T. Haemers, J. Wiesner, R. Busson, H. Jomaa, S. Van Calenbergh
FULL PAPER
2
2
62.59 (d, JC,P = 7.2 Hz, OCH2CH3), 63.09 (d, JC,P = 6.9 Hz, (OCH2CH3), 62.15 (OCH2CH3), 156.49 (C=O, major), 162.37
OCH2CH3), 78.29 (OCH2Ph), 128.86 (arom. C), 128.95 (arom. C), (C=O, minor) ppm. Exact mass (ESI-MS): calculated for
129.94 (arom. C), 129.69 (arom. C), 130.81 (arom. C), 131.24
(arom. C), 131.92 (arom. C), 132.93 (arom. C), 134.27 (arom. C),
135.87 (arom. C), 163.32 (m, HC=O) ppm. Exact mass (ESI-MS):
calculated for C21H27Cl2NO5P [M+H]+ 474.1004; found 474.1000.
C10H21NO5P [M+H]+ 266.1158; found 266.1131.
Diethyl [3-(N-Hydroxyformamido)cyclopentyl]phosphonate (trans-
1
22): Yield: 170 mg (35%). H NMR (300 MHz, CDCl3): δ = 1.18
(t, J = 7.0 Hz, 3 H, OCH2CH3), 1.18 (t, J = 6.8 Hz, 3 H,
OCH2CH3), 1.75–2.08 (m, 7 H, C5H7P), 3.95 (m, 4 H, OCH2CH3),
4.68 (s, 1 H, CHNOH), 7.80 (s, 1 H, HC=O, minor), 8.17 (s, 1 H,
HC=O, major), 9.78 (br. s, 1 H, NOH) ppm. 13C NMR (75 MHz,
Diethyl {3-[N-(Benzyloxy)formamido]cyclopentyl}phosphonate (20):
Yield: 1.3 g, mixture of cis and trans (97%). H NMR (300 MHz,
1
CDCl3): δ = 1.23 (m, 6 H, OCH2CH3), 1.64–2.39 (m, 7 H, C5H7P),
3.98–4.09 (m, 4 H, OCH2CH3), 4.4 (m, 1 H, CHN), 4.90 (br. s, 2
H, OCH2Ph), 7.30–7.32 (m, 5 H, arom. H), 8.10 and 8.13 (2×s, 1
3
CDCl3): δ = 16.60 (d, JC,P = 5.5 Hz, OCH2CH3), 25.25 (CH2),
28.08 (d, JC,P = 10.4 Hz, CH2, major), 28.83 (d, JC,P = 11.2 Hz,
H, HC=O) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.76 (d, JC,P
3
CH2, minor), 29.4 (s, CH2, major), 30.07 (CH2, minor), 33.41 (d,
1
1JC,P = 148.3 Hz, CHP, major), 34.22 (d, JC,P = 150.0 Hz, CHP,
= 5.8 Hz, 2 C, OCH2CH3), 24.40 (d, JC,P = 2.0 Hz, CH2), 25.60
3
3
1
minor), 55.44 (d, JC,P = 15.8 Hz, CHN, major), 60.50 (d, JC,P
=
(CH2), 29.98 (d, JC,P = 7.8 Hz, CH2), 33.31 (d, JC,P = 150.6 Hz,
1
18.1 Hz, CHN, minor), 62.10–62.47 (m, 2C, OCH2CH3), 156.43
(C=O, minor), 162.48 (C=O, major) ppm. Exact mass (ESI-MS):
calculated for C10H21NO5P [M+H]+ 266.1158; found 266.1143.
CHP), 33.66 (d, JC,P = 149.7 Hz, CHP), 57.73 (m, CHN), 59.03
(m, CHN), 62.01 (m, OCH2CH3), 79.50 (m, OCH2Ph), 128.95–
129.63 (3 arom. C), 134.72 (arom. C), 165.10 (m, HC=O) ppm.
Exact mass (ESI-MS): calculated for C17H27NO5P [M+H]+
356.1627; found 356.1629.
General Method for the Phosphonate Deprotection: Esters 14, 15,
22 or 23 (0.84 mmol) were dissolved in CH2Cl2 (10 mL) and treated
dropwise with TMSBr (3.36 mmol, 0.50 g) under N2. The reaction
mixture was stirred at room temperature for 2 h. After completion
of the reaction, the volatile compounds were removed in vacuo to
give the corresponding phosphonic acids in almost quantitative
yield. All final compounds were purified using a preparative HPLC
General Method for the Benzyl Deprotection of 12, 13, 20 and 21:
A solution of compounds 12 and 13 or 20 and 21 (0.9 mmol) in
MeOH (8 mL) was hydrogenated at atmospheric pressure in the
presence of Pd (10 wt.-% on activated carbon, 40 mg). After stir-
ring for 5 h, the reaction mixture was filtered through a Celite pad.
The solvent was removed under vacuum, and the crude mixture
was purified by column chromatography on silica gel (CH2Cl2/
MeOH, 95:5).
system on
a
C18 column (5 µm; Phenomenex; Luna;
250×21.2 mm) with a linear gradient of acetonitrile (0Ǟ100%) in
5 m NH4OAc solution at a flow rate of 17.5 mL/min over 20 min.
The purity of all target compounds was assessed by analytical
HPLC [5 µm; Phenomenex; C18(2), 250×4.6 mm] using the same
gradient at a flow rate of 1 mL/min. All final compounds were
obtained as hygroscopic powders after lyophilisation. All powders
were white, except the five-membered cyclic analogues which were
obtained as orange powders.
Diethyl
[1-(3,4-Dichlorophenyl)-3-(N-hydroxyformamido)propyl]-
phosphonate (14e): Yield: 157 mg (57%). 1H NMR (300 MHz,
CDCl3): δ = 1.09–1.24 (m, 6 H, OCH2CH3), 2.11 (m, 1 H,
CH2CHP), 2.46 (m, 1 H, CH2CHP), 3.01–3.17 (m, 1 H, CHP),
3.22–3.35 (m, 1 H, CH2N), 3.45–3.56 (m, 1 H, CH2N), 3.77–4.04
(m, 4 H, OCH2CH3), 7.08–7.11 (m, 1 H, arom. H), 7.32–7.37 (m,
2 H, arom. H), 7.55 (br. s, 1 H, HC=O), 8.24 (s, 1 H, NOH) ppm.
[1-(3,4-Dichlorophenyl)-3-(N-hydroxyformamido)propyl]phosphonic
Acid (1e): 1H NMR (300 MHz, D2O): δ = 1.93–2.15 (m, 1 H, β-
CH), 2.24–2.38 (m, 1 H, β-CH), 2.73–2.87 (m, 1 H, α-CH), 3.17–
3.47 (m, 2 H, γ-CH2), 7.07–7.12 (m, 1 H, arom. H), 7.33–7.39 (m,
2 H, arom. H), 7.44 and 8.07 (2×s, 1 H, HC=O) ppm. 13C NMR
13C NMR (75 MHz, CDCl3): δ = 16.48 (app. t, JC,P = 5.8 Hz,
3
OCH2CH3), 26.90 (CH2CHP, major), 27.08 (CH2CHP, minor),
40.09 (d, 1JC,P = 139.3 Hz, CHP, major), 40.96 (d, 1JC,P = 139.3 Hz,
3
CHP, minor), 44.60 (d, JC,P = 15.8 Hz, NCH2, minor), 47.45 (d,
1
3JC,P
=
15.0 Hz, NCH2, major), 62.84 (d, JC,P
=
6.9 Hz,
2
(75 MHz, D2O): δ = 26.49 (s, β-CH2), 42.82 (d, JC,P = 129.6 Hz,
2
α-CH), 48.86 (d, 3JC,P = 17.0 Hz, γ-CH2), 128.92 (d, JC,P = 5.8 Hz,
OCH2CH3, major), 63.01 (d, JC,P = 7.2 Hz, OCH2CH3, minor),
2
2
arom. C), 130.04 (d, JC,P = 3.8 Hz, arom. C), 130.55 (d, JC,P =
63.24 (d, JC,P = 6.9 Hz, OCH2CH3, major), 63.32 (d, JC,P
=
2.6 Hz, arom. C), 130.73 (d, JC,P = 6.0 Hz, arom. C), 131.88 (d,
JC,P = 3.2 Hz, arom. C), 138.80 (d, JC,P = 7.2 Hz, arom. C), 159.70
(C=O, major) and 163.76 (C=O, minor) ppm. 31P NMR (121 MHz,
D2O): δ = 21.46, 21.78 (major and minor isomers) ppm. Exact mass
(ESI-MS): calculated for C10H11Cl2NO5P [M–H]– 325.9751; found
325.9745.
6.1 Hz, OCH2CH3, minor), 128.81 (d, JC,P = 6.3 Hz, arom. C,
major), 128.95 (d, JC,P = 6.9 Hz, arom. C, minor), 130.69 (arom.
C, minor), 130.91 (arom. C, major), 131.14 (d, JC,P = 6.9 Hz, arom.
C, major), 131.24 (d, JC,P = 9.2 Hz, arom. C, minor), 131.74 (d,
JC,P = 3.8 Hz, arom. C, minor), 131.98 (d, JC,P = 3.8 Hz, arom. C,
major), 132.70 (d, JC,P = 2.6 Hz, arom. C, minor), 133.01 (d, JC,P
= 2.6 Hz, arom. C, major), 135.60 (d, JC,P = 7.2 Hz, arom. C,
major), 136.00 (d, JC,P = 7.5 Hz, arom. C, minor), 157.37 (C=O,
major), 163.03 (C=O, minor) ppm. Exact mass (ESI-MS): calcu-
lated for C14H21Cl2NO5P [M+H]+ 384.0535; found 384.0530.
[(1R,3R)-3-(N-Hydroxyformamido)cyclopentyl]phosphonic Acid and
[(1S,3S)-3-(N-Hydroxyformamido)cyclopentyl]phosphonic
Acid
(trans-3): 1H NMR (300 MHz, D2O): δ = 1.73–2.04 (m, 7 H, α-CH
and CH2), 4.13 (br. s, 1 H, NCH), 7.84, 8.07 (2×s, 1 H, major and
minor HC=O) ppm. 13C NMR (75 MHz, D2O): δ = 25.55 (d, JC,P
= 1.2 Hz, CH2), 28.56 (d, JC,P = 10.4 Hz, CH2), 31.10 (s, CH2),
35.94 (d, 1JC,P = 141.7 Hz, α-CH), 61.46 (d, JC,P = 17.3 Hz, NCH),
159.23 (C=O) ppm. 31P NMR (121 MHz, D2O): δ = 27.71, 27.91
(major and minor isomers) ppm. Exact mass (ESI-MS): calculated
for C6H11NO5P [M–H]– 208.0374; found 208.0366.
Diethyl [3-(N-Hydroxyformamido)cyclopentyl]phosphonate (cis-22):
1
Yield: 90 mg (19%). H NMR (300 MHz, CDCl3): δ = 1.26 (m, 6
H, OCH2CH3), 1.75–2.42 (m, 7 H, C5H7P), 4.03–4.22 (m, 4 H,
OCH2CH3), 4.83 (s, 1 H, CHNOH), 7.88 (s, 1 H, HC=O), 8.25 (s,
1 H, HC=O), 9.70 (s, 1 H, NOH) ppm. 13C NMR (75 MHz,
3
CDCl3): δ = 16.65 (d, JC,P = 5.8 Hz, OCH2CH3), 26.15 (CH2,
major), 26.66 (CH2, minor), 29.21 (d, JC,P = 12.7 Hz, CH2, minor),
29.81 (d, JC,P = 11.5 Hz, CH2, major), 29.81 (CH2, minor), 30.44
[(1R,3S)-3-(N-Hydroxyformamido)cyclopentyl]phosphonic Acid and
[(1S,3R)-3-(N-Hydroxyformamido)cyclopentyl]phosphonic Acid (cis-
3): H NMR (300 MHz, D2O): δ = 1.49–2.17 (m, 7 H, α-CH and
1
1
(CH2, major), 33,54 (d, JC,P = 148.3 Hz, CHP, major), 35,51 (d,
3
1JC,P = 148.9 Hz, CHP, minor), 55.08 (d, JC,P = 12.7 Hz, CHN,
CH2), 4.21 (br. m, 1 H, NCH), 7.88, 8.09 (2×s, 1 H, major and
3
major), 60.19 (d, JC,P
= 11.5 Hz, CHN, minor), 62.05
minor HC=O) ppm. 13C NMR (75 MHz, D2O): δ = 26.73 (d, JC,P
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Eur. J. Org. Chem. 2006, 3856–3863