D-mannose, which is eas-
ily protected with acetone in the presence of iodine to give
[2,3:5,6]-di-O-isopropylidene-b-D-mannofuranose 1 in
high yields.7 The preparation of methylphenylphosphi-
nate 2 follows a recent procedure described by Afarinkia
and Yu using phenylphosphinic acid and methyl
chloroformate.8
The phosphinosugar 4a (d = 31.1 ppm) analogous to
C-arylated heptopyranose shows a2,5 B boat structure
with P2(S), C3(R) configuration.
Deprotection of phosphinosugar 4a could be done effi-
ciently and quantitatively using Amberlyst 15 as acidic
proton exchange resin and monitoring the reaction by
31P NMR. Completion occurs after several days of stir-
ring at room temperature (also easily deduced from
complete dissolution of reaction mixture) and no race-
mization is observed ([a]D +50 (c 0.1, MeOH)). Indeed,
partial racemization should induce the formation of dia-
stereoisomers, which were not detected either by 31P
Methylphenylphosphinate 2 is added to the protected
mannofuranose 1 under basic activation with potassium
tert-butoxide (Scheme 1), affording a mixture of three
cyclic P-phenyl-oxaphosphinanes 4 (92%) and side
products (8%). The basic activation not only enhances
nucleophilicity of the hydrogenophosphinate 2 by
removing its acidic proton but also deprotonates the
open intermediates 3 allowing the spontaneous in situ
transesterification. The addition is stereoselective as
demonstrated by the presence of only three diastereoiso-
mers in different amounts (d = 31.1 (4a, 39%)/35.1 (4b,
26%)/38.2 (4c, 35%) ppm), among the four possible.
One diastereoisomer (d = 31.1 ppm, 4a) precipitates
from the reaction mixture and can be easily isolated
1
NMR or H NMR. Recrystallization in ethanol affor-
ded the pure fully deprotected arylphosphinosugar 5
(Scheme 2).
In summary, we have described the first synthesis on large
scale of P-phenyl-phosphinosugars under base-catalyzed
O
OMe
H
O
P
Ph
O
O
MeO O
Ph
O
P
O
Ph
O
O
OH
O
P
OH
2
O
OH
tBuOK
OH
THF
O
O
O
O
O
O
4a, 4b, 4c
1
3
31P NMR: δ=31.1/35.1/38.2ppm
(ratio 35/26/39)
Scheme 1. Synthesis of protected P-phenyl-phosphinosugars 4a–c.

H.-J. Cristau et al. / Tetrahedron Letters 46 (2005) 3741–3744
3743
tion mixture was quenched at 0 °C with sodium thiosul-
fate and sodium bicarbonate and the organic residues
extracted with chloroform. After three washings with
sodium bicarbonate (ca. 300 mL), the organic layer
was dried over MgSO4, concentrated, and crystallized
from an acetone/hexane mixture to produce 1 (62.4 g,
0.24 mol,
85%):
colorless
solid;
1H
NMR
(250.13 MHz, CDCl3): d 1.34 (s, 3H); 1.39 (s, 3H),
1.47 (s, 3H), 1.48 (s, 3H), 3.45 (d, 1H, J = 2.4 Hz),
4.08 (dd, 2H, J = 5.5 Hz, 1.0 Hz), 4.19 (dd, 1H, J =
7.0, 3.7 Hz), 4.41 (q, 1H, J = 5.5 Hz), 4.62 (d, 1H,
J = 5.9 Hz), 4.82 (dd, 2H, J = 5.9, 3.7 Hz), 5.38 (d, 1H,
J = 2.1 Hz); 13C NMR (62.90 MHz, CDCl3): d 112.4,
108.9, 100.9, 85.3, 79.9, 79.5, 73.2, 66.3, 26.7, 25.8,
25.1, 24.4.
Figure 3. ORTEP structure of compound 4a.
O
O
P
O
3.3. Synthesis of 4-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-
dimethyl-6-oxo-6-phenyl-tetrahydro-6k*5*-1,3] dioxolo
[4,5-d] [1,2]oxaphosphinin-7-ol 4a–c
O
P
HO
O
Amberlyst 15
O
OH
HO
OH
MeOH, r.t., 5 days
O
O
HO
OH
In a 250 mL flask containing 30.3 g of 1 (0.116 mol)
dissolved in 150 mL of tetrahydrofuran, 15 mL of
phenylphosphinate 2 (0.116 mol) was added under stir-
ring. Then, 38.5 mL of a 0.6 N potassium tert-butoxide
solution in tetrahydrofuran (0.02 mmol) was added
dropwise at ambient temperature. After 2 h stirring,
compound 4a precipitated as a white solid. After 24 h
stirring, compound 2 has completely disappeared and
three diastereoisomers 4a,b,c were obtained in a (35/
26/39) ratio. The white precipitate of 4a was filtered
off (15.5 g, 35% yield). A saturated NaClaq solution
was added to the yellow filtrate (pH ꢀ 7) and extracted
with chloroform. Organic layer was dried over sodium
sulfate and evaporated to dryness. Ether was added to
the foamy white solid in order to precipitate residual
4a. After filtration, of 4a (1.5 g, 4% yield), a crude
4b–c mixture is collected (23.2 g) and was separated
by column chromatography on SiO2 (gradient of
ether/ethyl acetate: 100/0–70/30) affording 4b (5.2 g,
12% yield) and 4c (15.7 g, 36% yield) as pure
diastereoisomers.
4a
5
Scheme 2. Deprotection of P-phenyl-phosphinosugar 4a.
transesterification conditions. The selective cleavage of
di-isopropylidene protective groups without oxaphosph-
inane ring opening affords an efficient access to polyhydr-
oxylated organophosphorus heterocycles analogous to
C-arylglycosides. Further developments by variation of
the substituents on phosphorus are in progress and will
be reported in due course.
3. Experimental
3.1. General methods
All reactions involving air or moisture sensitive reagents
or intermediates were carried out under dry nitrogen in
flame-dried glassware. Reagents and solvents were dis-
tilled before use and stored under nitrogen over sodium
wires (THF) or molecular sieves (dichloromethane). All
reactions were monitored by 31P NMR. Merck silica gel
(35–70 lm) was used for column chromatography.
NMR spectra were recorded on Bruker AC 200, 250,
or 400 (1H frequency: 200.13, 250.13, or 400.13 MHz;
13C frequency: 50.32, 62.89, or 100.62 MHz, 31P fre-
quency: 81.02, 101.25, or 162.04 MHz, respectively).
Chemical shifts are given in d units with respect to
TMS (1H, 13C NMR) or H3PO4 85% (31P), coupling
constants are expressed in hertz. Infrared spectra were
recorded on Perkin–Elmer 377 or FT-NICOLET 210
spectrometer. Mass spectra were measured on JEOL
JMS DX-300 spectrometer (positive FAB ionization
and high resolution using p-nitrobenzyl alcohol NBA).
3.4. Protected diastereoisomer 4
3.4.1. 4-(2,2-Dimethyl-[1,3]-dioxolan-4-yl)-2,2-dimethyl-
6-oxo-6-phenyl-tetrahydro-6k*5*-[1,3]dioxolo[4,5-d] [1,2]-
oxaphosphinin-7-ol. Compound
4a:
31P
NMR
(101.25 MHz, DMSO-d6): d = 31.01; 1H NMR
(250.13 MHz, DMSO-d6): d 1.29 (s, 3H), 1.32 (s, 3H),
1.35 (s, 3H), 1.50 (s, 3H), 3.86 (dd, 1H, J = 5.4,
8.1 Hz), 4.04 (t, 1H, J = 8.6 Hz), 4.26 (q, 1H,
J = 5.4 Hz), 4.44 (m, 2H), 4.53 (m, 1H), 4.68 (ddd, 1H,
J = 2.6, 8.1, 24.8 Hz), 5.81 (t, 1H, J = 8.6 Hz), 7.55–
7.90 (m, 5H); 13C NMR (62.90 MHz, DMSO-d6):
25.20, 25.98, 26.62, 27.24, 65.97 (d, J = 103.2 Hz),
66.43, 74.46, 74.88 (d, J = 8.6 Hz), 76.15 (d,
J = 7.2 Hz), 76.95 (d, J = 4.8 Hz), 109.52, 110.07,
129.41 (d, J = 12.5 Hz), 131.54 (d, J = 10.1 Hz),
132.51, 133.50 (d, J = 125.2 Hz); IR (KBr) : m = 3220,
3070, 2880, 2930, 2970, 2990, 1450, 1480, 1590, 1440,
1375, 1385, 1200, 1230, 1280, 1070, 1080, 1120, 980,
1015, 960, 735, 690; HRMS(FAB+): calcd for
C18H25O7P: 384.1416. Found: 384.1415; m/z = 769
3.2. Synthesis of [2,3:5,6]-di-O-isopropylidene-b-D-man-
nofuranose 1
To a suspension of D-mannose (50.8 g, 0.282 mol) in
2.5 L of acetone was added iodine (14.3 g, 56.4 mmol)
and the mixture was stirred for 2 h at 25 °C. The reac-

3744
H.-J. Cristau et al. / Tetrahedron Letters 46 (2005) 3741–3744
[2M+H]+ (5%), 385 [M+H]+ (80%), 185 (70%), 93
(100%). [a]D +62 (c 0.2, MeOH).
2.9 Hz); IR (KBr) : 3360, 2995, 2940, 1200, 1175,
1160, 1105, 1010; HRMS(FAB+): calcd for
C12H17O7P: 305.0790. Found: 305.0774; m/z = 154
(100%), 289 (70%), 136 (65%), 77 (16%). [a]D +50 (c
0.1, MeOH).
Compound 4b: 31P NMR (101.25 MHz, CDCl3): d
1
37.51; H NMR (250.13 MHz, CDCl3): d 1.28 (s, 6H),
1.35 (s, 3H), 1.36 (s, 3H), 4.03 (m, 2H), 4.35 (m, 2H),
4.44 (m, 2H), 4.78 (m, 1H, J = 24.2 Hz), 6.11 (m, 1H),
7.27–7.90 (m, 5H); 13C NMR (62.90 MHz, CDCl3):
24.56, 25.54, 26.09, 27.23, 63.69 (d, J = 93.1 Hz),
67.18, 72.51 (d, J = 3.4 Hz), 73.96 (d, J = 8.6 Hz),
74.47 (d, J = 5.3 Hz), 76.37, 109.55, 110.24, 128.69 (d,
J = 13.4 Hz), 132.34 (d, J = 11.0 Hz), 133.29, 129.11
(d, J = 135.8 Hz); IR (KBr) : 3200, 3030, 2860, 2900,
2960, 2980, 1435, 1460, 1580, 1420, 1360, 1370, 1190,
1230, 1040, 1060, 1115, 1030, 950, 710, 680;
HRMS(FAB+): calcd for C18H25O7P: 384.1416. Found:
384.1402; m/z = 769 [2M+H]+ (15%), 385 [M+H]+
(100%), 327 (60%), 269 (50%), 73 (35%). [a]D +50 (c
0.2, MeOH).
Acknowledgement
´ ˆ
Jerome Monbrun is grateful to MRT for a scholarship.
References and notes
1. (a) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Elsevier Science: Tarrytown, NY, 1995; (b) Postema, M. H.
D. C-Glycoside Synthesis; CRC: Boca Raton, FL, 1995.
2. (a) Sato, S.; Kuribayashi, T.; Ushiyama, S.; Yasumoto, T.;
Tanzawa, K.; Takahashi, M. World Patent 9831697, 1998;
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W.; Drueckhammer, D. G. J. Org. Chem. 1994, 59, 2976–
2985; (g) Hanessian, S.; Galeotti, N. Bioorg. Med. Chem.
Compound 4c: 31P NMR (81.02 MHz, DMSO-d6): d
40.84; 1H NMR (250.13 MHz, DMSO-d6): d 1.41 (s,
3H), 1.43 (s, 3H), 1.49 (s, 3H), 1.56 (s, 3H), 4.15 (m,
2H), 4.26 (ddd, 1H, J = 1.9, 6.2, 8.1 Hz), 4.49 (tq, 1H,
J = 5.4, 9.6 Hz), 4.57 (d, 1H, J = 3.4 Hz), 4.64 (dd, 1H,
J = 1.3, 7.4 Hz), 4.93 (ddd, 1H, J = 3.3, 7.4, 26.7 Hz),
5.25 (br s, 1H), 7.38–8.04 (m, 5H); 13C NMR
(62.90 MHz, DMSO-d6): d 24.52, 25.43, 25.93, 27.38,
66.94, 68.63 (d, J = 108.0 Hz), 73.99 (d, J = 9.1 Hz),
74.27, 74.88 (d, J = 5.8 Hz), 76.37, 110.31, 110.43,
127.28 (d, J = 152.1 Hz), 128.39 (d, J = 13.4 Hz),
133.16 (d, J = 2.4 Hz), 133.49 (d, J = 11.1 Hz); IR
(KBr) : 3240, 3040, 2870, 2920, 2970, 1450, 1585,
1430, 1365, 1375, 1160, 1190, 1235, 1070, 1120, 980,
1015, 950, 690; HRMS(FAB+): calcd for C18H25O7P:
384.1416. Found: 384.1431; m/z = 769 [2M+H]+ (2%),
385 [M+H]+ (70%), 307 (100%), 289 (70%), 107
(100%). [a]D +27 (c 0.2, MeOH).
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3.5. Deprotection of compound 4a
3.5.1. 6-(1,2-Dihydroxyethyl)-2-oxo-phenyl-2k*5*-[1,2]-
oxaphosphinane-3,4,5-triol 5. In a 50 mL flask, 2.0 g
of compound 4a (5.2 mmol), 2.0 g of AmberlystÒ 15 re-
sin, and 70 mL of methanol are stirred over 5 days until
the white suspension disappeared (monitoring by 31P
NMR).
Resin is filtered off and the crude filtrate is evaporated to
dryness and recrystallized from ethanol to afford color-
less solid of the fully deprotected compound 5.
31P NMR (101.25 MHz, D2O): d 40.77. 1H NMR
(250.13 MHz, D2O): d 3.67–3.76 (m, 2H), 3.83–3.89
(m, 2H), 3.99–4.03 (m, 2H), 4.73 (m, 1H), 7.50–7.70
(m, 5H); 13C NMR (62.90 MHz, D2O): d 62.39, 67.42
(d, J = 92.6 Hz), 68.94 (d, J = 9.6 Hz), 69.01 (d,
J = 3.8 Hz), 69.66 (d, J = 10.1 Hz), 78.22 (d,
J = 5.8 Hz), 126.15 (d, J = 119.0 Hz), 130.00 (d, J =
13.0 Hz), 130.32 (d, J = 10.6 Hz), 134.51 (d, J =
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