Synthesis of amino-L-lyxose phosphonates as fucosyl-phosphate mimics

Article abstract of DOI:10.1002/ejoc.200500990

Some reactions of nitrone 4 are described, namely the nucleophilic addition of dialkyl phosphites, HOP(OR)₂, 5a-c or of diethyl methylphosphonate 8 and the dipolar [2+3] cycloaddition of vinylphosphonate 11. Chemical transformations led to 4-am

Full text of DOI:10.1002/ejoc.200500990

FULL PAPER
DOI: 10.1002/ejoc.200500990
Synthesis of Amino- -Lyxose Phosphonates as Fucosyl-Phosphate Mimics
L
Carine Chevrier,[a] Didier Le Nouën,[a] Albert Defoin,*[a] and Céline Tarnus[a]
Keywords: Aminolyxose / Amino sugars / Phosphonates / Fucosidase inhibitors / Cycloaddition / Nucleophilic addition
Some reactions of nitrone 4 are described, namely the nucle-
ophilic addition of dialkyl phosphites, HOP(OR)2, 5a–c or of
diethyl methylphosphonate 8 and the dipolar [2+3] cycload-
dition of vinylphosphonate 11. Chemical transformations led
group in the 1α position linked to the pyrrolidine ring
through a chain of 0–2 carbon atoms. The target compounds
proved to be good-to-excellent α-L-fucosidase inhibitors.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
to 4-amino-L-fucose derivatives bearing a phosphonate
Introduction
The tetrasaccharide sialyl Lewis X is involved in inflam-
matory processes and more directly in the interaction of
leukocytes with the vascular endothelium through diverse
adhesion glycoprotein selectins.[1–3] It has been established
that the fucosyl moiety of the sialyl Lewis X is essential for
these interactions.[2,3] Consequently, inhibition of the bio-
synthesis of -fucose, which is believed to be triggered by
fucosyltransferases, can be a means to reduce leukocyte re-
cruitment; such inhibition would then be a potential anti-
inflammatory treatment.[1–3] One possible way to inhibit the
fucosyltransferases is to modify the fucose donator, that is,
GDP-fucose (1) (Scheme 1). It has been postulated that the
transition states of glycosidases and glycosyltransferases are
similar.[4,5] As a consequence, replacement of the fucose
moiety (shown in the box in Scheme 1) in GDP-fucose with
a fucose mimic has been studied by several groups in order
to obtain fucosyltransferase inhibitors. Recently, such in-
hibitors were obtained with Ki values in micromolar range
by using as fucose mimics cyclitol,[6] -fluorofucoses[7] or
iminosugars with a 5- or 6-membered ring of the -xy-
lose,[8,9] -fucose[10] or -fucose[6,11] series. It has also been
found that the stereochemistry at the anomeric position of
the fucose mimic is of variable importance for the inhibition
of fucosyltransferases.[7]
Scheme 1.
fucose mimics. The nitrone 4, which we have recently ob-
tained from -ribose,[12] was used as the starting material.
It was substituted either by direct nucleophilic SN2 addition
or by a polar (3+2) cycloaddition reaction. Inversion of the
obtained α anomeric isomers into β isomers was attempted
but without any success. The inhibition of α--fucosidase
with these phosphonates is discussed. A partial preliminary
communication of these results has already been pub-
lished.[12,14]
We have already shown that the pyrrolidine amino sugar
2 in the -lyxose series is a potent -fucosidase inhibi-
tor.[12,13] We describe herein new synthetic ways to synthe-
sise 1-α-phosphonate derivatives 3 of this amino-sugar 2 in
which the phosphonate moiety is linked, directly or through
a chain of one or two carbon atoms, to the pyrrolidine ring.
These compounds can be considered as precursors of GDP-
Results
Direct Addition of Nucleophiles
Addition of alkyl phosphites to nitrones has been carried
out by Lewis acid catalysis,[15,16] with its anion[17,18] or in
the absence of solvents.[19] By using this last condition
(Scheme 2), the reaction of nitrone 4 with dialkyl esters 5a–
c at 40 °C gave the N-hydroxy-phosphonates 6a,b in quanti-
tative yields whereas the bulky dibenzyl derivative 6c was
only obtained in a moderate yield (47%).
[a] Laboratoire de Chimie Organique et Bioorganique, UMR 7015,
École Nationale Supérieure de Chimie de Mulhouse, Université
de Haute-Alsace,
3, rue Alfred Werner, 68093 Mulhouse Cédex, France
Fax: +33-3-89336875
E-mail: A.Defoin@uha.fr
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2384–2392

Synthesis of Amino--Lyxose Phosphonates as Fucosyl-Phosphate Mimics
FULL PAPER
phonates as the dipolarophile have rarely been used in cy-
cloaddition reactions with nitrones[26] and in those cases a
weak regioselectivity was often observed.[26a,26b] Likewise in
our case (Scheme 4), the thermal reaction of vinylphos-
phonate 11 with nitrone 4 in ethylene perchloride was
weakly regio- and stereoselective and two pairs of exo and
endo regio-adducts 12a,b and 13a,b were formed in
30:52:13:6 proportions, respectively, the major isomer being
the endo adduct 12b. The minor endo isomer 13b was char-
Scheme 2.
1
acterised only by H NMR spectroscopic data.
The N–OH group is generally reduced by hydrogenolysis
over Pd/C,[15,18] and even better in the presence of aqueous
HCl.[16,17] We have verified that this reduction also occurred
by hydrogenolysis over Raney-nickel[20] but not over 5% Pd/
C alone. O,N-Bis-deprotection of 6a,b was finally carried
out by hydrogenolysis with 5% Pd/C in EtOH and aqueous
1  HCl to give in one step the pyrrolidine-phosphonates
7a,b as hydrochlorides. Reduction of the benzyl derivative
6c gave the N-hydroxy-phosphonic acid 7c, that is, without
reduction of the N–O bond. The ethyl ester 7b was also
obtained in the free amino form after purification over ion-
exchange resin [H(+) form].
Addition of the methylphosphonate anion to protected
sugars has already been described for the lactone[21,22] and
amino ether[23] series. In the case of nitrone 4, nucleophilic
addition of the anion of methylphosphonate 8 readily gave
the N-hydroxy-phosphonate 9 in near quantitative yield;
nevertheless, the reaction temperature (–78 °C) was critical
to give good results (Scheme 3). As for 7b, deprotection of Scheme 4.
9 provided the amino-phosphonate 10 in 65% overall yield
from the nitrone 4.
The major adduct 12b (together with 13b) and a mixture
of 12a/13a were separated by chromatography and their
1
structures ascertained by H and 13C NMR spectroscopy.
For the regioisomers 12a,b the C-2 atom bearing the phos-
phonate group is bound to the O-1 atom and appears in
the 13C NMR spectrum at 70–75 ppm as a doublet [J(2,P)
= 170–166 Hz]. For the regioisomer 13a, the corresponding
C-3 atom is strongly shielded at δ = 42 ppm [J(3,P) =
150 Hz]. The exo stereostructures of 12a and 13a were de-
termined by NOESY and NOE experiments: for 12a, a
NOE value of 10% was found for 6-H by irradiation of 2-
H, as well as a 5% effect with the near 3a-H; for 13a, NOE
values of 9 and 7%, respectively, were found for 3-H and
the nearby 3a-H by irradiation of 4-H. For all adducts, a
trans relationship between the protons 3a-H and 4-H was
ascertained by their very weak coupling [J(3a,4) Ϸ 0 Hz].
As for 1,2-oxazinanes,[27,28] the N–O bond of the bicyclic
adducts was easily hydrogenolysed over Pd/C at 40 °C
(Scheme 5). The major adduct 12b gave the imino-alditol
14b in 60–70% yield. The mixture of 12a/13a gave the corre-
sponding mixture of 14a/15 which was resolved by chroma-
tographic separation.
Scheme 3.
In all cases, nucleophilic addition occurred from the less
bulky side to provide the α-P anomers 6a–c and the α-C
anomer 9. The small J(1,2) values, around 1.2 Hz for 6a–c
and 0 Hz for 9, correspond to a trans relationship between
the two protons 1-H and 2-H.[24]
Hydrolysis of the acetonide moiety of 14a,b and 15 with
aqueous 6  HCl in ethanol gave the corresponding triols
16a,b and 17 as hydrochlorides in essentially quantitative
Cycloaddition with Vinylphosphonate 11
The [2+3] dipolar cycloaddition reaction of nitrones is a yields. Under the same conditions, the major adduct 12b
widely used synthetic method.[25] However, vinylphos- was hydrolysed to bicyclic diol 18.
Eur. J. Org. Chem. 2006, 2384–2392
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Chevrier, D. Le Nouën, A. Defoin, C. Tarnus
FULL PAPER
quantitative O,N-deprotection with 6  HCl followed by hy-
drogenolysis over Pd/C led to the hydrochloride of the ami-
nolyxitol-phosphonate 22. This latter pyrrolidine was ob-
tained in 10% overall yield from the nitrone 4.
Oxidation to Nitrones
We have obtained a diverse range of derivatives of 4-
amino--lyxose as the 1-α-P or 1-α-C anomers. One possible
way to obtain β anomers is to isomerise these α anomers
by oxidation of the pseudoanomeric position followed by
reduction. We have studied this possibility in the case of the
hydroxylamines 6b and 9. Unfortunately, these N-hydroxy-
pyrrolidines were mainly oxidised (with yellow HgO in
CHCl3) at the 5-position. Diethyl phosphonate 6b led to a
85:15 mixture of nitrones 23 and 24, respectively, whereas
its homologue 9 gave only nitrone 25 (Scheme 7).
Scheme 5.
In order to obtain a pyrrolidine phosphonate linked
through an ethyl chain from the major adduct 12b, the
alcohol function of the opened adduct 14b was eliminated
by a Barton–McCombie[29] radical elimination of a xan-
thate (see Scheme 6). Preliminary N-protection with benzyl
chloroformate in ethanol and 2 equiv. of base gave the car-
bamate alcohol 19 in a moderate yield. Subsequent acyl-
ation with thiocarbonyldiimidazole (Im2CS)[30–33] in THF
readily provided xanthate 20. By heating in toluene with
tributylstannane and AIBN as radical initiator, the xan-
thate 20 underwent reductive radical fragmentation to the
ethyl pyrrolidine-phosphonate 21 in good yield. Finally,
Scheme 7.
In the case of 9 the reaction was attempted under other
oxidative conditions[34,35] (HgO in EtOH, cyclohexane or
AcOH, benzoquinone in CHCl3, potassium ferricyanide in
ether, tert-butyl hydroperoxide in toluene) in order to
change the regioselectivity, but no change in the oxidation
process was observed and the nitrone 25 remained the only
product formed. Consequently, it would seem that the oxi-
dation was directed by abstraction of the more accessible
5-H.
Pyrrolidine-phosphonates as Glycosidase Inhibitors
All these pyrrolidines are fucosidase inhibitors. Their in-
hibition data were measured against α--fucosidase from
bovine kidney and the results are compiled in Table 1.
The pyrrolidines 16a,b, 17 and 22 possessing an alcohol
function at the β position of the lateral chain are submicro-
molar to nanomolar inhibitors, the best one being the 1ЈS
isomer 16b, without reaching the potency of the amino
sugar 2. Comparison between the unsubstituted amino--
lyxitol 26 (Ki = 0.05 µ[13] or 0.2 µ[36]) and the alcohol-
phosphonate 16b and other good inhibitors, such as the
alcohols 27 (Ki = 0.40 µ[36]) and 28 (Ki = 0.008 µ[12]) (see
Scheme 7), has led to the conclusion that a hydrophilic in-
Scheme 6.
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Eur. J. Org. Chem. 2006, 2384–2392

Synthesis of Amino--Lyxose Phosphonates as Fucosyl-Phosphate Mimics
FULL PAPER
Table 1. Inhibition constants (Ki) for pyrrolidine-phosphonates 7a–c, 10, 16a,b, 17, 18 and 22 against α--fucosidase from bovine kidney
and compared with the amino--lyxose 2.
Compounds
Ki [µ]
2[a]
7a
7b
7c
10
16a
16b
17
18
22
0.01
2.3
7.3
0.20
4.3
0.20
0.04
0.40
120
0.10
[a] See ref.[13]
.
uct was purified by chromatography (diethyl ether/MeOH, 95:5) to
teraction in the enzyme’s active site occurs near the ano-
meric position at a two-carbon-chain distance. It is evident
that bicyclic adduct 18 interacts unfavourably with this en-
zyme.
give 6a (328 mg, quant.). Yellowish resin. [α]2D0 = +30 (c = 1,
1
CHCl3). Rf = 0.46 (diethyl ether/MeOH, 95:5). H NMR (CDCl3,
295 K): δ = 1.24 (d, 5-Me), 1.30, 1.45 (2 s, CMe2), 3.66 (quint, 5-
H), 3.77, 3.81 (2 d, 2 OMe), 3.85 (d, 2-H), 4.63 (dd, 4-H), 4.95
(ddd, 3-H), ca. 6.0 (s, NOH). J(2,3) = 1.2, J(2,P) = ca. 13, J(3,4)
= 6.6, J(3,P) = 8.8, J(4,5) = 4.8, J(5,Me) = 6.6, J(OMe,P) =
11.1 Hz. 13C NMR (CDCl3, 295 K): δ = 11.7 (5-Me), 24.2, 26.0
(CMe2), 51.9 (d, OMeЈ), 53.4 (d, OMeЈЈ), 64.2 (C-5), 69.3 (d, C-2),
Conclusion
Starting from nitrone 4 we have presented a synthesis of
phosphonate derivatives of 4-amino--lyxose as 1-α ano-
mers in 40–60% yield for 7a–c, in 65% yield for 10 and in
10% yield for 22. Some phosphonates, such as 16b and 22,
are potent nanomolar fucosidase inhibitors. Attempts to in-
verse the anomeric position in β anomers proved unsuccess-
ful. The synthesis of GDP analogues of these phosphonates
and a study of their inhibition against fucosyltransferases
are currently under investigation.
78.9 (C-3), 79.6 (C-4), 111.6 (CMe2) ppm. J(2,P)
= 142.7,
J(OMeЈ,P) = 7.1, J(OMeЈЈ,P) = 5.7 Hz. 31P NMR (CDCl3, 295 K):
δ = 26.3 ppm. C10H20NO6P (281.25): C 42.71, H 7.17, N 4.98, P
11.01; found C 42.8, H 7.3, N 4.7, P 10.3.
Diethyl (2S,3R,4R,5S)-N-Hydroxy-3,4-isopropylidenedioxy-5-meth-
ylpyrrolidine-2-phosphonate (6b): Following the same procedure as
used for 6a with nitrone 4 (200 mg, 1.17 mmol) and diethyl ester
5b (230 µL 1.75 mmol, 1.5 equiv.) at 40 °C for 30 h. Purification by
chromatography (CH2Cl2/EtOH, 98:2) gave pure 6b (361 mg,
quant). Yellowish resin. [α]2D0 = +22 (c = 1, CHCl3). Rf = 0.18
(CH Cl /EtOH, 98:2). IR (KBr): ν = 631, 666, 754, 799, 879, 965,
˜
2
2
Experimental Section
1045, 1147, 1167, 1212, 1245, 1381, 1448, 2937, 2987, 3290 cm–1.
1H NMR (CDCl3, 295 K): δ = 1.31 (d, 5-Me), 1.32 (s, C–CH3),
1.34, 1.36 (2 t, 2 CH2CH3), 1.47 (s, C–CH3), 3.62 (quint, 5-H), 3.86
(dd, 2-H), 4.13–4.23 (m, 2 CH2CH3), 4.63 (dd, 4-H), 4.95 (ddd, 3-
H), 6.74 (s, NOH) ppm. J(2,3) = 1.3, J(2,P) = 13.0, J(4,3) = 6.5,
J(3,P) = 8.5, J(4,5) = 4.8, J(5,Me) = 6.6, J(5,P) = ca. 1.0,
J(CH2CH3) = 7.0 Hz. 13C NMR (CDCl3, 295 K): δ = 11.7 (5-Me),
16.2, 16.3 (2d, 2 CH2CH3), 24.2, 25.9 (CMe2), 61.3, 62.6 (2 d, 2
CH2CH3), 63.9 (C-5), 69.4 (d, C-2), 78.9 (C-4), 79.4 (C-3), 111.3
(CMe2) ppm. J(2,P) = 141.3, J(CH3CH2,P) = 6.0, J(CH2CH3,P)
= 7.2 Hz. 31P NMR (CDCl3, 295 K): δ = 23.9 ppm. C12H24NO6P
(309.30): C 46.60, H 7.82, N 4.53, P 10.01; found C 46.5, H 7.9, N
4.6, P 9.7.
General: Flash chromatography: silica gel (Merck 60, 230–
400 mesh). TLC: Al-roll silica gel (Merck 60, F254). Melting points:
Kofler hot plate, corrected values. IR spectra: Perkin–Elmer 157
G or Nicolet 405 FT-IR spectrometer; ν in cm–1. Specific Optical
˜
Rotation: Schmidt–Haensch Polartronic Universal or Perkin–El-
mer 341 LC polarimeter. 1H, 31P and 13C NMR (400, 161.9 and
100.6 MHz, respectively) spectra: Bruker Avance 400 or in some
cases Bruker AC-F 250 spectrometer; tetramethylsilane (TMS) or
natrium [D4]trimethylsilylpropionate ([D4]TSP) in D2O as internal
reference (1H NMR), 80% aqueous H3PO4 as external reference
(31P NMR) and CDCl3 or (in D2O) dioxane [δ(CDCl3) = 77.0 ppm
in D2O, δ(dioxane) = 67.4 ppm with respect to TMS] as internal
reference (13C NMR); δ in ppm and J in Hz. HRMS were measured
with a Waters Micromass Q-Tof Ultima API spectrometer at Basi-
lea Pharmaceuticals, Basel. Microanalyses were carried out by the
Service Central de Microanalyses du CNRS, 69390 Vernaison,
France, or by the Service de microanalyse de l’ICSN-CNRS, 91168
Gif sur Yvette, France.
Dibenzyl
(2S,3R,4R,5S)-N-Hydroxy-3,4-isopropylidenedioxy-5-
methylpyrrolidine-2-phosphonate (6c): Following the same pro-
cedure as used for 6a with nitrone 4 (150 mg, 0.9 mmol) and diben-
zyl ester 5c (300 µL, 1.3 mmol, 1.5 equiv.) at 45 °C for 30 h. Purifi-
cation by chromatography (CH2Cl2 then CH2Cl2/MeOH, 98:2)
gave pure 6c (180 mg, 47%). Colourless crystals. M.p. 78–80 °C
(iPrOH). [α]2D0 = +18.7 (c = 1, CHCl3). Rf = 0.26 (CH2Cl2/MeOH,
Reagents and Solvents: Raney nickel (aqueous suspension), tributyl-
stannane and 5% Pd/C were obtained from Fluka, dimethyl, di-
ethyl and dibenzyl phosphite, dimethyl methanephosphonate and
diethyl vinylphosphonate from Aldrich. Yellow HgO was pur-
chased from Prolabo, azobis(isobutyronitrile) (AIBN) from Merck
and Amberlite IR 120 from Rohm & Haas. Solvents were freshly
distilled, dry EtOH and MeOH were distilled over Mg/MgI2, dry
THF over Na and benzophenone, dry Et2O was distilled and stored
over Na, CH2Cl2 was distilled over P2O5 and kept over Na2CO3.
NEt3 and tetrachloroethylene (C2Cl4) were distilled before use.
98:2). IR (KBr): ν = 697, 735, 749, 874, 1017, 1038, 1056, 1215,
˜
1
1241, 1370, 1379, 1456, 2934, 2986, 3271 cm–1. H NMR (CDCl3,
295 K): δ = 1.26 (s, C–CH3), 1.30 (d, 5-Me), 1.44 (s, C–CH3), 3.68
(m, 5-H), 3.97 (d, 2-H), 4.57 (dd, 4-H), 4.93 (ddd, 3-H), 4.94, 5.03
(2 dd, J = 12.0 and 7.8 Hz, J = 12.0 and 8.8 Hz, CH2Ph), 5.09,
5.12 (2 dd, J = 12.0 and 9.0 Hz, J = 12.0 and 8.2 ppm, CH2Ph),
6.62 (s, NOH), 7.33 (m, 10 Har) ppm. J(2,3) = 1.2, J(2,P) = 12.4,
J(3,4) = 6.6, J(3,P) = 8.8, J(4,5) = 5.2, J(5,Me) = 6.4 Hz. 13C NMR
(CDCl3, 295 K): δ = 11.6 (5-Me), 24.4, 26.2 (CMe2), 64.4 (d, C-5),
67.0 (d, J(CH2,P) = 6.8 Hz, CH2Ph), 68.3 [d, J(CH2,P) = 6.3 Hz,
CH2Ph], 70.2 (d, C-2), 79.6 (d, C-3), 80.2 (C-4), 111.8 (CMe2),
128,1, 128.4 128.5, 128.6 (o,m,p-C), 136.4 (ipso-C) ppm. J(2,P) =
144.0, J(3,P) = 5.2, J(5,P) = 2.1 Hz. C22H28NO6P (433.45): C 60.96,
H 6.51, N 3.23, P 7.15; found C 60.7, H 6.5, N 3.4, P 6.7.
Direct Addition of Nucleophiles
Dimethyl
(2S,3R,4R,5S)-N-Hydroxy-3,4-isopropylidenedioxy-5-
methylpyrrolidine-2-phosphonate (6a): Nitrone 4[12] (200 mg,
1.17 mmol) and dimethyl ester 5a (160 µL, 1.75 mmol, 1.5 equiv.)
were heated for 20 h at 40 °C without any solvent. The crude prod-
Eur. J. Org. Chem. 2006, 2384–2392
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C. Chevrier, D. Le Nouën, A. Defoin, C. Tarnus
FULL PAPER
Diethyl (2S,3R,4R,5S)-3,4-Dihydroxy-5-methylpyrrolidine-2-phos-
phonate (7b): Phosphonate 6b (135 mg, 0.44 mmol) was hydro-
genolysed in EtOH (1.5 mL) and 1  HCl (2.2 mL) over 5% Pd/C
(20 mg) at room temp. for 48 h. The catalyst was then centrifuged
off, washed with EtOH (3×1 mL) and the combined solvents were
evaporated to give crude 7b (130 mg, quant.) as the hydrochloride.
This was purified over Amberlite IR-120 [H+ form] with successive
Diethyl [2R,3S,4R,5S]-(N-Hydroxy-3,4-isopropylidenedioxy-5-meth-
ylpyrrolidin-2-yl)methanephosphonate (9): A solution of BuLi (1.6 
in hexane) (0.36 mL, 0.58 mmol, 2 equiv.) was added dropwise to
a solution of freshly distilled methanephosphonate (8) (85 µL,
0.58 mmol, 2 equiv.) in THF (2 mL) at –78 °C. The white mixture
was further stirred at –78 °C for 15 min and then added to a solu-
tion of nitrone 4[12] (50 mg, 0.29 mmol) in THF (1 mL) at –78 °C.
elution with H2O, MeOH, NH4OH, 0.5  then 1 . The NH4OH After stirring at –78 °C for a further 2 h, aqueous 20% NH4Cl
phases were evaporated to give the amine 7b (73 mg, 61%).
was added and the mixture extracted with AcOEt (3×10 mL). The
organic phases were dried (Na2SO4) and evaporated to give pure 9
(93 mg, 98%). Colourless resin. [α]2D0 = +26 (c = 1, CHCl3). Rf =
0.63 (diethyl ether/MeOH, 9:1). 1H NMR (CDCl3, 295 K): δ = 1.23
(d, 5-Me), 1.29 (s, C-Me), 1.35 (t, 2 CH2CH3), 1.45 (s, C-Me), 1.59
(ddd, 1Ј-Hb), 2.56 (ddd, 1Ј-Ha), 2.99 (quint, 5-H), 3.68 (td, 2-H),
4.10 (m, 2 CH2CH3), 4.53 (t, 4-H), 4.72 (d, 3-H), 6.53 (s, OH) ppm.
J(1Јa,2) = 2.5, J(1Јb,2) = 11.8, J(1Јa,1Јb) = 15.3, J(1Јa,P) = 20.8,
J(1Јb,P) = 18.3, J(2,3) = 0, J(2,P) = 9.9, J(3,4) = 6.8, J(4,5) = 5.2,
J(5,5-Me) = 6.3, J(CH2CH3) = 7.0 Hz. 13C NMR (CDCl3, 295 K):
δ = 11.9 (5-Me), 16.2 16.3 (2 d, 2 CH2CH3), 19.5 (d, C-1Ј), 24.0,
25.5 (CMe2), 61.1 (C-5), 61.7, 61.8 (2 d, 2 CH2CH3), 63.9 (C-2),
77.3 (C-4), 80.0 (C-3), 110.7 (CMe2) ppm. J(1Ј,P) = 140.6,
J(CH2CH3,P) = 7.0, J(CH2CH3,P) = 6.4 Hz. 31P NMR (CDCl3,
295 K): δ = 31.7 ppm. HRMS (ESI-Q-TOF): calcd. for
C13H27NO6P [M]+: 323.1498; found 323.1503.
7b: Brown resin. R = 0.63 (EtOH). IR (KBr): ν = 974, 1033, 1130,
˜
f
1162, 1226, 1394, 1445, 1640, 2984, 3388 cm–1. 1H NMR (CD3OD,
295 K): δ = 1.15 (d, 5-Me), 1.33, 1.34 (2 t, 2 CH2CH3), 3.11 (qd,
5-H), 3.33 (t, 2-H), 3.77 (dd, 4-H), 4.16 (m, 2 CH2CH3), 4.41 (ddd,
3-H) ppm. J(2,3) = 7.6, J(2,P) = 7.3, J(3,4) = 4.3, J(3,P) = 16.2,
J(4,5) = 2.8, J(5,5-Me) = 6.6, J(CH2CH3) = 7.1 Hz. 13C NMR
(CD3OD, 295 K): δ = 14.0 (5-Me), 16.7 (d, 2 CH2CH3), 57.9 (d,
C-5), 59.2 (d, C-2), 63.9, 64.0 (2 d, 2 CH2CH3), 75.2 (d, C-4), 76.1
(d, C-3) ppm. J(2,P) = 166.7, J(3,P) = 2.1, J(4,P) = 7.1, J(5,P) =
4.9, J(CH2CH3,P) = 5.7, J(CH2CH3,P) = 6.7 Hz. 31P NMR
(CDCl3, 295 K): δ = 27.1 ppm. MS (TOF ES+): m/z (%) = 116 (20),
254 (100) [M + H]+, 507 (45) [2M + H]+. HRMS (TOF ES+) for
C9H21NO5P [M + H]+: calcd. 254.1157; found 254.117.
1
Hydrochloride 7b·HCl: H NMR (CD3OD, 295 K): δ = 1.40, 1.41
Diethyl (2R,3S,4R,5S)-(3,4-Dihydroxy-5-methylpyrrolidin-2-yl)-
methanephosphonate (10): Following the same procedure as used
for 7b with 9 (200 mg, 0.6 mmol) in EtOH (2 mL) and 1  HCl
(3 mL) over 5% Pd/C (50 mg) at room temp. for 24 h. Crude 10 as
the hydrochloride was purified on Amberlite IR-120 with successive
elution with H2O, EtOH, 0.5  NH4OH and 1  NH4OH. Evapo-
ration of the NH4OH phases gave 10 (113 mg, 68%).
(2 t, 2 CH2CH3), 1.41 (d, 5-Me), 3.63 (t, 2-H), 3.64 (qd, 5-H), 4.04
(dd, 4-H), 4.28 (m, 2 CH2CH3), 4.54 (ddd, 3-H) ppm. J(2,3) = 9.2,
J(2,P) = 10.6, J(3,4) = 3.6, J(3,P) = 14.9, J(4,5) = 2.4, J(5,5-Me)
= 6.8, J(CH2CH3) = 7.1 Hz. 13C NMR (CD3OD, 295 K): δ = 12.0
(5-Me), 16.7 (d, 2 CH2CH3), 55.7 (d, C-2), 60.4 (d, C-5), 65.3, 65.6
(2 d, 2 CH2CH3), 72.9 (d, C-4), 74.6 (C-3) ppm. J(2,P) = 158.2,
J(4,P) = 10.0, J(5,P) = 2.0, J(CH2CH3,P) = 7.0, J(CH2CH3,P) =
5.7 Hz. 31P NMR (CD3OD, 295 K): δ = 18.3 ppm.
10: Yellowish resin. [α]2D0 = –35 (c = 1, MeOH). Rf = 0.53 (EtOH).
IR (KBr): ν = 969, 1026, 1050, 1099, 1162, 1212, 1395, 1445, 1652,
˜
Dimethyl (2S,3R,4R,5S)-3,4-Dihydroxy-5-methylpyrrolidine-2-phos-
phonate Hydrochloride (7a·HCl): Following the same procedure as
used for 7b with 6a (88 mg, 0.31 mmol) in EtOH (1 mL), 6  HCl
(1.6 mL) over 5% Pd/C (30 mg) for 30 h to give 7a as the hydro-
chloride (30 mg, 43%). Yellowish resin. [α]2D0 = –13 (c = 1, MeOH).
2940, 2986, 3408 cm–1. 1H NMR (D2O, 295 K): δ = 1.18 (d, 5-Me),
1.35 (t, 2 CH2CH3), 2.12 (td, 1Ј-Ha), 2.32 (dd, 1Ј-Hb), 3.42 (m, 2-
H, 5-H), 4.00 (m, 3-H, 4-H), 4.18 (m, 2 CH2CH3) ppm. 13C NMR
(D2O, 295 K): δ = 13.6 (5-Me), 16.0 (d, 2 CH2CH3), 29.0 (C-1Ј),
55.4 (C-5), 55.8 (C-2), 63.9, 64.0 (2 d, 2 CH2CH3), 73.3 (d, C-4),
78.4 (d, C-3) ppm. J(2,P) = 5.7, J(1Ј,P) = 142.0, J(3,P) = 14.8,
J(4,P) = 1.4, J(CH2CH3,P) = 6.4, J(CH2CH3,P) = 7.2 Hz. 31P
NMR (D2O, 295 K): δ = 32.7 ppm. HRMS (ESI-Q-TOF): calcd.
for C10H32O5NP [M]+: 267.1236; found 267.1239.
R = 0.69 (MeOH). IR (KBr): ν = 1042, 1124, 1156, 1187, 1237,
˜
f
1403, 1452, 1631, 2984, 3417 cm–1. H NMR (CD3OD, 295 K): δ
1
= 1.41 (d, 5-Me), 3.68 (t, 2-H), 3.69 (m, 5-H), 3.91, 3.92 (2 d, 2
OCH3), 4.04 (t, 4-H), 4.55 (ddd, 3-H) ppm. J(2,3) = 9.3, J(2,P) =
10.8, J(3,4) = 3.5, J(3,P) = 14.9, J(4,5) = ca. 2.0, J(5,5-Me) = 6.6,
J(OCH3,P) = 11.0 Hz. 13C NMR (CD3OD, 295 K): δ = 11.9 (5-
Me), 54.7, 55.1 (2 d, 2 OCH3), 55.2 (C-2), 60.4 (C-5), 72.9 (C-4),
74.6 (C-3) ppm. J(2,P) = 158.9, J(4,P) = 9.9, J(5,P) = 2.1,
J(OCH3,P) = 7.1 Hz. 31P NMR (CD3OD, 295 K): δ = 21.0 ppm.
HRMS (ESI-Q-TOF) for C7H16NO5P [M]+: calcd. 225.0766; found
225.0747. MS (TOF ES+): m/z (%) = 116 (15), 212 (10), 226 (100)
[M + H]+.
10·HCl: 1H NMR (D2O, 295 K): δ = 1.32 (d, 5-Me), 1.35 (t, 2
CH2CH3), 2.31 (td, 1Ј-Ha), 2.46 (dd, 1Ј-Hb), 3.61 (td, 2-H), 3.67
(qd, 5-H), 4.10 (td, 4-H), 4.14 (dd, 3-H), 4.21 (m, 2 CH2CH3) ppm.
J(1Јa,1Јb) = 16.0, J(1Јa,2) = 10.2, J(1Јb,2) = 3.7, J(1Јa,P) = 16.0,
J(1Јb,P) = 19.7, J(2,P) = 8.8, J(2,3) = 8.8, J(3,4) = 3.8, J(4,5) = 2.9,
J(5,5-Me) = 6.8, J(CH2CH3) = 7.0 Hz. 13C NMR (D2O, 295 K): δ
= 12.1 (CH3), 15.9 (d, 2 CH2CH3), 27.3 (d, C-1Ј), 55.8 (d, C-2),
56.8 (C-5), 64.2, 64.3 (2 d, 2 CH2CH3), 72.8 (C-4), 77.3 (C-3) ppm.
31P NMR (D2O, 295 K): δ = 31.7 ppm.
1,3-Dipolar Cycloaddition: A solution of nitrone 4[12] (200 mg,
1.17 mmol) in C2Cl4 (1 mL) was stirred at 50 °C with vinylphos-
phonate 11 (0.360 mL, 2 equiv., 2.34 mmol) for 16 h. The solution
was evaporated to give a mixture of cycloadducts 12a,b and 13a,b
in the proportions 30:52:13:6 (quant. yield) and resolved by
chromatography (diethyl ether/EtOH, 95:5) to give mixture of
12b,13b (200 mg, Rf = 0.49, 51%) and of 12a,13a (190 mg, Rf =
0.34, 48%).
(2S,3R,4R,5S)-N,3,4-Trihydroxy-5-methylpyrrolidine-2-phosphonic
Acid, Hydrochloride (7c·HCl): Following the same procedure as
used for 7b with 6c (175 mg, 0.4 mmol) in EtOH (1.5 mL), 1  HCl
(4 mL) over 5% Pd/C (50 mg) for 24 h to give 7c as the hydrochlo-
1
ride (94 mg, quant.). Brown resin. [α]2D0 = +20 (c = 1, MeOH). H
NMR (D2O, 295 K): δ = 1.46 (d, 5-Me), 3.82 (br. s, 2-H), 3.95 (br.
s, 5-H), 4.31 (m, 4-H), 4.54, 4.74 (2 rotamers, 2 m, 3-H) ppm. J(5,5-
Me) = 6.6 Hz. 13C NMR (D2O, 295 K): 2 rotamers M and m, δ =
8.2 (5-Me m), 9.2 (5-Me M), 66.3 (d, C-2 M), 67.7 (C-5 M), 71.2
(C-5 m, C-4 M + m), 71.9 (C-3 M + m), 74.5 (d, C-2 m) ppm.
J(2,P) (M) = 147, J(2,P) (m) = 142 Hz. 31P NMR (D2O): 8.1 ppm. Mixture of Isomers 12b and 13b: Diethyl (2S,3aS,4S,5R,6S)-4,5-Iso-
MS (TOF ES+): 214 (28) [M + H]+, 427 (100) [2M + H]+, 640 (27)
[3M + H]+.
propylidenedioxy-6-methylhexahydropyrrolo[1,2-b]isoxazole-2-
phosphonate (12b) and Diethyl (3S,3aR,4S,5R,6S)-4,5-Iso-
2388
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2384–2392

Synthesis of Amino--Lyxose Phosphonates as Fucosyl-Phosphate Mimics
FULL PAPER
propylidenedioxy-6-methylhexahydropyrrolo[1,2-b]isoxazole-3-phos-
phonate (13b)
CH2CH3), 67.2 (d, C-2), 72.0 (C-3a), 79.9 (d, C-4), 80.3 (C-5), 111.4
(CMe2 ) ppm. J(2,P) = 2.1, J(3,P) = 150.5, J(4,P) = 2.1,
J(CH2CH3,P) = 5.7, J(CH2CH3,P) = 7.1 Hz. 31P NMR (CDCl3,
295 K): δ = 27.6 ppm.
12b: Colourless resin. [α]2D0 = +25 (c = 1, CHCl3). Rf = 0.49 (diethyl
ether/MeOH, 95:5). IR (CH2Cl2): 790, 877, 964, 1026, 1053, 1165,
1211, 1233, 1246, 1373, 1381, 1457, 1630, 1713, 2913, 2936,
Diethyl (1ЈS,2S,3S,4R,5S)-1Ј-Hydroxy-2Ј-(3,4-isopropylidene-
dioxy-5-methylpyrrolidin-2-yl)ethanephosphonate (14b): A solution
of 12b (200 mg, 0.6 mmol) in EtOH (2 mL) was hydrogenolysed
over 5% Pd/C (30 mg) at 40 °C for 48 h. The catalyst was centri-
fuged off and washed with EtOH. The combined solvents were
evaporated and the resulting resin purified by chromatography (di-
ethyl ether/MeOH, 95:5) to give 14b (120 mg, 61 %). Colourless
resin. [α]2D0 = +15 (c = 1, CHCl3). Rf = 0.22 (diethyl ether/MeOH,
1
2986 cm–1. H NMR (CDCl3, 295 K): δ = 1.28 (d, 6-Me), 1.31 (s,
C–CH3), 1.32, 1.35 (2 t, 2 CH2CH3), 1.49 (s, C–CH3), 2.19 (tdd, 3-
Ha), 2.56 (tdd, 3-Hb), 3.38 (quint, 6-H), 3.79 (dd, 3a-H), 4.13 (m,
CH2CH3), 4.22 (m, CH2CH3, 2-H), 4.67 (dd, 5-H), 4.68 (d, 4-
H) ppm. J(2,3-Ha) = 11.3, J(2,3-Hb) = 5.5, J(2,P) not determined,
J(3-Ha,3-Hb) = 12.3, J(3-Ha,3a-H) = 10.9, J(3-Ha,P) = 20.4, J(3-
Hb,3a-H) = 7.2, J(3-Hb,P) = 7.8, J(3a-H,4) = ca. 0, J(4,5) = 6.6,
J(5,6) = 3.8, J(6,6-Me) = 6.5, J(CH3CH2) = 7.1 Hz. 1H NMR
(C6D6, 295 K): δ = 1.01, 1.11 (t, CH2CH3), 1.19, 1.54 (2 s, CMe2),
1.54 (d, 6-Me), 1.88 (dddd, 3-Hb), 2.11 (dddd, 3-Ha), 3.54 (qd, 6-
H), 3.66 (dd, 3a-H), 3.87 (m, CH2CH3), 4.02 (ddd, 2-H), 4.14 (m,
CH2CH3), 4.24 (dd, 5-H), 4.25 (d, 4-H) ppm. J(2,P) = 2.4, J(2,3-
Ha) = 11.0, J(2,3-Hb) = 7.9, J(3-Hb,3-Ha) = 12.1, J(3-Ha,3a-H) =
11.0, J(3-Ha,P) = 21.0, J(3-Hb,3a-H) = 7.2, J(3-Hb,P) = 5.7, J(3a-
H,4) = ca. 0, J(4,5) = 6.5, J(5,6) = 4.5, J(6,Me) = 6.4, J(CH3CH2)
= 7.1 Hz. 13C NMR (CDCl3, 295 K): δ = 12.8 (6-Me), 16.3 (2 d, 2
CH2CH3), 24.9, 25.9 (CMe2), 33.7 (C-3), 62.1, 63.4 (2 d, 2
CH2CH3), 64.1 (C-6), 70.8 (d, C-3a), 75.2 (d, C-2), 79.5 (C-4), 80.6
(C-5), 111.3 (CMe2) ppm. J(2,P) = 166.7, J(3a,P) = 7.1,
J(CH2CH3,P) = 5.7, J(CH2CH3,P) = 6.7 Hz 31P NMR (CDCl3,
295 K): δ = 23.5 ppm. C14H26O6NP (335.34): C 50.14, H 7.82, N
4.18, P 9.24; found C 50.2, H 8.0, N 4.1, P 9.2.
95:5). IR (KBr): ν = 873, 967, 1052, 1083, 1164, 1211, 1249, 1382,
˜
1450, 1625, 2935, 2984, 3253, 3400 cm–1. 1H NMR (CDCl3, 295 K):
δ = 1.19 (d, 5-Me), 1.30 (s, CCH3), 1.34, 1.35 (2 t, 2 CH2CH3),
1.45 (s, CCH3), 1.65–1.80 (m, CH2-2Ј), 3.23 (qd, 5-H), 3.42 (m, 2-
H), 4.13–4.25 (m, 2 CH2CH3, 1Ј-H), 4.40 (d, 3-H), 4.50 (dd, 4-
H) ppm. J(2,CH2-2Ј) = 5.4 and 11.0, J(2,3) = 0, J(3,4) = 5.2, J(4,5)
= 4.0, J(5,5-Me) = 6.6, J(CH3CH2) = 7.0 Hz. 13C NMR (CDCl3,
295 K): δ = 13.0 (5-Me), 16.5 (2 d, 2 CH2CH3), 23.9, 26.0 (CMe2),
28.7 (d, C-2Ј), 55.3 (C-5), 62.1, 62.8 (2 d, 2 CH2CH3), 66.0 (C-2),
69.1 (d, C-1Ј), 82.7 (C-4), 87.0 (d, C-3), 111.0 (CMe2) ppm. J(1Ј,P)
= 173.1, J(2,P) = 19.1, J(2Ј,P) = 1.4, J(3,P) = 5.0, J(CH2CH3,P) =
5.7, J(CH2CH3,P) = 7.1 Hz. 31P NMR (CDCl3, 295 K): δ =
24.2 ppm. HRMS (ESI-Q-TOF) for C14H28NO6P [M]+: calcd.
337.1654; found 337.1656.
Diethyl (1ЈR,2S,3S,4R,5S)-1Ј-Hydroxy-2Ј-(3,4-isopropylidene-
dioxy-5-methylpyrrolidin-2-yl)ethanephosphonate (14a) and Diethyl
(2ЈR,2S,3S,4R,5S)-2Ј-Hydroxy-1Ј-(3,4-isopropylidenedioxy-5-meth-
ylpyrrolidin-2-yl)ethanephosphonate (15): Following the same pro-
cedure as used for 14b with the mixture of 12a and 13a (200 mg,
0.6 mmol). Separation by chromatography (diethyl ether/MeOH,
95:5) gave 14a (86 mg, 43%) and 15 (52 mg, 25%).
13b: 1H NMR (CDCl3, 295 K), partial data: δ = 1.25 (d, 6-Me),
3.02 (sext, 3-H), 3.20 (quint, 6-H), 3.90 (dd, 3a-H), 4.10 (m, 2-Ha,
2-Hb), 4.64 (dd, 5-H), 5.17 (d, 4-H) ppm. J(2a,3) = J(2b,3) = 9.8,
J(3,3a) = 11.0, J(3,P) = 17.6, J(3a,P) = 15.4, J(3a,4) = 0, J(4,5) =
6.6, J(5,6) = 5.2, J(6,6-Me) = 6.6 Hz.
Mixture of Isomers 12a and 13a: Diethyl (2R,3aS,4S,5R,6S)-4,5-
Isopropylidenedioxy-6-methylhexahydropyrrolo[1,2-b]isoxazole-2-
phosphonate (12a) and Diethyl (3R,3aR,4S,5R,6S)-4,5-Isopropyl-
idenedioxy-6-methylhexahydropyrrolo[1,2-b]isoxazole-3-
phosphonate (13a). Mixture of 12a and 13a: Colourless resin.
[α]2D0 = +70 (c = 1, CHCl3). Rf = 0.34 (diethyl ether/MeOH, 95:5).
14a: Colourless resin. [α]2D0 = +19 (c = 1, CHCl3). Rf = 0.33 (diethyl
ether/MeOH, 95:5). IR (KBr): ν = 875, 952, 967, 1024, 1046, 1167,
˜
1211, 1243, 1271, 1373, 1381, 1450, 1620, 2877, 2934, 2986, 3237,
3390, 3499 cm–1. 1H NMR (CDCl3, 295 K): δ = 1.19 (d, 5-Me),
1.30 (s, C–CH3), 1.34, 1.35 (2 t, 2 CH2CH3), 1.45 (s, C–CH3), 1.75–
1.92 (m, CH2-2Ј), 3.19 (qd, 5-H), 3.88 (m, 2-H), 4.12 (m, 1Ј-H),
4.13–4.25 (m, 2 CH2CH3), 4.37 (d, 3-H), 4.50 (dd, 4-H) ppm.
J(2,CH2-2Ј) = ca. 5.0 and 12.0, J(2,3) = 0, J(3,4) = 5.5, J(4,5) =
4.0, J(5,5-Me) = 6.6, J(CH3CH2) = 7.0 Hz. 13C NMR (CDCl3,
295 K): δ = 13.1 (5-Me), 16.4, 16.5 (2 d, 2 CH2CH3), 23.9, 26.0
(CMe2), 28.6 (d, C-2Ј), 55.3 (C-5), 62.0 (d, CH2CH3), 62.3 (d, C-
2), 62.8 (d, CH2CH3), 67.7 (d, C-1Ј), 82.9 (C-4), 87.3 (C-3), 110.9
(CMe2) ppm. J(1Ј,P) = 162.5, J(2,P) = 4.9, J(2Ј,P) = 2.8,
J(CH2CH3,P) = 4.9, J(CH2CH3,P) = 7.1 Hz. 31P NMR (CDCl3,
295 K): δ = 25.6 ppm. HRMS (ESI-Q-TOF) for C14H28NO6P
[M]+: calcd. 337.1654; found 337.1655.
IR (CH Cl ): ν = 752, 794, 876, 967, 1022, 1054, 1133, 1144, 1164,
˜
2
2
1212, 1234, 1378, 1448, 1458, 1652, 2937, 2986 cm–1.
12a: 1H NMR (CDCl3, 295 K): δ = 1.31 (d, 6-Me), 1.31 (s, C–
CH3), 1.34 (2 t, 2 CH2CH3), 1.40 (s, C–CH3), 2.17 (dddd, 3-Hb),
2.68 (dddd, 3-Ha), 2.88 (m, 6-H), 3.83 (t, 3a-H), 4.15–4.25 (m, 2
CH2CH3), 4.47 (ddd, 2-H), 4.64, 4.65 (m, 4-H, 5-H) ppm. J(2,3-
Ha) = 5.1, J(2,3-Hb) = 10.6, J(2,P) = 2.0, J(3-Ha,3-Hb) = 13.1,
J(3-Ha,3a-H) = 9.0, J(3-Ha,P) = 19.0, J(3-Hb,3a-H) = 9.6, J(3-
Hb,P) = 21.1, J(3a-H,4) = ca. 0, J(4,5) = 7.3, J(5,6) = 4.3, J(6,6-
Me) = 6.3, J(CH3CH2) = 7.1 Hz. 13C NMR (CDCl3, 295 K): δ =
12.9 (6-Me), 16.3 (2 d, 2 CH2CH3), 24.9, 25.9 (C-Me2), 33.8 (d, C-
3), 61.7 (C-6), 62.8, 62.9 (2 d, 2 CH2CH3), 70.3 (C-3a), 72.0 (d, C-
2), 80.0 (C-4), 80.3 (C-5), 111.4 (CMe2) ppm. J(2,P) = 170.3, J(3,P)
= 1.0, J(3a,P) = 3.7, J(CH3CH2,P) = 5.6, J(CH3CH2,P) = 6.2 Hz.
31P NMR (CDCl3, 295 K): δ = 21.9 ppm.
15: Colourless resin. [α]2D0 = +22 (c = 1, CHCl3). Rf = 0.32 (CH2Cl2/
EtOH, 98:2). 1H NMR (CDCl3, 295 K): δ = 1.20 (d, 5-Me), 1.31
(s, C–CH3), 1.33, 1.34 (2 t, 2 CH2CH3), 1.46 (s, C–CH3), 2.07
(dddd, 1Ј-H), 3.11 (qd, 5-H), 3.52 (dd, 2-H), 3.86 (ddd, 2Ј-Ha), 3.97
(ddd, 2Ј-Hb), 4.08–4.19 (m, 2 CH2CH3), 4.50 (dd, 4-H), 5.12 (d, 3-
H) ppm. J(1Ј,2) = 12.2, J(1Ј,2Јa) = 9.6, J(1Ј,2Јb) = 3.0, J(1Ј,P) =
21.0, J(2,P) = 7.8, J(2Јa,2Јb) = 11.4, J(2Јa,P) = 2.7, J(2Јb,P) = 7.8,
J(2,3) = 0, J(3,4) = 5.4, J(4,5) = 3.9, J(5,5-Me) = 6.6, J(CH3CH2)
= 7.0 Hz. 13C NMR (CDCl3, 295 K): δ = 13.0 (5-Me), 16.4 (2 d, 2
CH2CH3), 24.0, 26.0 (CMe2), 38.5 (d, C-2Ј), 55.7 (C-5), 62.0, 62.1
(2 d, 2 CH2CH3), 63.0 (C-1Ј), 66.3 (d, C-2), 82.5 (C-4), 85.9 (C-3),
1
13a: H NMR (CDCl3, 295 K): δ = 1.30 (d, 6-Me), 1.35, 1,36 (2 t,
2 CH2CH3), 1.36, 1.51 (2 s, CMe2), 2.54 (dtd, 3-H), 2.88 (qd, 6-H),
3.87 (dd, 3a-H), 4.09 (td, 2-Ha), 4.15–4.25 (m, 2 CH2CH3), 4.29
(ddd, 2-Hb), 4.64 (dd, 5-H), 4.75 (d, 4-H) ppm. J(2a,2b) = 8.7,
J(2a,3) = 7.9, J(2a,P) = 17.0, J(2b,3) = 10.2, J(2b,P) = 12.3, J(3,3a-
H) = 10.0, J(3,P) = 15.3, J(3a-H,P) = 15.1, J(3a-H, 4) = 0, J(4,5)
= 6.5, J(5,6) = 5.1, J(6,6-Me) = 6.5, J(CH3CH2) = 7.1 Hz. 13C
NMR (CDCl3, 295 K): δ = 12.8 (6-Me), 16.4 (2 d, 2 CH2CH3), 110.6 (CMe2) ppm. J(1Ј,P) = 132.1, J(2,P) = 2.0, J(CH2CH3,P) =
24.9, 25.9 (CMe2), 41.9 (d, C-3), 61.8 (C-6), 62.3, 62.5 (2 d, 2
5.7, J(CH2CH3,P) = 7.1 Hz. 31P NMR (CDCl3, 295 K): δ =
Eur. J. Org. Chem. 2006, 2384–2392
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2389

C. Chevrier, D. Le Nouën, A. Defoin, C. Tarnus
FULL PAPER
28.1 ppm. HRMS (ESI-Q-TOF) for C14H28O6NP [M]+: calcd.
337.1654; found 337.1660.
Diethyl (2S,3aS,4S,5R,6S)-4,5-Dihydroxy-6-methylhexahydropyr-
rolo[1,2-b]isoxazole-2-phosphonate (18): A solution of 12b (135 mg,
0.4 mmol) in ethanol (1 mL) and 6  HCl (1 mL) was stirred at
room temp. for 16 h. After evaporation of the solvent, the resulting
resin was purified by chromatography (AcOEt/EtOH, 7:3) to give
18 (111 mg, 93%). Colourless resin. [α]2D0 = +32 (c = 1, MeOH). Rf
= 0.35 (AcOEt/EtOH, 7:3), Rf = 0.2 (diethyl ether/MeOH, 95:5).
Diethyl (1ЈS,2S,3S,4R,5S)-2Ј-(3,4-Dihydroxy-5-methylpyrrolidin-2-
yl)-1Ј-hydroxyethanephosphonate Hydrochloride (16b·HCl): A solu-
tion of 14b (100 mg, 0.29 mmol) was stirred in EtOH (0.1 mL) and
6  HCl (0.3 mL) at room temp. for 16 h. The solvent was evapo-
rated to give 16b as the hydrochloride (88 mg, 90 %). Yellowish
IR (KBr): ν = 544, 592, 655, 773, 789, 976, 1028, 1051, 1161, 1229,
˜
resin. [α]2D0 = –13 (c = 1, CHCl ). IR (KBr): ν = 980, 1029, 1060,
˜
1446, 1652, 2950, 2990, 3386 cm–1. 1H NMR (D2O, 295 K): δ =
1.21 (d, 5-Me), 1.35 (2 t, 2 CH2CH3), 2.40 (dddd, 3-Ha), 2.90
(dddd, 3-Hb), 3.50 (qd, 6-H), 3.75 (q, 3a-H), 4.19–4.27 (m, 2
CH2CH3), 4.25–4.30 (m, 4-H, 5-H), 4.41 (dd, 2-H) ppm. J(2,3-Hb)
= 7.4, J(2,3-Ha) = 10.4, J(2,P) = 1.0, J(3-Ha,3-Hb) = 12.6, J(3-
Ha,P) = 18.4, J(3-Ha,3a-H) = 7.0, J(3-Hb,3a-H) = 8.2, J(3-Hb,P)
= 5.9, J(3a-H,4) = 5.8, J(4,5) not determined, J(5,6) = 4.0, J(6,6-
Me) = 6.9, J(CH2CH3) = 7.1 Hz. 13C NMR (D2O, 295 K): δ = 12.8
(6-Me), 16.1 (d, 2 CH2CH3), 35.4 (C-3), 65.1, 65.3 (2d, 2 CH2CH3),
65.9 (C-6), 69.2 (d, C-3a), 74.4 (d, C-2), 75.6, 75.8 (C-4, C-5) ppm.
J(2,P) = 167.4, J(3a,P) = 8.5, J(CH2CH3,P) = 4.9, J(CH2CH3,P) =
7.1 Hz. 31P NMR (D2O, 295 K): δ = 23.5 ppm. HRMS (TOF ES+)
for C11H23NO6P [M + H]+: calcd. 296.1; found 296.2.
3
1130, 1165, 1207, 1395, 1444, 1638, 3000, 3380 cm–1. 1H NMR
(D2O, 295 K): δ = 1.34, 1.35 (2 t, 2 CH2CH3), 1.37 (d, 5-Me), 2.15
(tdd, 2Ј-Hb), 2.27 (tdd, 2Ј-Ha), 3.64 (td, 2-H), 3.79 (qd, 5-H), 4.13
(t, 4-H), 4.19 (dd, 3-H), 4.22 (m, 2 CH2CH3), 4.28 (ddd, 1Ј-H) ppm.
J(1Ј,2Јa) = 2.8, J(1Ј,2Јb) = 11.6, J(1Ј,P) = 5.8, J(2,2Јa) = 4.8,
J(2,2Јb) = J(2,3) = 8.8, J(2Јa,2Јb) = 14.9, J(2Јa,P) = 3.8, J(2Јb,P)
= 8.8, J(3,4) = 3.8, J(4,5) = 2.8, J(5,5-Me) = 6.8, J(CH3CH2) =
7.0 Hz. 13C NMR (D2O, 295 K): δ = 11.6 (5-Me), 16.2, 16.3 (2 d,
2 CH2CH3), 32.0 (d, C-2Ј), 57.5 (C-5), 59.7 (d, C-2), 64.8, 65.1 (2
d, 2 CH2CH3), 65.3 (d, C-1Ј), 71.6 (C-4), 76.4 (C-3) ppm. J(1Ј,P)
= 166.7, J(2,P) = 19.1, J(2Ј,P) = 3.5, J(CH2CH3,P) = 4.2,
J(CH2CH3,P) = 7.8 Hz. 31P NMR (D2O, 295 K): δ = 25.9 ppm.
HRMS (ESI-Q-TOF) for C11H24NO6P [M]+: calcd. 297.1341;
found 297.1329.
Diethyl (1ЈS,2S,3S,4R,5S)-2Ј-(N-Benzyloxycarbonyl-3,4-isopropyl-
idenedioxy-5-methylpyrrolidin-2-yl)-1Ј-hydroxyethanephosphonate
(19): A suspension of 14b (315 mg, 0.93 mmol) in dry EtOH
(3.2 mL) under Ar with NaHCO3 (157 mg, 1.87 mmol, 2 equiv.)
and benzyl chloroformate (0.145 mL, 1.03 mmol, 1.1 equiv.) was
stirred for 8 h at room temp. The solids were centrifuged off and
washed with CH2Cl2. The combined organic phases were evapo-
rated. The crude product was purified by chromatography (AcOEt)
to obtain 19 (230 mg, 52%). Colourless crystals. M.p. 74–75 °C.
[α]2D0 = +65 (c = 1, CHCl3). Rf = 0.63 (diethyl ether/MeOH, 95:5),
Diethyl (1ЈR,2S,3S,4R,5S)-2Ј-(3,4-Dihydroxy-5-methylpyrrolidin-2-
yl)-1Ј-hydroxyethanephosphonate, hydrochloride (16a·HCl): Follow-
ing the same procedure as used for 14b with 14a (100 mg,
0.29 mmol) in EtOH (0.1 mL) and 6  HCl (0.3 mL) at room temp.
for 16 h to give 16a as the hydrochloride (88 mg, 90%). Yellowish
resin. [α]2D0 = –31 (c = 1, CHCl ). IR (KBr): ν = 568, 795, 977,
˜
3
1023, 1040, 1161, 1219, 1395, 1443, 1640, 2942, 2986, 3390 cm–1.
1H NMR (CD3OD, 295 K): δ = 1.36 (t, 2 CH2CH3), 1.39 (d, 5-
Me), 2.17 (tdd, 2Ј-Hb), 2.23 (tdd, 2Ј-Ha), 3.72 (qd, 5-H), 3.82 (td,
2-H), 4.00 (t, 4-H), 4.06 (dd, 3-H), 4.15 (ddd, 1Ј-H), 4.17–4.25 (m,
2 CH2CH3) ppm. J(1Ј,2Јa) = 9.0, J(1Ј,2Јb) = 4.3, J(1Ј,P) = 7.3,
J(2,2Јa) = 3.4, J(2,2Јb) = 9.7, J(2,3) = 9.1, J(2Јa,2Јb) = 15.3,
J(2Јa,P) = 9.2, J(2Јb,P) = 12.6, J(3,4) = 3.6, J(4,5) = 2.8, J(5,5-Me)
= 6.8, J(CH3CH2) = 7.0 Hz. 13C NMR (CD3OD, 295 K): δ = 12.2
(5-Me), 16.8, 16.9 (2 d, 2 CH2CH3), 32.7 (d, C-2Ј), 58.2 (C-5), 59.0
(d, C-2), 64.3, 64.6 (2 d, 2 CH2CH3), 65.1 (d, C-1Ј), 72.8 (C-4),
77.1 (C-3) ppm. J(1Ј,P) = 168.1, J(2,P) = 12.0, J(2Ј,P) = 2.8,
J(CH2CH3,P) = 4.9, J(CH2CH3,P) = 7.0 Hz. 31P NMR (CD3OD,
295 K): δ = 22.7 ppm. HRMS (ESI-QTOF) for C11H24NO6P
[M]+: calcd. 297.1341; found 297.1328.
R = 0.27 (AcOEt). IR (KBr): ν = 981, 1030, 1051, 1102, 1170,
˜
f
1209, 1242, 1291, 1410, 1712, 2936, 2987, 3302 cm–1 1H NMR
.
(CDCl3, 328 K): δ = 1.29, 1.31 (2 t, CH2CH3), 1.32 (s, C–CH3),
1.40 (br. s, 5-Me), 1.47 (s, C–CH3), 2.00, 2.11 (2 br. s, CH2-2Ј), 2.8–
3.6 (br. s, 1Ј-OH), 3.87 (br. s, 1Ј-H), 3.91 (quint, 5-H), 4.05–4.18
(m, 2 CH2CH3), 4.28 (br. d, 2-H), 4.59 (d, 3-H), 4.69 (t, 4-H), 5.12,
5.13 (2 d, CH2Ph), 7.28–7.35 (m, Ph) ppm. J(2,2Ј) = 7.2, J(2.3) =
0, J(3,4) = 6.0, J(4,5) = 6.3, J(5,5-Me) = 6.5, J(CH2Ph) = 12.6,
J(CH2CH3) = 7.0 Hz. 13C NMR (CDCl3, 295 K): δ = 14.8 (5-Me),
16.5 (d, 2 CH2CH3), 24.9, 26.0 (CMe2), 32.9 (C-2Ј), 58.1 (C-5), 60.6
(C-2), 62.9 (d, 2 CH2CH3), 64.9 (d, C-1Ј), 66.9 (CH2Ph), 80.5 (C-
4), 83.4 (C-3), 111.4 (CMe2), 128.1, 128.5 (o,m,p-C), 136.5 (ipso-
C), ca. 155 (C=O) ppm. J(1Ј,P) = 163.0, J(CH2CH3,P) = 5.3,
J(CH2CH3,P) = 7.0 Hz. 31P NMR (CDCl3, 295 K): δ = 25.3 ppm.
HRMS (ESI-Q-TOF) for C22H34NO8P [M]+: calcd. 471.2022;
found 471.2012.
Diethyl (1ЈR,2R,3S,4R,5S)-1Ј-(3,4-Dihydroxy-5-methylpyrrolidin-2-
yl)-2Ј-hydroxyethanephosphonate, hydrochloride (17·HCl): Follow-
ing the same procedure as used for 14b with 15 (35 mg, mmol) in
EtOH (0.2 mL) and 6  HCl (0.3 mL) at room temp. for 16 h to
give 17 as the hydrochloride (30 mg, 87%). Orange resin. [α]2D0
=
Diethyl (1ЈS,2S,3S,4R,5S)-2Ј-(N-Benzyloxycarbonyl-3,4-isopropyl-
idenedioxy-5-methylpyrrolidin-2-yl)-1Ј-(imidazole-1ЈЈ-thiocarbonyl-
–8 (c = 1, MeOH). IR (KBr): ν = 790, 977, 1018, 1039, 1125, 1160,
˜
1
1224, 1395, 1638, 2987, 3418 cm–1. H NMR (CD3OD, 295 K): δ oxy)ethanephosphonate (20): Thiocarbonyldiimidazole (174 mg,
= 1.38 (2 t, 2 CH2CH3), 1.41 (d, 5-Me), 2.46 (dq, 1Ј-H), 3.76 (qd, 0.98 mmol, 2 equiv.) was added to a solution of 19 (230 mg,
5-H), 3.88 (ddd, 2-H), 4.03 (m, 4-H), 4.13 (ddd, 2Ј-Ha), 4.19 (ddd, 0.49 mmol) in dry THF (3 mL) under Ar at room temp. After stir-
2Ј-Hb), 4.17–4.28 (m, 2 CH2CH3), 4.46 (dd, 3-H) ppm. J(1Ј,2) = ring for 16 h at room temp., brine was added and the mixture ex-
3.0, J(1Ј,2Јa) = 4.5, J(1Ј,2Јb) = 3.6, J(1Ј,P) = 23.8, J(2Јa,2Јb) =
tracted with AcOEt (3×20 mL). The organic phases were dried
11.6, J(2Јa,P) = 9.6, J(2Јb,P) not determined, J(2,3) = 9.3, J(2,P) (MgSO4), evaporated and the crude product was purified by
= 12.1, J(3,4) = 3.5, J(4,5) = 2.5, J(4,P) = 1.6, J(5,5-Me) = 6.8,
J(CH2CH3) = 7.0 Hz. 13C NMR (CD3OD, 295 K): δ = 12.0 (5-
Me), 16.7 (2 d, 2 CH2CH3), 37.9 (d, C-1Ј), 58.7 (d, C-2Ј), 59.1 (C-
chromatography (AcOEt) to give pure 20 (253 mg, 89%). Colour-
less resin. [α]2D0 = +23 (c = 1, CHCl3). This compound is relatively
unstable and was only characterised by NMR spectroscopy. 1H
5), 61.0 (d, C-2), 64.3, 64.4 (2 d, 2 CH2CH3), 72.9 (C-4), 74.7 (d, NMR (CDCl3, 328 K) 1.31 (br. s, 2 CH2CH3), 1.31, 1.43 (2 s,
C-3) ppm. J(1Ј,P) = 140.6, J(2,P) = 4.2, J(2Ј,P) = 3.0, J(3,P) = 10.6,
CMe2), 1.45 (br. s, 5-Me), 2.10, 2.40, 2.70 (3 br. s, CH2-2Ј), 3.87
(quint, J = 6.2 Hz, 5-H), 4.07 (br. s, 2-H), 4.15 (br. s, 2 CH2CH3),
J(CH2CH3,P) = 5.7, J(CH2CH3,P) = 7.0 Hz. 31P NMR (CD3OD,
295 K): δ = 26.2 ppm. HRMS (ESI-Q-TOF) for C11H24NO6P 4.54 (br. s, 3-H), 4.63 (br. s, 4-H), 4.95–5.25 (m, CH2Ph), 6.19 (dt,
[M]+: calcd. 297.1341; found 297.1346.
J = 2 and 10 Hz, 1Ј-H), 6.96, 7.07 (2 br. s, 4-HЈЈ imidazole), 7.34
2390
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2384–2392

Synthesis of Amino--Lyxose Phosphonates as Fucosyl-Phosphate Mimics
(s, Ph), 7.35, 7.70 (2 br. s, 5-HЈЈ imidazole), 8.10, 8.40 (2 br. s, 2-
FULL PAPER
23: Yellowish resin. [α]2D0 = +14 (c = 1, CHCl3). H NMR (CDCl3,
1
HЈЈ imidazole) ppm. 13C NMR (CDCl3, 295 K): δ = 15.3 (5-Me), 295 K): δ = 1. 36 (t, CH2CH3), 1.37 (s, C–CH3), 1.40 (t, CH2CH3),
16.4, 16.5 (2 d, CH2CH3), 24.9, 25.8 (CMe2), 31.1 (C-2Ј), 57.2 (C- 1.40 (s, C–CH3), 2.10 (dt, 5-Me), 4.21–4.34 (m, 2 CH2CH3), 4.44
5), 59.1 (d, C-2), 63.3, 63.6 (2 d, 2 CH2CH3), 67.0 (CH2Ph), 73.5 (dsext, 2-H), 4.96 (dt, 3-H), 5.25 (dsext, 4-H) ppm. J(2,3) = 0.8,
(d, C-1Ј), 80.0 (C-4), 81.6 (C-3), 111.8 (CMe2), 117.9 (C-5ЈЈ Im),
128.2, 128.6 (Car), 131.2 (C-4ЈЈ Im), 136.3 (ipso-C), 137.2 (C-2ЈЈ
Im), 154.5 (C=O), 183.3 (C=S) ppm. J(1Ј,P) = 166.0, J(2,P) = 15.5,
J(2,4) = 1.0, J(2,5-Me) = 1.4, J(2,P) = 14.1, J(3,P) = 7.2, J(3,4) =
6.0, J(4,5-Me) = 1.5, J(4,P) = 1.5, J(5-Me,P) = 4.5, J(CH2CH3) =
7.1 Hz. 13C NMR (CDCl3, 295 K): δ = 10.7 (d, 5-Me), 16.3, 16.4
J(CH3CH2,P) = 5.7, J(CH2CH3,P) = 6.4 Hz. 31P NMR (CDCl3, (2 d, 2 CH2CH3), 26.1, 27.2 (CMe2), 63.3, 64.6 (2 d, 2 CH2CH3),
295 K): δ = 18.5 ppm.
74.4 (d, C-3), 75.3 (d, C-2), 82.0 (C-4), 112.1 (CMe2), 143.7 (d, C-
5) ppm. J(2,P) = 153.7, J(3,P) = 6.4, J(5,P) = 8.5, J(5-Me,P) = 2.1,
J(CH3CH2,P) = 6.0, J(CH3CH2,P) = 7.1 Hz. 31P NMR (CDCl3,
295 K): δ = 17.0 ppm. C12H22NO6P (307.29): C 46.91, H 7.22, N
4.56; found C 46.7, H 7.4, N 4.4.
Diethyl (2S,3S,4R,5S)-2Ј-(N-Benzyloxycarbonyl-3,4-isopropyl-
idenedioxy-5-methylpyrrolidin-2-yl)ethanephosphonate (21): A solu-
tion of 20 (220 mg, 0.38 mmol) was refluxed under Ar for 15 min in
dry toluene. Bu3SnH (0.155 mL, 0.97 mmol, 1.5 equiv.) and AIBN
(1.5 mg, 0.008 mmol, 0.02 equiv.) were then added. The solution
was refluxed for a further 2 h 45 min and CHCl3 was then added
in order to destroy the tin compounds. Evaporation of the solvent
and purification by chromatography (AcOEt) gave pure 21
(125 mg, 76%). Colourless resin. [α]2D0 = +58 (c = 1, CHCl3). Rf =
0.30 (AcOEt). 1H NMR (CDCl3, 295 K): δ = 1.29 (br. s, 2
CH2CH3), 1.32, 1.46 (2 s, CMe2), 1.46 (br. s, 5-Me), 1.70 (br. s,
CH2-2Ј), 1.90–2.10 (br. m, CH2-1Ј), 3.84 (br. s, 5-H), 4.02 (br. s, 2-
H, 2 CH2CH3), 4.40 (d, 3-H), 4.61 (t, 4-H), 5.09, 5.14 (2 d, CH2Ph),
7.29–7.35 (m, Ph) ppm. J(3,4) = 6.0, J(4,5) = 6.0, J(CH2Ph) =
12.3 Hz. 13C NMR (CDCl3, 295 K), two rotamers: δ = 14.5, 15.9
(2 s, 5-Me), 16.4 (d, 2 CH2CH3), 22.1 (d, C-1Ј), 23.7, 24.7 (C-2Ј),
24.9, 25.9 (CMe2), 56.6, 57.0 (C-5), 61.6 (d, 2 CH2CH3), 63.3 (C-
2), 66.7 (CH2Ph), 80.4 (C-4), 82.0 (C-3), 111.6 (CMe2), 127.9, 128.4
(o,m,p-C), 136.4 (ipso-C), 154.8 (C=O) ppm. J(1Ј,P) = 144.0,
J(CH2CH3,P) = 6.0, J(CH2CH3,P) = 6.4 Hz. 31P NMR (CDCl3,
295 K), two rotamers: δ = 31.7, 31.2 ppm. HRMS (ESI-Q-TOF)
for C22H34NO7P [M]+: calcd. 455.2073; found 455.2101.
1
24: Only characterised by H NMR (CDCl3, 400 MHz, 295 K): δ
= 1.37 (t, 2 CH2CH3), 1.41, 1.47 (2 s, CMe2), 1.50 (d, 5-Me), 4.17
(dquint, 5-H), 4.29 (m, 2 CH2CH3), 4.87 (dt, 4-H), 5.46 (d, 3-
H) ppm. J(3,4) = 6.0, J(4,5) = 5.6, J(4,P) = 1.0, J(5,5-Me) = 6.8,
J(5,P) = 2.6, J(CH2CH3) = 7.0 Hz.
Diethyl (2S,3R,4R)-(3,4-Isopropylidenedioxy-5-methyl-1-oxido-5-
pyrrolinium-2-yl)methanephosphonate (25): A solution of 9 (200 mg,
0.62 mmol) in EtOH (2 mL) was stirred for 20 h at room temp.
with yellow HgO (201 mg, 0.93 mmol, 1.5 equiv.). The solids were
centrifuged off, washed with EtOH and the combined solvents
evaporated to give nitrone 25 (198 mg, quant.). Colourless resin.
[α]2D0 = +7 (c = 0.5, CHCl3). Rf = 0.24 (diethyl ether/EtOH, 9:1).
IR (KBr): ν = 972, 1027, 1049, 1161, 1213, 1236, 1384, 1617, 2958,
˜
1
2987, 3429 cm–1. H NMR (CDCl3, 295 K): δ = 1.34, 1.35 (2 t, 2
CH2CH3), 1.38 (s, CMe2), 2.08 (t, 5-Me), 2.15 (ddd, 1Ј-Hb), 2.65
(ddd, 1Ј-Ha), 4.13 (m, 2 CH2CH3), 4.25 (ddm, 2-H), 4.96 (dt, 3-
H), 5.18 (dt, 4-H) ppm. J(1Јa,P) = 19.6, J(1Јa,1Јb) = 15.4, J(1Јa,2)
= 3.5, J(1Јb,2) = 9.8, J(1Јb,P) = 16.8, J(2,4) = 1.5, J(2,5-Me) = 1.5,
J(2,3) = 1.0, J(2,P) = 20.0, J(3,4) = 6.2, J(3,P) = 1.0, J(4,5-Me) =
Diethyl (2S,3S,4R,5S)-2Ј-(3,4-Dihydroxy-5-methylpyrrolidin-2-yl)-
ethanephosphonate Hydrochloride (22·HCl): A solution of 21
(104 mg, 0.23 mmol) was stirred in EtOH (0.5 mL) and 6  HCl
(1.5 mL) for 16 h at room temp., then the solvent was evaporated
and the crude product hydrogenolysed in EtOH (0.5 mL) and H2O
(0.5 mL) over 5% Pd/C (50 mg) at room temp. for 8 h. The catalyst
was centrifuged off, washed with EtOH and H2O (3×1 mL) and
the combined solvents were evaporated to give pure 22 as the hy-
drochloride (66 mg, 91%). Colourless resin. [α]2D0 = –19 (c = 1,
3
1.5, J(CH3CH2) = 7.0 Hz. C NMR (CDCl3, 295 K): δ = 10.8 (5-
Me), 16.4 (d, 2 CH2CH3), 25.9 (CMe), 26.4 (d, C-1Ј), 27.1 (CMe),
62.2, 62.5 (2 d, 2 CH2CH3), 74.4 (d, C-2), 76.0 (C-3), 81.3 (C-4),
112.1 (CMe2) ppm. J(1Ј,P) = 142.7, J(2,P) = 1.4, J(CH2CH3,P) =
5.6, J(CH2 CH3 ,P) = 6.4 Hz. HRMS (ESI-Q-TOF) for
C13H24NO6P [M]+: calcd. 321.1341; found 321.1329.
Acknowledgments
MeOH). IR (KBr): ν = 991, 1028, 1161, 1206, 1396, 1445, 1636,
˜
2942, 2987, 3401 cm–1 1H NMR (D2O, 295 K): δ = 1.27 (t, 2
.
The support of the Centre National de la Recherche Scientifique
(UMR 7015) is gratefully acknowledged. We also wish to thank the
Ministère de l’Enseignement et de la Recherche for a Ph. D. grant
to C. C. We thank Mr. Mathias Wind of Basilea Pharmaceuticals
(Basel) for HR-mass spectrometry measurements.
CH2CH3), 1.32 (d, 5-Me), 1.95–2.10 (m, CH2-1Ј, CH2-2Ј), 3.46 (q,
2-H), 3.74 (dq, 5-H), 4.07–4.17 (m, 2 CH2CH3, 3-H, 4-H) ppm.
J(2,3) = J(2,CH2-2Ј) = 7.0, J(4,5) = 2.5, J(5,5-Me) = 6.8,
J(CH2CH3) = 7.0 Hz. 13C NMR (D2O, 295 K): δ = 11.6 (5-Me),
16.1 (d, 2 CH2CH3), 21.5 (d, C-1Ј), 24.0 (d, C-2Ј), 57.4 (C-5), 61.0
(d, C-2), 64.1 (d, 2 CH2CH3), 72.3 (C-4), 76.1 (C-3) ppm. J(1Ј,P)
= 141.0, J(2,P) = 19.1, J(2Ј,P) = 4.2, J(CH2CH3,P) = 5.7,
J(CH2CH3,P) = 6.4 Hz. 31P NMR (D2O, 295 K): δ = 34.3 ppm.
HRMS (ESI-Q-TOF) for C11H24NO5P [M]+: calcd. 281.1392;
found 281.1374.
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C. A. A. van Boeckel, J. H. van Boom, “Concept and synthesis
of potential fucosyltransferase inhibitors” in Carbohydrate
mimics, concepts and methods (Ed.: Y. Chapleur), Wiley-VCH,
Weinheim, 1998, pp. 491–510.
[2] E. E. Shimanek, G. J. McGarvey, J. A. Jablonowski, C.-H.
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[3] P. Sears, C.-H. Wong, Chem. Commun. 1998, 1161–1170.
[4] P. Compain, O. R. Martin, Bioorg. Med. Chem. 2001, 9, 3077–
3092.
[5] L. Qiao, B. W. Murray, M. Shimazaki, J. Schultz, C.-H. Wong,
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Oxidation into Nitrones
Diethyl (2S,3R,4R)-3,4-Isopropylidenedioxy-5-methyl-1-oxido-5-
pyrrolinium-2-phosphonate (23) and Diethyl (3R,4R,5S)-3,4-Isopro-
pylidenedioxy-5-methyl-1-oxido-1-pyrrolinium-2-phosphonate (24):
A solution of 6b (50 mg, 0.16 mmol) in CHCl3 (0.5 mL) was stirred
for 24 h with yellow HgO (42 mg, 0.19 mmol, 1.2 equiv.). Solids
were centrifuged off and washed with CH2Cl2. The combined sol-
vents were evaporated. The crude (85:15) mixture of nitrones 23
and 24 was resolved by TLC (Et2O/EtOH, 97:3) to give 23 (26 mg,
53%) and 24 (8 mg, 15%).
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Received: December 20, 2005
Published Online: March 17, 2006
2392
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2384–2392