Cyclic phosphonomethylphosphinates: A new type of phosphorus-containing sugars

Article abstract of DOI:10.1016/S0040-4039(03)00241-7

The first synthesis of arabino-configured cyclic phosphonomethylphosphinates is described. The key step is the condensation of the triethylester of H-phosphinylphosphonate 10 on an hydroxyaldehyde 11 derived from a D-arabinal derivative followed by a cyclization induced under acetylation conditions.

Full text of DOI:10.1016/S0040-4039(03)00241-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2351–2354
Cyclic phosphonomethylphosphinates: a new type of
phosphorus-containing sugars
Philippe Bisseret,* Jean-Guy Boiteau and Jacques Eustache*
Laboratoire de Chimie Organique et Bioorganique associe´ au CNRS, Universite´ de Haute-Alsace, Ecole Nationale Supe´rieure de
Chimie de Mulhouse 3, rue Alfred Werner, F-68093 Mulhouse Cedex, France
Received 27 November 2002; revised 22 January 2003; accepted 24 January 2003
Abstract—The first synthesis of arabino-configured cyclic phosphonomethylphosphinates is described. The key step is the
condensation of the triethylester of H-phosphinylphosphonate 10 on an hydroxyaldehyde 11 derived from a D-arabinal derivative
followed by a cyclization induced under acetylation conditions. © 2003 Elsevier Science Ltd. All rights reserved.
Sugar analogs like I and II (see below), in which the
anomeric carbon atom is replaced by phosphorus (gly-
cophostones) have received continuous attention.1
These compounds may mimic the transition state
involved in glycosidase-catalyzed hydrolytic reactions
and have been suggested as possible inhibitors of these
enzymes. Similarly, cyclic phosphonomethylphosphi-
nates of type III or IV can be viewed as stable transi-
Our first, apparently straightforward approach to this
class of compounds (shown in Fig. 1), involves the
Abramov coupling of a phosphite with protected D-ery-
throse and the cyclization of the resulting a-hydroxy
phosphinate to the corresponding phostone, followed
by activation and coupling with a methyl phosphonate.
In such an approach, stereoselectivity problems were
anticipated. There are only a few examples of type II
phostones preparation1f–h which renders the stereoselec-
tivity of the Abramov reaction (to give either ribo- or
arabino-derivatives) difficult to predict. Another issue
was the unknown stereochemical outcome of the
tion
state
analogs
of
reactions
involving
sugar-1-phosphates (e.g. glycosyltransferases, purine
phosphorylases, …etc.). Despite their potentially inter-
esting biological properties, structures like III and IV
are, to the best of our knowledge, unprecedented in the
literature.
unprecedented
subsequent
coupling
with
a
methylphosphonate.
In this work, we describe the synthesis of the first type
As can be seen in Scheme 1, the synthesis worked well
up to the transient cyclic phosphochloridate 6. Thus,
starting from thymidine, the di-O-t-butyldimethylsilyl-
arabinal 2 was obtained in 60% overall yield.3 Oxida-
tive opening of this arabinal yielded the aldehyde 3
which was converted to the mixture of hydroxyphos-
phonates 4 by treatment with trimethylphosphite in
acetic acid. Finally, base-induced cyclization to the
phostonic methyl ester 5 (a mixture of four isomers)
followed by treatment with hot oxalylchloride as previ-
ously described4 led to the phosphochloridate 6. Unfor-
tunately, although the formation of 6 could be
ascertained by clean conversion back to phostonic
III,
D-arabinose-derived, cyclic phosphonomethylphos-
phinate. This compound was designed as possible tran-
sition state inhibitor of mycobacterial arabino-
syltransferases known to play a crucial role in the
biosynthesis of the arabinan part of the mycobacterial
cell wall. Inhibition of arabinosyltransferases may con-
stitute a new approach to the treatment of mycobacte-
rial diseases.2
* Corresponding authors. Tel.: +33-3-8933-6858; fax: +33-3-8933-
6860; e-mail: j.eustache@uha.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00241-7

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P. Bisseret et al. / Tetrahedron Letters 44 (2003) 2351–2354
Figure 1. Initial retrosynthetic approach to type III phosphonymethylphostones.
Scheme 1. Reagents and conditions: (a) OsO4, NMO, 6 h, rt, then NaIO4, 1 h, rt; (b) P(OCH3)3, AcOH, 1.5 h, rt, 68% for a and
b; (c) CH3ONa, THF, 1.5 h, 0°C, then TBDMSCl, DMF, 48 h, 45°C, 72%; (d) (COCl)2, 12 h, 65°C; (e) CH3P(O)(OBn)2, n-BuLi,
THF, −78°C to rt.
esters (e.g. benzyl), every effort to couple 6 with the
mation of 12 proved to be beneficial by rendering
possible the selective activation of the free phosphinic
acid. Our initial attempts to activate PꢀOH by treat-
ment with DCC, mesylchloride, or pivaloylchloride, as
occasionally reported in the literature,10 met with little
success. In contrast, treatment by acetic anhydride in
pyridine, which proved to be very efficient in our group
for the synthesis of other carbohydrate-derived phos-
tones,11 led, after much experimentation, to phostones
13 and 14, obtained in satisfactory (42%) yield.12
anion derived from methyldibenzylphosphonate failed.5
Faced with the failure of our initial synthetic plans, we
turned to an alternative strategy based upon our
recently described method for preparing phosphono-
methylphosphinates from aldehydes.6 This approach,
which is depicted in Scheme 2, would allow the entire
phosphonomethylphosphino moiety to be introduced
prior to cyclization, avoiding the preceding problems.
The 3-formyloxyaldehyde 8 was prepared by oxidative
cleavage of the di-O-benzylarabinal 77 (obtained from
2%,3%-di-O-benzylthymidine).8 Although quite unstable,
aldehyde 8 could be obtained with a purity of over
The structure of the protected phostones 13 and 14 and,
in particular the arabino configuration and the configu-
ration of the anomeric phosphorus was determined by
careful NMR studies13 and comparison with literature
data when available. In 31P{1H} NMR, the ring phos-
phorus in 13 and 14 appears as a doublet at 45 and 54
ppm, respectively, relative to H3PO4 in agreement with
other previously described five-membered ring phostone
1
95%, as evidenced by H and 13C NMR, by fast filtra-
tion over a short pad of silicagel, using CH2Cl2 as
eluent. Coupling of 8 with the H-phosphinylphospho-
nate 10 proceeded smoothly to afford the phos-
phinylphosphonate 9 in 60% yield. Unfortunately,
unlike simple phosphonates, 9 proved to be reluctant to
base-induced formate removal/cyclization, giving rise
only to complex mixtures of undefined polar com-
pounds as shown by TLC and 31P NMR. Using the
deformylated aldehyde 119 led to an intriguing result.
Instead of the expected phostone, we observed the
exclusive formation of the acyclic phosphinic acid 12.
One can reasonably assume the following sequence of
events: (1) coupling of the H-phosphinylphosphonate
10 with 11, (2) transient formation of a phostone by
intramolecular attack of the free 5-hydroxyl group (see
Scheme 2 for numbering), (3) hydrolysis of the phos-
tone by traces of water present in the potassium car-
bonate used as a base or in the solvent. Although the
foreseen cyclization did not occur, the unexpected for-
1
derivatives.1f,h,11 In H NMR, complete attribution of
the protons was deduced from the COSY spectra of 13
and 14. In the case of 13, the absence of coupling
1
beween H-3 and P, observed in H NMR spectroscopy
and the small coupling observed for 14 (JH-3,P=1.9 Hz)
are indicative of an arabino configuration. These values
have been previously observed in the case of 3,6-
dideoxy-arabino-phostones as opposed to the ribo
analogs (JH-3,P ]4 Hz).1g The arabino configuration of
13 and 14 as well as their configuration at P-2 were
further established using NOESY experiments.14
1
Inspection of the H NMR spectra of 13 and 14 con-
firmed the configuration of the ring phosphorus: in 14,
H-3 is deshielded by 0.2 ppm compared to the same
proton in 13 in agreement with its cis relationship with
the oxygen atom in the neighbouring PꢁO.1g,i

P. Bisseret et al. / Tetrahedron Letters 44 (2003) 2351–2354
2353
Scheme 2. Reagents and conditions: (a) OsO4, NMO, 12 h, rt, then SiO2 chromatography, 77%; (b) NaIO4, 3 h, rt, then filtration
over SiO2 (eluent CH2Cl2), 50%; (c) (H)(OEt)P(O)CH2P(O)(OEt)2=10, K2CO3, 12 h, THF, rt, 60%; (d) CH3ONa cat. THF, 1.5
h, 0°C; (e) OsO4, NMO, 12 h, rt, then NaIO4, 4 h, rt, 75%; (f) 10, K2CO3, 12 h, THF, rt, 55%; (g) Ac2O, 1 h, rt, then pyridine,
12 h, 42%; (h) TMSBr (20 equiv.), CH2Cl2, rt, 24 h, then Et3N, 65%; (i) BCl3 (15 equiv.), CH2Cl2; 12 h, −40°C (j) NaOH (0.1N),
2 min, rt, then HCl (0.1N) down to pH 6, 90% for i and j.
Phostone 13 could be deprotected as follows: treatment
with TMSBr and quenching with Et3N afforded the
unstable mono triethylammonium salt 15.15 Using the
same conditions, 14 led to a complex, untractable mix-
ture. Sequential boron trichloride treatment (to remove
the benzyl-protecting groups) and brief treatment with
diluted sodium hydroxide (to remove the remaining
acetate) afforded the free phosphonylphostone 16 in
2. See for instance: Lee, R. E.; Brennan, P. J.; Besra, G. S.
Bioorg. Med. Chem. Lett. 1998, 8, 951–954 and references
cited therein.
3. Cameron, M.; Cush, S.; Hammer, R. J. Org. Chem. 1997,
62, 9065–9069.
4. See for instance: Jacobsen, N. E.; Bartlett, P. A. J. Am.
Chem. Soc. 1983, 105, 1613–1619.
5. Coupling was also attempted directly on the phostonic
1
over 90% purity as evidenced by H and 31P NMR.13,15
methylester 5, without success.
6. Bisseret, P.; Eustache, J. Tetrahedron Lett. 2001, 42,
8451–8453.
Acknowledgements
7. Benzyl protecting groups were chosen in order to avoid
migration problems which can be encountered with silyl
protecting groups. Better results were obtained when the
oxidative cleavage was performed using the isolated diols
resulting from the osmylation step.
We thank Drs. D. Le Nouen and S. Bourg for help
with NMR recording and spectra interpretation. This
work was done within the frame of a COST program
(action D13 New Molecules for Human Health).
8. Marcotte, S.; Baudoin, G.; Pannecoucke, X.; Feasson, C.;
Quirion, J.-C. Synthesis 2001, 929–933.
9. The stability of the formyl group toward aqueous meta-
periodate is limited. See: Takahashi, Y.; Ueda, C.;
Tsuchiya, T.; Kobayashi, Y. Carbohydr. Res. 1993, 249,
57–76. We took advantage of this observation for the
preparation of 11. At the oxidative cleavage step, 11
(contaminated with about 15% of starting material) was
obtained by simply maintaining the reaction mixture at
room temperature for a few hours. The freshly prepared,
crude aldehyde, was used as such for the next coupling
step.
10. See for instance: (a) Gilham, P. T.; Khorana, H. G. J.
Am. Chem. Soc. 1958, 80, 6212–6222; (b) Sigurdssoon, S.;
Stomberg, R. J. Chem. Soc., Perkin Trans. 2 2002, 1682–
1688.
11. Bosco, M.; Bisseret, P.; Eustache, J. Tetrahedron Lett.
2003, 44, 2347–2349.
References
1. See for instance for phostones of type I: (a) Darrow, J.
W.; Drueckhammer, D. G. J. Org. Chem. 1994, 59,
2976–2985; (b) Harvey, T. C.; Simiand, C.; Weiler, L.;
Withers, S. G. J. Org. Chem. 1997, 62, 6722–6725; (c)
Hannessian, S.; Rogel, O. Bioorg. Med. Chem. Lett. 1999,
9, 2441–2446; (d) Hannessian, S.; Rogel, O. J. Org.
Chem. 2000, 65, 2667–2674; (e) Stoianova, D. S.; Hanson,
P. R. Org. Lett. 2001, 3, 3285–3288; for phostones of type
II: (f) Wroblewski, A. E. Carbohydr. Res. 1984, 125,
C1–C4; (g) Wroblewski, A. E Z. Naturforsch. 1986, 41b,
791–792; (h) Wroblewski, A. E. Liebigs Ann. Chem. 1986,
1448–1455; (i) Wroblewski, A. E. Tetrahedron 1983, 39,
1809–1816.

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P. Bisseret et al. / Tetrahedron Letters 44 (2003) 2351–2354
12. The best results were obtained by adding acetic anhydride
directly to the reaction mixture containing 12, removal of
the solvents and treatment of the crude residue with
acetic anhydride/pyridine. The very sensitive phostones
could be purified, although with much decomposition.
Rapid filtration on a small column of SiO2 or even
neutral Al2O3 resulted in a total decomposition of the
phostones but two successive chromatographies on 0.2
mm thick silicagel plates, afforded 13 and 14 in 15 and
5% yield, respectively. After the first chromatography,
only a mixture of 13 and 14, in a respective 3/2 ratio,
could be obtained in 42% yield.
carbon), 169.06 (OC(O)CH3). 31P NMR (161.9 MHz,
CDCl3, 300 K) l 16.99 (d, J=6 Hz, P-8), 53.95 (d, J=6
Hz, P-2). HRMS calcd for C25H39O9P2 (M+H+) 541.1756,
found 541.1725. 15: 1H NMR (400 MHz, CD3OD, 300
K) l 1.20 (9H, t, J=7 Hz, HN+(CH2CH3)3), 2.02 (3H, s,
-C(O)-CH3), 2.57 (1H, ddd, J=16, 19.9, 22.6 Hz, H-7),
2.92 (1H, broad q, J=16 Hz), 3.09 (6H, q, J=7 Hz,
HN+(CH2CH3)3), 3.55 (1H, broad d, J=11.5 Hz, H-6),
3.68 (1H, broad d, J=11.5 Hz, H-6), 4.38 (1H, ABq,
J=11.8 Hz, -OCH2Ph), 4.40 (2H, m, H-4 and H-5), 4.47
(1H, ABq, J=11.8 Hz, -OCH2Ph), 4.53 (1H, ABq, J=
11.8 Hz, -OCH2Ph), 4.62 (1H, ABq, J=11.8 Hz,
-OCH2Ph), 5.27 (1H, broad d, J=8 Hz, H-3). 31P NMR
(161.9 MHz, CD3OD, 300 K) l 11.96 (d, J=9.8 Hz, P-8),
1
13. Selected analytical data: 13: H NMR (400 MHz, CDCl3,
300 K) l 1.26 (3H, t, J=7.2 Hz, -OCH2CH3), 1.29 (3H,
t, J=7.2 Hz, -OCH2CH3), 2.15 (3H, s, -C(O)-CH3), 2.72
(1H, ddd, J=16, 20.8, 22.8 Hz, H-7), 3.14 (1H, dt, J=16,
18.4 Hz, H-7), 3.62 (1H, dd, J=5.2, 11.6 Hz, H-6), 3.72
(1H, dd, J=2.4, 11.6 Hz, H-6), 4.14 (4H, m, -OCH2CH3),
4.46 (1H, t, J=8 Hz, H-4), 4.51 (1H, m, H-5), 4.52 (1H,
ABq, J=11.6 Hz, -OCH2Ph), 4.58 (1H, ABq, J=11.6
Hz, -OCH2Ph), 4.60 (1H, ABq, J=12 Hz, -OCH2Ph),
4.72 (1H, ABq, J=12 Hz, -OCH2Ph), 5.35 (1H, d, J=8
Hz, H-3), 7.2–7.4 (10H, m, Ph). 13C NMR (100.6 MHz,
CDCl3, 300 K) l 16.26 (OCH2CH3), 16.32 (OCH2CH3),
20.24 (OC(O)CH3), 28.10 (dd, J=87, 135 Hz, C-7), 62.54
(d, J=6.5 Hz, OCH2CH3), 62.76 (d, J=6.5 Hz,
OCH2CH3), 68.92 (d, J=4Hz, C-6), 72.97 (CH2Ph),
73.45 (CH2Ph), 75.92 (d, J=94.6 Hz, C-3), 77.02 (d,
J=17Hz, C-4), 79.92 (d, J=3.5 Hz, C-5), 127.7–128.4
(aromatic carbons), 137.23 (aromatic quaternary carbon),
137.79 (aromatic quaternary carbon), 171.22 (d, J=2.5
Hz, OC(O)CH3). 31P NMR (161.9 MHz, CDCl3, 300 K)
l 17.48 (d, J=9.6 Hz, P-8), 45.59 (d, J=9.6Hz, P-2).
HRMS calcd for C25H39O9P2 (M+H+) 541.1756, found
1
49.82 (d, J=9.8 Hz, P-2) 16: H NMR (400 MHz, D2O,
300 K) l 2.06 (1H, broad q, J=16 Hz, H-7), 2.15 (1H,
broad q, J=16 Hz, H-7), 3.65 (1H, dd, J=6.5, 11.8 Hz,
H-6), 3.79 (1H, broad dt, J=2.8, 6.5 Hz, H-5), 3.83 (1H,
broad dd, J=2.8, 11.8 Hz, H-6), 3.88–4.00 (2H, m, H-3,
H-4). 13C NMR (100.6 MHz, D2O, 300 K) l 63.44 (C-6),
70.25 (d, J=107.3 Hz, C-3), 70.79 (C-4 or C-5), 71.28 (d,
J=8.4 Hz, C-4 or C-5). 31P NMR (161.9 MHz, D2O, 300
K) l 14.60 (P-8), 38.40 (P-2).
14. The results from the NOESY experiments are shown
below:
15. The free phosphonylphostone 16 appears to be more
stable than its partially protected precursor 15. The struc-
ture of 16 is tentatively attributed. Five-membered ring
phostones are base-sensitive (see Ref. 11) and, although
we used the mildest possible conditions for acetate
removal, we cannot absolutely exclude that a furano-/
pyrano- isomerization took place. However, the relatively
high chemical shift of the ring phosphorus P-2 (38.40
ppm relative to H3PO4) compared to the expected value
for an acyclic phosphinic acid (ca. 28 ppm for 12) as well
as for a six-membered ring phostone derivative (below 25
ppm, see: Refs. 1a–e) favors the proposed structure. As
further evidences, the preference for the formation of
five- over six-membered ring arabino phostones from
acyclic precursors has been already stated (Ref. 1g) and
in the case of a pyranose derivative, at least one of the
H-6 is expected to be strongly coupled to P-2 (Ref. 1b).
1
541.1766. 14: H NMR (400 MHz, CDCl3, 300 K) l 1.35
(6H, t, J=7.1 Hz, -OCH2CH3), 2.17 (3H, s, -C(O)CH3),
2.67 (2H, m, H-7), 3.58 (1H, dd, J=4.9, 11.3 Hz, H-6),
3.71 (1H, dd, J=4, 8.2 Hz, H-4), 4.30 (1H, dt, J=4, 8
Hz, H-4), 4.38 (1H, m, H-5), 4.39 (1H, ABq, J=11.2 Hz,
-OCH2Ph), 4.51 ( 1H, ABq, J=12.2 Hz, -OCH2Ph), 4.59
(1H, ABq, J=12.2 Hz, -OCH2Ph), 4.63 (1H, ABq, J=
11.2 Hz, -OCH2Ph), 5.65 (1H, dd, J=1.9, 4 Hz, H-3),
7.2–7.4 (10H, m, Ph). 13C NMR (100.6 MHz, CDCl3, 300
K)
l 16.28 (OCH2CH3), 16.34 (OCH2CH3), 20.67
(OC(O)CH3), 26.01 (dd, J=86.9, 136 Hz, C-7), 63.03 (d,
J=4.8 Hz, OCH2CH3), 63.09 (d, J=6 Hz, OCH2CH3),
66.77 (d, J=103.5 Hz, C-3), 68.98 (d, J=3Hz, C-6), 72.97
(CH2Ph), 73.61 (CH2Ph), 75.51 (d, J=17.3 Hz, C-4),
82.17 (C-5), 127.8–128.6 (aromatic carbons), 136.54 (aro-
matic quaternary carbon), 137.60 (aromatic quaternary