Synthesis of Unnatural Phosphonosugar Analogues

Article abstract of DOI:10.1002/ejoc.201301543

The first synthesis of new cyclic phosphonates (phostones), analogues of pentafuranoses containing a phosphorus atom in place of the anomeric carbon in the deoxyribose and deoxyxylose series, is described. Two methods, of respectively six and seven steps, were developed in parallel, and each gave the racemic phosphonosugars in good yields. Compounds analogous to the alpha and beta anomers were isolated and fully characterized by NMR spectroscopy.

Full text of DOI:10.1002/ejoc.201301543

FULL PAPER
DOI: 10.1002/ejoc.201301543
Synthesis of Unnatural Phosphonosugar Analogues
Bénédicte Dayde,[a,b] Claire Pierra,[b] Gilles Gosselin,[b,c] Dominique Surleraux,[b]
Amadou Tidjani Ilagouma,[d] Coralie Laborde,[a] Jean-Noel Volle,[a] David Virieux,*[a] and
Jean-Luc Pirat*[a]
Keywords: Medicinal chemistry / Glycomimetics / Bioisosteres / Carbohydrates / Phosphorus heterocycles
The first synthesis of new cyclic phosphonates (phostones),
analogues of pentafuranoses containing a phosphorus atom
in place of the anomeric carbon in the deoxyribose and de-
oxyxylose series, is described. Two methods, of respectively
six and seven steps, were developed in parallel, and each
gave the racemic phosphonosugars in good yields. Com-
pounds analogous to the alpha and beta anomers were iso-
lated and fully characterized by NMR spectroscopy.
induce a biological response higher than the reference com-
pound, racemic hydroxybupropion. This result highlights
the fact that strategic replacement of a carbon atom by
phosphorus could be really useful for enhancing the bio-
logical response, and more particularly in this case, for the
treatment of depression and attention-deficit hyperactivity
disorder (ADHD).[2a] Phostines 2, specifically designed as
a combination of glycopyranosides and C-arylglycosides
represent a new family of glycomimetics designed to target
CNS (central nervous system) cancer without affecting nor-
mal astrocytes. They showed the ability to induce cytotoxi-
city in C6 glial strain cells at micromolar concentrations.[2b]
Introduction
The search for new bioisosteric groups that will be able
to modulate the metabolic and/or the drug pharmacoki-
netic properties is a critical issue for innovation in drug dis-
covery. Changes in pharmacological activity or bioavail-
ability, or even adverse effects of a drug can result from
minor changes of the original lead compound. Bioiso-
sterism represents a fruitful approach that medicinal chem-
ists can use to elicit biological activity.[1] Recent studies in
our group demonstrated that the phosphinolactone group
(O–P=O) can be considered to be a bioisostere of a hemi-
acetal functionality (O–C–OH).[2] This idea has been suc-
cessfully used in the development of two families of cyclic
phosphorus heterocycles with completely different bio-
logical activities (Figure 1). Considering oxazaphosphinane
1, there is an analogy between the phosphinolactone and
the lactol group of hydroxybupropion, and these two struc-
tures have a close correspondence in terms of both polarity
and biological activity. When 1,4,2-oxazaphosphinane 1
was screened for biological activity in the forced-swimming
test with mice, it was found firstly to have the ability to
diffuse through the blood–brain barrier, and secondly to
[a] AM2N, Institut Charles Gerhardt, UMR 5253, ENSCM,
8, rue de l’Ecole Normale, 34296 Montpellier, France
E-mail: david.virieux@enscm.fr
jean-luc.pirat@enscm.fr
http://am2n.enscm.fr/
[b] Idenix Pharmaceuticals, Medicinal Chemistry Laboratory, Cap
Gamma,
1682 rue de la Valsière, BP50001, 34189 Montpellier CEDEX
4, France
[c] DACAN, Institut Max Mousseron, UMR 5247, Université
Montpellier 2,
34095 Montpellier, France
[d] Departement de Chimie, Faculté des Sciences, Université
Abdou Moumouni,
Figure 1. Analogy between the lactol and phosphinolactone
groups, and phosphonate analogue 4 of 2-deoxy ribose or 2-deoxy
xylose.
B.P. 10662, Niamey, Niger
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301543
Eur. J. Org. Chem. 2014, 1333–1337
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1333

D. Virieux, J.-L. Pirat et al.
FULL PAPER
Phostones 3, cyclic phosphonic acids based on a five-
membered ring have gained considerable attention due to
their diverse biological profiles. They have been considered
as candidate inhibitors for purine nucleotide phosphorylase
(PNP) and also for various isomerase enzymes.[3]
In this paper, we describe the synthesis of new unnatural
phospha-analogues 4 of 2-deoxy ribose and the 2-deoxy
xylose that are unknown to date.[4] Recently, modified pent-
oses have been shown to act as substrates of aldolases.[5]
Scheme 1. Synthesis of diethyl (Z)-4-benzyloxy-but-2-enylphos-
phonate (5).
ation with m-chloroperbenzoic acid in 72% yield, followed
by the epoxide-ring opening under aqueous acidic condi-
Results and Discussion
All the target structures were synthesized starting from tions in 56% yield.[10] This ring opening reaction was com-
diethyl (Z)-4-benzyloxy-but-2-enylphosphonate (5). The pletely stereospecific, which can be explained by proton-
synthesis of 5 itself (Scheme 1) began with the mono-benz- ation of the epoxide without formation of a carbocation.
ylation of cis-buten-1,4-diol with sodium hydride and Then, under acidic conditions [4-toluenesulfonic acid
benzyl chloride, which occurred in 81% yield.[6] In an Appel (PTSA) in toluene], open-chain intermediates 6 or 8 cy-
reaction using triphenylphosphine and carbon tetrachlor- clized in an intramolecular transesterification process to
ide,[7] the hydroxy compound was converted in 77% yield give mixtures of diastereomers 9a and 9b (1:1) or dia-
into the alkyl chloride, which was used as an electrophile stereomers 9c and 9d (1:1), all as racemates, in 51 and 42%
in the next step. The synthesis of the P–C linkage using a yields, respectively. Purification of the mixtures 9a/9b and
Michaelis–Arbuzov reaction was carried out without sol- 9c/9d by silica gel column chromatography allowed the sep-
vent at 140 °C for 17 h with 2 equiv. of triethyl phosphite, aration of each diastereomer of phospha deoxyribose (i.e.,
and the desired phosphonate (i.e., 5) was formed in high 9a and 9b) and phospha deoxyxylose (i.e., 9c and 9d). De-
yield (94%).[8]
protection of the benzyl group of each diastereomer of 9 by
Then, the first goal was to develop the appropriate con- catalytic hydrogenolysis (H2/Pd/C) gave the free 5Ј-hydroxy
ditions for the phospha-lactonization. The like diol (i.e., 6) analogues (i.e., 4a–4d). Finally, the lithium salt of the free
was obtained, using conditions described in the literature, acid (i.e., 10) was obtained by heating the diastereomeric
in 86% yield from 5 by the reaction of N-methylmorpholine mixture of 4a and 4b in acetonitrile with anhydrous lithium
N-oxide (NMO) as co-oxidant and osmium tetraoxide (9% bromide. The formation of only one diastereomer con-
solution in water; Scheme 2).[9] From alkene 5, unlike diol 8 firmed that 4a and 4b were epimeric only at the phosphorus
was also obtained by a two-step sequence involving epoxid- atom.
Scheme 2. Synthesis of the unnatural phospha-sugar analogues 4a–4d.
1334
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1333–1337

Synthesis of Unnatural Phosphonosugar Analogues
200 μm; heptane/ethyl acetate, 100:0 to 80:20) to give the mono-
protected diol (14 g, 81%) as a colourless oil. b.p. 110–112 °C/
0.07 Torr. 1H NMR (400.13 MHz, CDCl3): δ = 3.01 (s, 1 H), 4.08–
4.12 (m, 2 H), 4.13–4.17 (m, 2 H), 4.54 (s, 2 H), 5.70–5.77 (m, 1
H), 5.78–5.86 (m, 1 H), 7.27–7.44 (m, 5 H) ppm. 13C NMR
(100.61 MHz, CDCl3): δ = 58.55, 65.65, 72.49, 127.86, 127.91,
128.02, 128.51, 132.52, 137.87 ppm.
The relative configurations of the carbon chiral centres in
compounds 9a–9d were determined by evaluating proton–
proton coupling constants and by NOE spectroscopy (Fig-
ure 2).
(Z)-[(4-Chlorobut-2-enyloxy)methyl]benzene:[11] Under nitrogen, tri-
phenylphosphine (19.60 g, 75 mmol, 1.2 equiv.) was added to a
solution of (Z)-4-(benzyloxy)but-2-en-1-ol (11.48 g, 64 mmol,
1.0 equiv.) in CCl4 (46 mL). The mixture was stirred at 80 °C for
2 h, then pentane (60 mL) was added at ambient temperature, and
part of the triphenylphosphine oxide was removed by filtration.
The combined organic phases were dried with MgSO4, filtered, and
concentrated. The residue was purified by flash chromatography
(SiO2 35–70 μm; heptane/CH2Cl2, 100:0 to 20:80) to give the
chloro-compound (9.69 g, 77%) as a colourless oil. 1H NMR
(400.13 MHz, CDCl3): δ = 4.12–4.16 (m, 2 H), 4.17–4.20 (m, 2 H),
4.58 (s, 2 H), 5.80–5.92 (m, 2 H), 7.31–7.49 (m, 5 H) ppm. 13C
NMR (100.61 MHz, CDCl3): δ = 59.25, 65.18, 72.48, 127.84,
127.86, 128.49, 128.52, 130.82, 137.99 ppm.
Figure 2. Key NOE correlations for 4a–4d.
For compound 9a, NOEs were observed between 2α-H
and OEt and between 2α-H and 4-H, which suggests that
the ethoxy and benzyloxymethyl groups were on opposite
faces of the ring. In contrast, for diastereomer 9b, NOEs
were observed between 2β-H, OEt, and the benzyloxy-
methyl substituents, consistent with a cis relationship.
Furthermore, the difference between the NOEs observed
for 9c and 9d and those observed for diastereomers 9a and
9b clearly demonstrated that 9c and 9d belonged to the de-
oxyxylose series.
Diethyl (Z)-4-(Benzyloxy)but-2-enylphosphonate (5): In a round-
bottomed flask equipped with a Dean–Stark trap and a condenser,
under nitrogen, triethyl phosphite (14.2 mL, 83 mmol, 2.0 equiv.)
and (Z)-[(4-chlorobut-2-enyloxy)methyl]benzene (8.13 g, 41 mmol,
1.0 equiv.) were mixed, and the mixture was heated at 140 °C for
17 h. The mixture was then concentrated, and the residue was puri-
fied by flash chromatography (SiO2 70–200 μm; heptane/EtOAc,
100:0 to 50:80) to give phosphonate 5 (11.67 g, 94%) as a colourless
oil. 31P NMR (161.97 MHz, CDCl3): δ = 27.04 ppm. 1H NMR
3
Conclusions
(400.13 MHz, CDCl3): δ = 1.22 (t, JH,H = 7.1 Hz, 6 H), 2.55 (dd,
3
2JP,H = 22.4, JH,H = 8.0 Hz, 2 H), 3.88–4.11 (m, 6 H), 4.44 (s, 2
In conclusion, a six–seven-step synthesis in the racemic
series was developed to give new unnatural analogues of de-
oxyribo- and deoxyxylose in good yields. Further work di-
rected towards the synthesis of nucleoside-bearing unnatural
H), 5.46–5.64 (m, 1 H), 5.67–5.84 (m, 1 H), 7.12–7.32 (m, 5 H)
3
ppm. 13C NMR (100.61 MHz, CDCl3): δ = 16.42 (d, JC,P
=
6.0 Hz), 26.33 (d, 1JC,P = 140.2 Hz), 61.92 (d, 2JC,P = 6.7 Hz), 65.61
(d, JC,P = 2.3 Hz), 72.38, 121.47 (d, JC,P = 11.3 Hz), 127.67,
sugar analogues and their biological applications is currently 127.77, 128.39, 130.81 (d, JC,P = 13.7 Hz), 138.09 ppm. HRMS
4
2
3
(ESI): calcd. for C15H24O4P 299.1412; found 299.1419.
underway, and the results will be reported in due course.
(like)-(؎) Diethyl (2R,3R)-4-(Benzyloxy)-2,3-dihydroxybutylphos-
phonate (6): At room temperature under nitrogen, phosphonate 5
(3.0 g, 10 mmol), N-methylmorpholine N-oxide (2.7 g, 20 mmol),
and osmium tetraoxide (25 mg, 0.01 mmol) were sequentially
added to a mixture of acetone and water (8:2; 315 mL). After 3 d,
the reaction mixture was diluted with CH2Cl2, and the resulting
mixture was washed with Na2SO3 (10% aq.) and brine. The organic
phase was dried with MgSO4, filtered, and concentrated to dryness.
The residue was purified by flash chromatography (SiO2 35–70 μm;
CH2Cl2/EtOAc, 100:0 to 0:100) to give dihydroxy butylphos-
Experimental Section
General Remarks: Unless otherwise stated, commercially available
chemicals were used as received without further purification. Before
use, solvents were heated at reflux over the appropriate drying agent
and distilled under a nitrogen atmosphere. All moisture sensitive
reactions were performed in flame-dried septum-sealed glassware
under a nitrogen atmosphere. H, 31P, and 13C NMR spectra were
1
recorded with a Bruker DRX 400 MHz spectrometer in [D6]DMSO,
CDCl3, or D2O as solvent, operating at frequencies of 400.13 MHz
(1H), 100.62 MHz (13C), and 161.97 MHz (31P). The 31P NMR
spectra are decoupled. HRMS measurements were carried out with
a Micromass Q-TOF instrument (ESI+ ionization mode).
(Z)-4-(Benzyloxy)but-2-en-1-ol:[6] At 0 °C under a nitrogen atmo-
sphere, cis-butene-1,4-diol (30 g, 340 mmol) was carefully added to
phonate
6 (2.59 g, 86%) as a
colourless oil. 31P NMR
(161.97 MHz, CDCl3): δ = 31.27 ppm. 1H NMR (400.13 MHz,
3
2
CDCl3): δ = 1.25 (t, JH,H = 7.1 Hz, 6 H), 1.91 (ddd, JP,H = 15.8,
2JH,H = 15.5, JH,H = 9.5 Hz, 1 H), 2.12 (ddd, JP,H = 19.2, JH,H
3
2
2
3
3
= 15.5, JH,H = 2.8 Hz, 1 H), 3.04 (d, JH,H = 4.9 Hz, 1 H), 3.54
(dd, 2JH,H = 9.7, JH,H = 6.1 Hz, 1 H), 3.58 (dd, JH,H = 9.7, JH,H
3
2
3
3
a
suspension of sodium hydride (4.8 g, 120 mmol) in THF
= 4.2 Hz, 1 H), 3.64–3.71 (m, 1 H), 3.87 (d, JH,H = 3.6 Hz, 1 H),
2
(140 mL). The mixture was stirred at room temperature for 1 h,
then benzyl chloride (14.4 mg, 110 mmol) was added, and the re-
3.89–3.98 (m, 1 H), 3.98–4.15 (m, 4 H), 4.47 and 4.49 (2 d, JH,H
= –11.9 Hz, 2 H), 6.96–7.57 (m, 5 H) ppm. 13C NMR (100.61 MHz,
3
1
sulting mixture was stirred overnight at 75 °C. The reaction was CDCl3): δ = 16.38 and 16.40 (2 d, JC,P = 6.1 Hz), 29.13 (d, JC,P
2
2
quenched at ambient temperature with NH4Cl (saturated aq.), and
the mixture was extracted with CH2Cl2 (3ϫ 50 mL). The combined
organic extracts were dried with MgSO4, filtered, and concentrated.
The residue was purified by flash chromatography (SiO2 70–
= 139.8 Hz), 62.03 and 62.05 (2 d, JC,P = 6.5 Hz), 67.81 (d, JC,P
= 5.4 Hz), 71.00, 72.91 (d, JC,P = 14.9 Hz), 73.50, 127.80, 127.85,
3
128.47, 137.79 ppm. HRMS (ESI): calcd. for C15H26O6P 333.1467;
found 333.1461.
Eur. J. Org. Chem. 2014, 1333–1337
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1335

D. Virieux, J.-L. Pirat et al.
FULL PAPER
(؎)-Diethyl (2S,3S)-[4-(Benzyloxymethyl)oxiran-2-yl]methylphos-
phonate (7): Compound 5 (2.0 g, 6.7 mmol) was dissolved in
CH2Cl2 (10 mL) in a Pyrex tube with a screw cap. A solution of
dry m-CPBA (3.31 g, 15 mmol) in CH2Cl2 (10 mL) in the presence
of MgSO4 was added. The reaction mixture was stirred at room
temperature for 40 h, then it was washed with Na2CO3 (saturated
aq.; 12 mL) and water. The organic phase was dried with MgSO4,
filtered, and concentrated to dryness. The residue was purified by
flash chromatography (SiO2 35–70 μm; CH2Cl2/EtOAc, 100:0 to
50:50) to gve compound 7 (1.51 g, 72%) as a colourless oil. 31P
16.46 (d, 3JC,P = 5.8 Hz), 28.98 (d, 1JC,P = 120.1 Hz), 62.72 (d, 2JC,P
= 6.7 Hz), 69.97 (d, 3JC,P = 7.3 Hz), 70.11 (d, 2JC,P = 6.1 Hz), 73.71,
83.85 (d, JC,P = 6.3 Hz), 127.76, 127.90, 128.51, 137.55 ppm.
2
Data for 9b: P(S),3C(R),4C(R). 31P NMR (161.97 MHz, CDCl3): δ
1
= 44.36 ppm. H NMR (400.13 MHz, CDCl3): δ = 1.19 (t, 3JH,H
=
7.1 Hz, 3 H), 2.03 (ddd, 2JP,H = 15.4, 2JH,H = 15.1, 3JH,H = 6.8 Hz,
1 H), 2.24 (ddd, JH,H = 15.1, JP,H = 13.3, JH,H = 6.8 Hz, 1 H),
2
2
3
3.54–3.70 (m, 2 H), 3.92–4.13 (m, 2 H), 4.25–4.33 (m, 1 H), 4.33–
4.41 (m, 1 H), 4.47 and 4.49 (2JH,H = 12.0 Hz, 2 H), 7.13–7.32 (m,
3
5 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 16.37 (d, JC,P
=
NMR (161.97 MHz, CDCl3):
δ =
26.63 ppm. 1H NMR
5.9 Hz), 29.21 (d, 1JC,P = 119.0 Hz), 62.81 (d, 2JC,P = 6.6 Hz), 69.54
(d, JC,P = 7.9 Hz), 69.72 (d, JC,P = 4.3 Hz), 73.53, 84.13 (d, JC,P
(400.13 MHz, CDCl3): δ = 1.25 (t, 3JH,H = 7.1 Hz, 6 H), 1.91 (ddd,
3
2
2
2
2
2
3JH,H = 6.4, JH,H = 15.4, JP,H = 19.8 Hz, 1 H), 2.07 (ddd, JP,H
= 5.8 Hz), 127.62, 127.82, 128.43, 137.69 ppm.
2
3
= 19.2, JH,H = 15.4, JH,H = 6.2 Hz, 1 H), 3.12–3.27 (m, 2 H),
3.44 (dd, 2JH,H = 11.4, 3JH,H = 6.3 Hz, 1 H), 3.74 (dd, 2JH,H = 11.4,
(unlike)-(؎)-(4S,5R)-5-Benzyloxymethyl-2-ethoxy-4-hydroxy-2-oxo-
2-phosphatetrahydrofurans (9c–9d): Under nitrogen, PTSA (114 mg,
0.6 mmol, 0.2 equiv.) was added to a solution of 8 (0.93 g,
2.8 mmol, 1 equiv.) in toluene (38 mL). The reaction mixture was
stirred at reflux for 21 h, and then it was concentrated to dryness.
The residue was purified by flash chromatography (SiO2 35–70 μm;
EtOAc/EtOH, 100:0 to 95:5) to give compound 9c (Ϯ)-
P(S),3 C(S),4 C(R) (0.25 g, 31 %) and compound 9d (Ϯ)-
P(R),3C(S),4C(R) (0.09 g, 11%). HRMS (ESI): calcd. for the mix-
ture (9c and 9d) C13H20O5P [M + H]+ 287.1048; found 287.1053.
3JH,H = 3.8 Hz, 1 H), 3.97–4.15 (m, 4 H), 4.47 and 4.56 (2JH,H
=
11.9 Hz, 2 H), 7.19–7.30 (m, 5 H) ppm. 13C NMR (100.61 MHz,
3
1
CDCl3): δ = 16.43 (d, JC,P = 5.9 Hz), 26.19 (d, JC,P = 139.8 Hz),
50.36 (d, JC,P = 1.5 Hz), 55.14 (d, JC,P = 7.3 Hz), 62.02 (d, JC,P
= 5.9 Hz), 62.06 (d, JC,P = 6.6 Hz), 68.00, 73.38, 127.30, 127.87,
2
3
2
2
128.47, 137.67 ppm. HRMS (ESI): calcd. for C15H23O5P 315.1361;
found 315.1350.
(unlike)-(؎)-Diethyl (2S,3R)-4-(Benzyloxy)-2,3-dihydroxybutylphos-
phonate (8): H2SO4 (1 m aq.; 1 mL) was added to a solution of 7
(1.51 g, 4.8 mmol) in THF (30 mL). The mixture was stirred at
50 °C for 7 h. After the starting material had been completely con-
sumed (31P NMR), NaOH (1 m aq.; 1.8 mL) was added. The solu-
tion was concentrated to dryness, and CH2Cl2 was added to the
residue. The mixture was filtered, then the filtrate was dried with
MgSO4, filtered, and concentrated to dryness. The residue was
purified by flash chromatography (SiO2 35–70 μm; CH2Cl2/EtOAc,
100:0 to 50:50) to give compound 8 (0.93 g, 58%) as a colourless
oil. 31P NMR (161.97 MHz, CDCl3): δ = 30.47 ppm. 1H NMR
(400.13 MHz, CDCl3): δ = 1.33 (t, 3JH,H = 7.1 Hz, 6 H), 1.97 (ddd,
Data for 9c: P(S),3C(S),4C(R). 31P NMR (161.97 MHz, CDCl3): δ
1
= 46.02 ppm. H NMR (400.13 MHz, CDCl3): δ = 1.24 (t, 3JH,H
=
7.1 Hz, 3 H), 2.00 (ddd, 2JH,H = 15.6, 2JP,H = 11.7, 3JH,H = 2.7 Hz,
1 H), 2.08 (ddd, JP,H = 15.8, JH,H = 15.6, JH,H = 5.9 Hz, 1 H),
2
2
3
3
3.76 (d, JH,H = 5.2 Hz, 2 H), 3.84 (s, 1 H), 4.10 and 4.12 (2 dq,
3JP,H = 9.3, JH,H = 3.7 Hz, 2 H), 4.35 (tt, JH,H = 5.2, JH,H
=
3
3
3
3JP,H = 3.7 Hz, 1 H), 4.50 and 4.52 (AB system, JH,H = 11.9 Hz,
2 H), 4.46–4.58 (m, 1 H), 7.14–7.32 (m, 5 H) ppm. 13C NMR
(100.61 MHz, CDCl3): δ = 16.43 (d, 3JC,P = 5.7 Hz), 29.87 (d, 1JC,P
2
2
3
= 119.7 Hz), 63.34 (d, JC,P = 6.6 Hz), 68.74 (d, JC,P = 8.2 Hz),
69.74 (d, JC,P = 2.0 Hz), 73.71, 80.94 (d, JC,P = 9.3 Hz), 127.78,
2
2
2
3
2
2JP,H = 19.4, JH,H = 15.3, JH,H = 3.9 Hz, 1 H), 2.04 (ddd, JP,H
= 16.5, 2JH,H = 15.3, 3JH,H = 9.0 Hz, 1 H), 3.18 (d, 3JH,H = 6.3 Hz,
1 H), 3.52 (dd, JH,H = 9.6, JH,H = 5.8 Hz, 1 H), 3.55 (dd, JH,H
= 9.6, JH,H = 4.5 Hz, 1 H), 3.61–3.68 (m, 1 H), 3.74 (d, JH,H
128.00, 128.53, 137.40 ppm.
2
3
2
Data for 9d: P(R),3C(S),4C(R). 31P NMR (161.97 MHz, CDCl3): δ
3
3
1
= 45.53 ppm. H NMR (400.13 MHz, CDCl3): δ = 1.26 (t, 3JH,H
=
=
=
2
7.1 Hz, 3 H), 2.06 (ddd, 2JP,H = 15.3, 2JH,H = 15.3, 3JH,H = 6.0 Hz,
1 H), 2.13 (ddd, JH,H = 15.3, JP,H = 12.7, JH,H = 3.4 Hz, 1 H),
4.3 Hz, 1 H), 3.97–4.15 (m, 5 H), 4.47 and 4.49 (dd, JH,H
11.9 Hz, 2 H), 7.36–7.66 (m, 5 H) ppm. 13C NMR (100.61 MHz,
2
2
3
3
1
2
3
4
CDCl3): δ = 16.36 and 16.42 (2 d, JC,P = 6.2 Hz), 30.12 (d, JC,P
= 139.7 Hz), 61.94 and 62.02 (2 d, JC,P = 6.3 Hz), 67.13 (d, JC,P
= 4.4 Hz), 71.70, 72.61 (d, JC,P = 14.4 Hz), 73.55, 127.77, 127.80,
3.79 (ddd, JH,H = 10.8, JH,H = 4.5, JP,H = 0.8 Hz, 1 H), 3.81
2
2
(ddd, 2JH,H = 10.8, 3JH,H = 5.4, 4JP,H = 0.2 Hz, 1 H), 4.04–4.15 (m,
3
3
3
3
3
2 H), 4.23 (dddd, JH,H = 5.4, JH,H = 4.5, JH,H = 3.8, JP,H
=
2.8 Hz, 1 H), 4.50 (ddd, 3JP,H = 24.7, 3JH,H = 6.0, 3JH,H = 3.4 Hz, 1
128.44, 137.83 ppm. HRMS (ESI): calcd. for C16H26O6P 333.1467;
found 333.1464.
H), 4.54 (s, 2 H), 7.20–7.37 (m, 5 H) ppm. 13C NMR (100.61 MHz,
3
1
CDCl3): δ = 16.43 (d, JC,P = 5.7 Hz), 29.87 (d, JC,P = 119.7 Hz),
63.34 (d, JC,P = 6.6 Hz), 68.74 (d, JC,P = 8.2 Hz), 69.74 (d, JC,P
= 2.0 Hz), 73.71, 80.94 (d, JC,P = 9.3 Hz), 127.78, 128.00, 128.53,
(like)-(؎)-(4R,5R)-5-Benzyloxymethyl-2-ethoxy-4-hydroxy-2-oxo-2-
phosphatetrahydrofurans (9a–9b): Under nitrogen, PTSA (149 mg,
0.9 mmol) was added to a solution of 6 (1.21 g, 3.6 mmol) in tolu-
ene (49 mL). The mixture was heated at reflux for 18 h, then it was
concentrated to dryness. The residue was purified by flash
chromatography (SiO2 35–70 μm; EtOAc/EtOH, 100:0 to 95:5) to
give diastereomer 9a (Ϯ)-P(R),3C(R),4C(R) (0.10 g, 10%), dia-
stereomer 9b (Ϯ)-P(S),3C(R),4C(R) (0.21 g, 21%), and a mixture of
9a and 9b (0.22 g, 21%). HRMS (ESI): calcd. for the mixture (9a
and 9b) C13H20O5P 287.1048; found 287.1055.
2
3
2
2
137.40 ppm.
General Procedure for Deprotection of the Benzyl Group by Cata-
lytic Hydrogenation: In a Schlenk tube, Pd (10% on C; 10–20 wt-
%) was added to a solution of 9a–9d (1.0 equiv.) in ethanol (0.5–
0.6 mmol/mL). The mixture was degassed twice under vacuum, re-
filling each time with hydrogen. The reaction mixture was stirred
at room temperature for 24–48 h. Then the mixture was filtered,
and the filtrate was concentrated to dryness.
Data for 9a: P(R),3C(R),4C(R). 31P NMR (161.97 MHz, CDCl3): δ
1
= 44.47 ppm. H NMR (400.13 MHz, CDCl3): δ = 1.34 (t, 3JH,H
=
(؎)-2-Ethoxy-4-hydroxy-5-hydroxymethyl-2-oxo-2-phosphatetra-
7.1 Hz, 3 H), 1.94 (ddd, 2JP, H = 2JH,H = 15.2, 3JH,H = 5.9 Hz, 1 H), hydrofuran (4a): From 9a (57 mg, 0.20 mmol) with Pd (10% on C;
2.35 (ddd, 2JH,H = 15.2, 2JP, H = 13.8, 3JH,H = 7.4 Hz, 1 H), 3.68 (d, 20 wt-%) in ethanol (1 mL) for 48 h, 4a (28 mg, 72%) was obtained
3
3JH,H = 4.6 Hz, 2 H), 4.01 (d, JH,H = 4.6 Hz, 1 H), 4.11–4.30 (m, as a colourless oil. P(R),3C(R),4C(R). 31P NMR (161.97 MHz,
2
1
3 H), 4.35–4.47 (m, 1 H), 4.54 and 4.60 (2 d, JH,H = –12.0 Hz, 2
CDCl3): δ = 44.34 ppm. H NMR (400.13 MHz, CDCl3): δ = 1.27
H), 7.23–7.44 (m, 5 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = (t, 3JH,H = 7.1 Hz, 3 H), 2.03 (ddd, 2JP,H = 16.4, 2JH,H = 15.1, 3JH,H
1336
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1333–1337

Synthesis of Unnatural Phosphonosugar Analogues
2
2
3
= 7.4 Hz, 1 H), 2.29 (ddd, JH,H = 15.1, JP,H = 12.7, JH,H
=
at 80 °C for 18 h, then the liquid was removed in vacuo and water
(0.5 mL) was added to the residue. The residue was purified by
2
3
4
7.1 Hz, 1 H), 3.67 (ddd, JH,H = 12.4, JH,H = 5.0, JP,H = 0.9 Hz,
2
3
3
1 H), 3.77 (dd, JH,H = 12.4, JH,H = 3.8 Hz, 1 H), 4.09 (dq, JP,H flash chromatography (C18 40–70 μm; water 100%) to give com-
3
3
3
3
= 8.9, JH,H = 7.1 Hz, 2 H), 4.23 (dddd, JP,H = 8.7, JH,H = 5.9,
pound 10 (5 mg, 29%) as a colourless oil. C(S),4C(R). 31P NMR
3JH,H = 5.0, JH,H = 3.8 Hz, 1 H), 4.36 (dddd, JP,H = 11.6, JH,H
(161.97 MHz, D2O): δ = 36.56 ppm. 1H NMR (400.13 MHz, D2O):
3
3
3
= 7.4, JH,H = 7.1, JH,H = 5.9 Hz, 1 H) ppm. 13 C NMR
δ = 1.65 (ddd, JP,H = 17.7, JH,H = 14.2, JH,H = 9.1 Hz, 1 H),
3
3
2
2
3
(100.61 MHz, CDCl3): δ = 16.44 (d, 3JC,P = 5.7 Hz), 29.21 (d, 1JC,P
2.14 (ddd, JH,H = 14.2, JP,H = 11.0, JH,H = 7.6 Hz, 1 H), 3.56
2
2
3
3
2
2
3
2
= 119.2 Hz), 62.20 (d, JC,P = 4.6 Hz), 63.16 (d, JC,P = 6.5 Hz),
68.91 (d, JC,P = 8.5 Hz), 85.69 (d, JC,P = 4.9 Hz) ppm. HRMS
(ESI): calcd. for C6H14O5P 197.0579; found 197.0595.
(dd, JH,H = 12.5, JH,H = 6.2 Hz, 1 H), 3.75 (dd, JH,H = 12.5,
2
2
3
3JH,H = 2.8 Hz, 1 H), 3.80–3.87 (m, 1 H), 4.16 (dddd, JH,H = 9.1,
3JH,H
=
3JP,H = 7.6, JH,H = 5.6 Hz, 1 H) ppm. 13C NMR
3
(100.61 MHz, D2O): δ = 29.77 (d, 1JC,P = 109.9 Hz), 61.68 (d, 3JC,P
= 6.6 Hz), 68.34 (d, 2JC,P = 10.1 Hz), 82.34 (d, 2JC,P = 3.5 Hz) ppm.
HRMS (ESI): calcd. for C4H10O5P 169.0266; found 169.0269.
(؎)-2-Ethoxy-4-hydroxy-5-hydroxymethyl-2-oxo-2-phosphatetra-
hydrofuran (4b): From 9b (140 mg, 0.49 mmol) with Pd (10% on C;
20 wt-%) in ethanol (1 mL) for 48 h, 4b (75 mg, 78%) was obtained
as a colourless oil. P(S),3C(R),4C(R). 31P NMR (161.97 MHz,
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra and HR mass spectra for all new
compounds.
1
CDCl3): δ = 45.36 ppm. H NMR (400.13 MHz, CDCl3): δ = 1.29
(t, 3JH,H = 7.1 Hz, 3 H), 1.92 (ddd, 2JP,H = 16.2, 2JH,H = 15.1, 3JH,H
2
2
3
= 6.6 Hz, 1 H), 2.35 (ddd, JH,H = 15.1, JP,H = 13.2, JH,H
=
2
3
4
7.0 Hz, 1 H), 3.70 (ddd, JH,H = 12.7, JH,H = 3.3, JP,H = 1.9 Hz,
2
3
Acknowledgments
1 H), 3.79 (dd, JH,H = 12.7, JH,H = 3.0 Hz, 1 H), 4.03 (dddd,
3JH,H = 6.3, JP,H = 6.2, JH,H = 3.3, JH,H = 3.0 Hz, 1 H), 4.09
3
3
3
3
3
3
This research was supported in part by grants from Idenix Pharma-
ceuticals, Montpellier, France (IDENIX) and from the Agence Na-
tionale de la Recherche et de la Technologie (ANRT).
(dq, JP,H = 8.9, JH,H = 7.1 Hz, 2 H), 4.48 (dddd, JP,H = 12.9,
3JH,H = 7.0, JH,H = 6.6, JH,H = 6.3 Hz, 1 H), 5.13 (s, 1 H) ppm.
3
3
13C NMR (100.61 MHz, CDCl3): δ = 16.38 (d, JC,P = 5.9 Hz),
3
1
3
29.06 (d, JC,P = 119.4 Hz), 61.13 (d, JC,P = 5.8 Hz), 63.02 (d,
2JC,P = 6.6 Hz), 67.95 (d, JC,P = 8.2 Hz), 85.82 (d, JC,P = 5.2 Hz)
2
2
[1] a) G. A. Patani, E. J. LaVoie, Chem. Rev. 1996, 96, 3147–3176;
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ppm. HRMS (ESI): calcd. for C6H14O5P 197.0579; found 197.0589.
(؎)-2-Ethoxy-4-hydroxy-5-hydroxymethyl-2-oxo-2-phosphatetra-
hydrofuran (4c): From 9c (60 mg, 0.21 mmol) with Pd (10% on C;
10 wt-%) in ethanol (1 mL) for 24 h, 4c (23 mg, 56%) was obtained
as a colourless oil. P(R),3C(S),4C(R). 31P NMR (161.97 MHz,
1
CDCl3): δ = 46.82 ppm. H NMR (400.13 MHz, CDCl3): δ = 1.39
(td, 3JH,H = 7.1, 4JP,H = 0.4 Hz, 3 H), 2.06 (ddd, 2JH,H = 15.7, 2JP,H
= 11.5, 3JH,H = 2.5 Hz, 1 H), 2.16 (ddd, JP,H = 15.9, JH,H = 15.7,
2
2
3JH,H = 6.0 Hz, 1 H), 3.89 (d, JH,H = 5.3 Hz, 1 H), 4.16 (dqd,
3
2JH,H = 9.1, JH,H = 7.1, JP,H = 1.2 Hz, 1 H), 4.29 (ddd, JH,H
=
3
3
3
3
3
3
5.3, JH,H = 3.6, JP,H = 3.4 Hz, 1 H), 4.62 (dddd, JP,H = 28.1,
3JH,H = 6.0, JH,H = 3.6, JH,H = 2.5 Hz, 1 H) ppm. 13C NMR
3
3
(100.61 MHz, CDCl3): δ = 16.37 (d, 3JC,P = 5.7 Hz), 29.83 (d, 1JC,P
3
2
= 119.9 Hz), 61.08 (d, JC,P = 8.2 Hz), 63.70 (d, JC,P = 6.6 Hz),
69.81 (d, JC,P = 1.9 Hz), 81.85 (d, JC,P = 8.7 Hz) ppm. HRMS
(ESI): calcd. for C6H14O5P 197.0579; found 197.0579.
2
2
(؎)-2-Ethoxy-4-hydroxy-5-hydroxymethyl-2-oxo-2-phosphatetra-
hydrofuran (4d): From 9d (240 mg, 0.84 mmol) with Pd (10% on C;
10 wt-%) in ethanol (2 mL) for 24 h, 4d (156 mg, 95%) was ob-
tained as a colourless oil. P(S),3 C(S),4 C(R). 3 1 P NMR
(161.97 MHz, CDCl3): δ = 47.40 ppm. 1H NMR (400.13 MHz,
CDCl3): δ = 1.30 (t, JH,H = 7.1 Hz, 3 H), 2.05 (ddd, 2JH,H = 15.4,
3
2JP,H = 15.2, JH,H = 6.0 Hz, 1 H), 2.11 (ddd, JH,H = 15.4, JP,H
3
2
2
= 12.5, 3JH,H = 3.4 Hz, 1 H), 3.88 (dd, 2JH,H = 12.4, 3JH,H = 4.7 Hz,
[5] R. M. Archer, S. F. Royer, W. Mahy, C. L. Winn, M. J. Danson,
S. D. Bull, Chem. Eur. J. 2013, 19, 2895–2902.
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Chem. 1997, 62, 3332–3339.
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415–430; b) H.-J. Cristau, D. Virieux, P. Mouchet, A. Fruchier,
Eur. J. Org. Chem. 1999, 1561–1569.
2
3
1 H), 3.90 (dd, JH,H = 12.4, JH,H = 5.5 Hz, 1 H), 3.92–4.13 (m,
2 H), 4.16 (dddd, JH,H = 5.5, JH,H = 4.7, JH,H = 3.7, JP,H
3
3
3
3
=
3
3
3
3.5 Hz, 1 H), 4.60 (dddd, JP,H = 25.3, JH,H = 6.0, JH,H = 3.7,
3JH,H = 3.4 Hz, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ =
3
1
16.44 (d, JC,P = 6.0 Hz), 29.88 (d, JC,P = 121.5 Hz), 60.77 (d,
3JC,P = 8.6 Hz), 62.72 (d, 2JC,P = 6.7 Hz), 69.12 (d, 2JC,P = 2.4 Hz),
82.47 (d, JC,P = 7.4 Hz) ppm. HRMS (ESI): calcd. for C6H14O5P
2
[9] C. Mukai, S. Hirai, M. Hanaoka, J. Org. Chem. 1997, 62,
6619–6626.
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M. Sandri, Tetrahedron: Asymmetry 2007, 18, 562–568.
Received: October 10, 2013
197.0579; found 197.0572.
(؎)-4-Hydroxy-5-hydroxymethyl-2-oxo-2-phosphatetrahydrofuran
Lithium Salt (10): In a Schlenk tube, anhydrous lithium bromide
(18 mg, 0.025 mmol) was added to a solution of 4a and 4b (20 mg,
0.1 mmol) in acetonitrile (1.5 mL). The reaction mixture was stirred
Published Online: December 12, 2013
Eur. J. Org. Chem. 2014, 1333–1337
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1337