A novel synthesis of diethyl (R)-3-(N-benzyloxyamino)-2- hydroxypropylphosphonate, a precursor to hydroxylamine antibiotics FR-33289 and FR-33699

Article abstract of DOI:10.1016/j.tetasy.2004.08.003

Regioselective opening of the oxirane ring at C(3) of diethyl 2,3-epoxypropylphosphonate 6 with N- or O-benzylhydroxylamine led to 3-(N-benzyl-N-hydroxyamino)- or 3-(N-benzyloxyamino)-2- hydroxypropylphosphonates, 10 or 8. From (S)-6 (ee 94%), the phosphonate (S)-10 (ee 98%) was prepared in 80% yield. Highly enantiomerically enriched (R)- and (S)-8 (ee 97%) were obtained from (R)- and (S)-6 (ee 88% and 94%), respectively.

Full text of DOI:10.1016/j.tetasy.2004.08.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3201–3205
A novel synthesis of diethyl (R)-3-(N-benzyloxyamino)-
2-hydroxypropylphosphonate, a precursor to hydroxylamine
antibiotics FR-33289and FR-33699
*
Andrzej E. Wroblewski and Anetta Hałajewska-Wosik
´
´ ´ ´ ´ ´
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łodz, 90-151 Łodz, Muszynskiego 1, Poland
Received 7 July 2004; accepted 9 August 2004
Available online 2October 2004
Abstract—Regioselective opening of the oxirane ring at C(3) of diethyl 2,3-epoxypropylphosphonate 6 with N- or O-benzylhydroxyl-
amine led to 3-(N-benzyl-N-hydroxyamino)- or 3-(N-benzyloxyamino)-2-hydroxypropylphosphonates, 10 or 8. From (S)-6 (ee 94%),
the phosphonate (S)-10 (ee 98%) was prepared in 80% yield. Highly enantiomerically enriched (R)- and (S)-8 (ee 97%) were obtained
from (R)- and (S)-6 (ee 88% and 94%), respectively.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ylphosphonate11 (R)-5 as a starting material.9,10 Ana-
logues of 1–4 have also been prepared.12 The key step
in syntheses of the phosphonates 1–4 is the introduction
of the hydroxylamino group at C(3) by nucleophilic dis-
placement with a suitably protected hydroxylamine
derivatives,6,8–10 by the Mitsunobu reaction12 or by the
reductive amination5 (Scheme 1).
A series of propylphosphonates 1–4, which contain an
unusual N-acylated hydroxylamine substituent at C(3),
has been isolated from broths of strains of Streptomyces
over 25years ago.1–3 Their high antibacterial activity has
been recognized first, but later on it appeared that 1 and
2 also exhibit antimalarial activity.4 Several prodrugs of
1 and 2 have recently been reported.5,6
R
OH
N
R'
P(O)(OH)2
Structural assignments in the phosphonates 1–4 were
based on spectroscopic studies7 and finally proved by
chemical synthesis.8–10 The (R)-configuration in 3 and
4 was established using diethyl (R)-2,3-dihydroxyprop-
O
1 - 4
R
R
O
R
L.G.
P(O)(OR'')2
HO
P(O)(OR'')2
P(O)(OR'')2
OH
H
R
N
P(O)(OH)2
5 R=OH
O
Scheme 1. The known strategies to the phosphonates 1–4; R = H, OH.
R=H FR-31564
1
R=Me FR-900098 2
Recently, we have elaborated the efficient approach to
highly enantiomerically enriched diethyl (S)-2,3-epoxy-
propylphosphonate, (S)-6 by a hydrolytic kinetic resolu-
tion (HKR)13 of the racemic epoxide 6.14,15 The
phosphonate (S)-6 has later been used in the synthesis
of the enantiomerically pure phosphonate analogues of
carnitine, (S)-7a15 and GABOB, (S)-7b16 (Scheme 2).
Herein we present the application of the epoxide 6 in
the synthesis of diethyl (R)-3-(N-benzyloxyamino)-2-
hydroxypropylphosphonate 8,5 a precursor to (R)-3
and (R)-4.
OH OH
R
N
P(O)(OH)2
O
R=H FR-33699 (R)-3
R=Me FR-33289 (R)-4
*
Corresponding author. Fax: +48 42678 83 98; e-mail: aewplld@
ich.pharm.am.lodz.pl
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.08.003

´
A. E. Wroblewski, A. Hałajewska-Wosik / Tetrahedron: Asymmetry 15 (2004) 3201–3205
3202
BnO
HN
HO
N
OH
OH
OH
O
+
P(O)(OH)O-
R
R3N
P(O)(OEt)2
PO3H2
P(O)(OEt)2
O
6
(R)-3 R=H
(R)-4 R=Me
(R)-8
(S)-7a R=Me
(S)-7b R=H
Scheme 2.
2. Results and discussion
ride in the presence of triethylamine in aqueous ethanol,
a mixture of diethyl 3-(N-benzyloxyamino)-2-hydroxy-
propylphosphonate 8, the chlorophosphonate 9 and bis-
phosphonates 13 (dl d 31P = 30.52and meso 30.44ppm)
in a 76:5:12:7 ratio, respectively, was obtained (Scheme
4). Chromatographic purification gave the phosphonate
8 in 56% yield.
In preliminary experiments opening of the oxirane ring
in the racemic phosphonate 6 with hydroxylamine
hydrochloride was studied. In the presence of triethyl-
amine or sodium bicarbonate in aqueous ethanol the
opening was complete at room temperature, but com-
plex reaction mixtures were formed. Trace amounts of
diethyl 3-chloro-2-hydroxypropylphosphonate15 9 were
separated by column chromatography from crude reac-
tion mixtures. In the nonpolar solvent CH2Cl2 in the
presence of triethylamine the reaction of the epoxyphos-
phonate 6 with hydroxylamine was incomplete even
after 3days at room temperature leaving an 82:18 mix-
ture of 9 and 6.
Under the same conditions, from (S)-6 (ee 94%) a
68:11:4:17 mixture of (S)-8, (R)-9 and (S,S)-13 contain-
ing unreacted starting epoxyphosphonate was formed.
After chromatographic purification (S)-8 (ee 97%) was
separated in 53% yield. Significant improvements in
transforming the epoxyphosphonate 6 into the phospho-
nate 8 (Scheme 4) were achieved using freshly prepared
O-benzylhydroxylamine.20 Refluxing the ethanolic solu-
tion of highly enantiomerically enriched phosphonate
(R)-6 and O-benzylhydroxylamine for 24h afforded mix-
tures consisting of (R)-8, (R,R)-13 and (R,S)-13. No
traces of the unreacted starting material or unwanted
chlorophosphonate 9 were observed. Furthermore,
phosphonates (R)-8 were cleanly separated from the bis-
phosphonates 13 on a silica gel column in over 80%
yield. When (R)-6 (ee 52%) was used, the enantiomeric
purity of (R)-8 was not increased after chromatography
on silica gel. However, from (R)-6 (ee 88%) the phos-
phonate (R)-8 (ee 97%) was obtained.
The epoxide ring opening in the phosphonate 6 with
N-benzylhydroxylamine hydrochloride17–19 occurred
exclusively at C(3) leading to the formation of
diethyl 3-(N-benzyl-N-hydroxyamino)-2-hydroxyprop-
ylphosphonate 10. However, the expected product 10
was contaminated with various amounts of the chloro-
phosphonate 9 (Scheme 3).
RO
OH
OR
O
a
+
P(O)(OEt)2
Cl
P(O)(OEt)2
P(O)(OEt)2
BnN
10 R=H
12 R=Ac
6
9
Scheme 3. Reagents and conditions: (a) BnNHOHÆHCl, NEt3, etha-
nol/water, rt, 24h.
3. Conclusions
N- and O-Benzylhydroxylamines react with diethyl 2,3-
epoxypropylphosphonate 6 regiospecifically at C(3) to
Depending on the reaction conditions ratios of 10 and 9
varied from 95:5 (NEt3, ethanol/water, 24h) to 91:9
(NaHCO3, CH2Cl2, 48h) and to 83:17 (NEt3, CH2Cl2,
6days). Chromatographic separation of the crude prod-
uct obtained in aqueous ethanol gave pure phospho-
nates 10 and 9 in 74% and 4% yield, respectively.
Final proof of the exclusive C(3) opening in the epoxy-
phosphonate 6 was achieved by transforming the phos-
phonate 10 into diacetate 12 and careful analysis of
its 1H NMR spectrum. When the epoxide (S)-6
(ee 94%) was subjected to the reaction with N-benz-
ylhydroxylamine, (S)-10 (ee 98%) was obtained in 80%
yield after column chromatography (Scheme 3).
produce
diethyl
3-(N-benzyl-N-hydroxyamino)-2-
hydroxypropylphosphonate 10 and 3-(N-benzyloxy-
amino)-2-hydroxypropylphosphonate 8, respectively, as
major products. Up to 15% of meso- and dl-bisphospho-
nates 13 was formed in the reaction of O-benzylhydrox-
ylamine with 6. When N- and O-benzylhydroxylamines
were prepared in situ from their hydrochlorides, up to
5% of diethyl 3-chloro-2-hydroxypropylphosphonate 9
was found in the crude products. From (S)-6 (ee 94%),
the phosphonate (S)-10 (ee 98%) was prepared in 80%
yield. Highly enantiomerically enriched (R)- and (S)-8
(ee 97%) were obtained from the epoxyphosphonates
(R)- and (S)-6 (ee 88% and 94%), respectively. The phos-
phonate (R)-8 is a key intermediate in the synthesis of
hydroxylamine antibiotics FR-33289 and FR-33699.
On the other hand, when the racemic epoxyphosphonate
6 was reacted with O-benzylhydroxylamine hydrochlo-
Bn
BnO
HN
HO
O
N
OH
OH
O
a
9
+
+
(EtO)2(O)P
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
8
6
13
Scheme 4. Reagents and conditions: (a) BnONH2ÆHCl, NEt3, ethanol/water, rt, 48h or BnONH2, ethanol, reflux, 24h.

´
A. E. Wroblewski, A. Hałajewska-Wosik / Tetrahedron: Asymmetry 15 (2004) 3201–3205
3203
20
½aŠ ¼ ꢀ14:3 (c 1.68, CHCl3) (ee 98%). Anal. Calcd
4. Experimental
D
for C14H24NO5PÆ0.2H2O: C, 52.40; H, 7.66; N, 4.37.
Found: C, 52.40; H, 7.76; N, 4.19.
1H NMR spectra were recorded with a Varian Mercury-
300 spectrometer; chemical shifts d in ppm with
respect to TMS; coupling constants J in Hz. 13C and
31P NMR spectra were recorded on a Varian Mercury-
300 machine at 75.5 and 121.5MHz, respectively. IR
spectral data were measured on an Infinity MI-60
FT-IR spectrometer. Elemental analyses were performed
by the Microanalytical Laboratory of this Faculty on a
Perkin Elmer PE 2400 CHNS analyzer. Polarimetric
measurements were conducted on a Perkin Elmer 241
MC apparatus.
4.1.2. In the presence of sodium bicarbonate in methylene
chloride. To a solution of 6 (0.100g, 0.515mmol) in
methylene chloride (2mL), N-benzylhydroxylamine
hydrochloride (0.120g, 0.750mmol) was added followed
by sodium bicarbonate (0.063g, 0.75mmol) and the sus-
pension was stirred at room temperature for 2days. The
reaction mixture was diluted with methylene chloride
(10mL), washed with water (3 · 2mL) and the aqueous
layer was extracted with methylene chloride (3mL). Or-
ganic phases were dried over MgSO4 and concentrated
in vacuo. The crude product was chromatographed on
a silica gel column with methylene chloride/methanol
(50:1, v/v) to give the phosphonate 10 (0.099g, 61%)
as a colourless oil.
Diethyl (R)- and (S)-2,3-epoxypropylphosphonates 6 (ee
52% or 88% and 94%, respectively) were prepared
according to the literature procedure.15
4.1. Reaction of the racemic epoxyphosphonate 6 with
N-benzylhydroxylamine hydrochloride
4.1.3. In the presence of NEt3 in methylene chlo-
ride. The procedure described in the previous section
replacing sodium bicarbonate with triethylamine
(0.104mL, 0.750mmol) was followed. After 6days the
reaction mixture was worked up and the crude product
was purified to afford the phosphonate 10 (0.083g,
52%).
4.1.1. In the presence of triethylamine in aqueous etha-
nol. A mixture of 6 (1.00g, 5.15mmol), N-benzylhydr-
oxylamine hydrochloride (1.23g, 7.73mmol) and
triethylamine (1.07mL, 7.73mmol) in ethanol/water
(1:1, v/v, 4mL) was stirred at room temperature for
24h. The reaction mixture was extracted with CH2Cl2
(3 · 4mL), the organic extracts were washed with water
(1 · 3mL), dried over MgSO4 and concentrated in
vacuo. The crude product was chromatographed on a
silica gel column with methylene chloride/methanol
(50:1, v/v) to give less polar phosphonate 10 (1.21g,
74%) as a colourless oil and more polar chlorophospho-
nate 915 (0.07g, 4%).
4.2. Diethyl 2-acetyloxy-3-(N-acetyloxy-N-benzyl)amino-
propylphosphonate 12
Standard acetylation (acetic anhydride, NEt3, DMAP)
of the phosphonate 10 gave the diacetate 12 in 69% yield
after chromatography on silica gel with methylene chlo-
ride/methanol (100:1, v/v). IR (film): m = 2984, 2933,
2909, 1743, 1443, 1369, 1240, 1028, 965, 750, 700cmꢀ1
;
4.1.1.1. Diethyl 3-(N-benzyl-N-hydroxy)amino-2-
hydroxypropylphosphonate 10. IR (film): m = 3330,
3063, 3030, 2983, 2932, 2908, 1454, 1393, 1221, 1047,
1H NMR (CDCl3): d = 1.30 (t, J = 7.0Hz, 6H), 1.91 (s,
3H), 2.04 (s, 3H), 2.16 (ddd, J1a-P = 18.3Hz, J1a-1b
15.6Hz, J1a-2 = 6.9Hz, 1H, H-1a), 2.42 (ddd, J1b-P
=
=
18.6Hz, J1a-1b = 15.6Hz, J1b-2 = 5.7Hz, 1H, H-1b),
966, 750, 700cmꢀ1
;
J = 7.1Hz, 6H), 1.98 (ddd, J1a-P = 17.4Hz, J1a-1b
15.3Hz, J1a-2 = 7.8Hz, 1H, H-1a), 2.04 (ddd, J1b-P
1H NMR (CDCl3): d = 1.32(t,
=
=
3.09 (ddd, J3a-3b = 13.8Hz, J3a-2 = 5.7Hz, J3a-P
1.2Hz, 1H, H-3a), 3.15 (dd, J3a-3b = 13.8Hz, J3b-2
=
=
8.6Hz, J1a-1b = 15.3Hz, J1b-2 = 5.1Hz, 1H, H-1b), 2.82
and 2.83 (AB part of ABX system, J3a-3b = 12.9Hz,
J3a-2 = 6.3Hz, J3b-2 = 5.4Hz, 2H, H-3ab), 3.88 and
3.89 (AB, JAB = 13.2Hz, 2H, H2C-Ph), 3.83–3.93 (br s,
5.7Hz, 1H, H-3b), 3.88 and 3.89 (AB, JAB = 13.2Hz,
2H, H2C-Ph), 4.02–4.16 (m, 4H), 5.24 (ddddd, J2-P
=
14.0Hz, J2-1a = 6.9Hz, J2-3a = 5.7Hz, J2-3b = 5.7Hz,
J2-1b = 5.7Hz, 1H, H-2), 7.25–7.36 (m, 5H); 13C NMR
(CDCl3): d = 16.6 (d, J = 6.3Hz), 19.6, 21.3, 28.5 (d,
J = 140.9Hz, C-1), 60.2(d, J = 9.5Hz, C-3), 61.9 (d,
J = 6.6Hz), 63.8, 66.7 (d, J = 2.9Hz, C-2), 127.9,
128.4, 129.6, 135.3, 169.2, 169.9; 31P NMR
(121.5MHz, CDCl3): d = 28.04. Anal. Calcd for
C18H28NO7P: C, 53.86; H, 7.03; N, 3.49. Found: C,
54.13; H, 6.87; N, 3.71.
1H, OH), 4.03–4.16 (m, 4H), 4.34 (ddddd, J2-P
=
11.1Hz, J2-1a = 7.8Hz, J2-3a = 6.3Hz, J2-3b = 5.4Hz,
J2-1b = 5.1Hz, 1H, H-2), 5.86 (br s, 1H, OH), 7.25–
7.37 (m, 5H); 13C NMR (CDCl3): d = 16.7 (d,
J = 6.0Hz), 31.8 (d, J = 140.3Hz, C-1), 61.9 and 62.2
(2d, J = 6.3Hz), 64.6 (d, J = 3.4Hz, C-2), 65.3, 65.6
(d, J = 16.0Hz, C-3), 127.5, 128.4, 129.6, 137.1; 31P
NMR (121.5MHz, CDCl3): d = 31.04. Anal. Calcd for
C14H24NO5PÆ1/5H2O: C, 52.40; H, 7.66; N, 4.37. Found:
C, 52.49; H, 7.85; N, 4.42.
4.3. Diethyl 3-(benzyloxyamino)-2-hydroxypropylphos-
phonate 8
4.1.1.2. Diethyl (S)-3-(N-benzyl-N-hydroxy)amino-2-
hydroxypropylphosphonate (S)-10. As described for the
racemic compound (Section 4.1.1), from (S)-6 (0.810g,
4.17mmol, ee 94%), N-benzylhydroxylamine hydrochlo-
ride (1.00g, 6.26mmol) and triethylamine (0.868g,
6.26mmol) in aqueous ethanol (8.0mL, 1:1) (S)-10
A
mixture of the epoxyphosphonate
6
(1.00g,
5.15mmol), O-benzylhydroxylamine hydrochloride
(1.23g, 7.72mmol) and triethylamine (1.07mL,
7.72mmol) in aqueous ethanol (5mL, 1:1) was stirred
at room temperature for 48h. Organic compounds were
extracted with methylene chloride (5 · 5mL), the com-
bined organic layers were washed with water (5mL),
(1.09g, 80%) was obtained as
a colourless oil.

´
A. E. Wroblewski, A. Hałajewska-Wosik / Tetrahedron: Asymmetry 15 (2004) 3201–3205
3204
dried over MgSO4 and concentrated in vacuo. The crude
product was chromatographed on a silica gel column
with chloroform/methanol (100:1, v/v) to give the phos-
phonate 8 (0.930g, 56%) as a colourless oil. IR (film):
m = 3357, 3063, 3031, 2982, 2910, 2869, 1454, 1224,
J = 3.0Hz, C-2), 65.4 (d, J = 15.1Hz, C-3, dl), 65.6 (d,
J = 15.0Hz, C-3, meso), 75.7 (C2Ph, dl), 76.1 (C2Ph,
meso), 128.3, 128.5, 129.0, 136.6; 31P NMR (121.5
MHz, CDCl3): d = 30.52( dl), 30.44 (meso). Anal. Calcd
for C21H39NO9P2: C, 49.31; H, 7.69; N, 2.74. Found: C,
49.12; H, 7.43; N, 3.02.
1
1020, 966, 835, 746, 699cmꢀ1; H NMR (CDCl3): d =
1.32and 1.34 (2t, J = 7.0Hz, 6H), 1.92(ddAB, J1a-P
16.9Hz, J1a-1b = 15.2Hz, J1a-2 = 8.1Hz, 1H, H-1a),
1.94 (ddAB, J1b-P = 18.6Hz, J1a-1b = 15.2Hz, J1b-2
=
In a similar manner, from (R)-6 (0.500g, 2.58mmol, ee
88%) and O-benzylhydroxylamine prepared from the
hydrochloride (0.822g, 5.15mmol) (R)-8 (0.663g, 81%)
=
4.4Hz, 1H, H-1b), 2.89 (dAB, J3a-3b = 13.5Hz,
J3a-2 = 8.1Hz, 1H, H-3a), 3.08 (dAB, J3a-3b = 13.5Hz,
J3b-2 = 3.6Hz, 1H, H-3b), 3.58 (d, J = 2.8Hz, 1H,
OH), 4.06–4.19 (m, 4H), 4.20–4.30 (m, 1H, H-2), 4.70
(s, 2H, H2C-Ph), 5.97 (br s, 1H, NH), 7.27–7.37 (m,
5H); 13C NMR (CDCl3): d = 16.7 and 16.7
(2d, J = 6.0Hz), 31.8 (d, J = 139.3Hz, C-1), 58.2(d,
J = 16.6Hz, C-3), 62.1 and 62.2 (2d, J = 6.3Hz), 64.0
(d, J = 4.6Hz, C-2), 76.4, 128.1, 128.5, 128.5, 137.7;
31P NMR (121.5MHz, CDCl3): d = 30.75. Anal. Calcd
for C14H24NO5PÆ1/3H2O: C, 52.01; H, 7.69; N, 4.33.
Found: C, 51.99; H, 7.71; N, 4.55.
20
was obtained as a colourless oil. ½aŠ ¼ þ12:0 (c 1.20,
D
CHCl3) (ee 97%).
4.4. General procedures for the estimation of eeꢀs21,22
4.4.1. Diethyl (R)-3-(benzyloxyamino)-2-hydroxypropyl-
phosphonate, (R)-8. 31P NMR spectrum was taken
for a solution of (S)-8 (0.010g, 0.032mmol) and quinine
(0.005g, 0,015mmol) in chloroform-d (0.7mL);
d = 30.80 [(S)-8] and 30.68ppm [(R)-8].
4.4.2.
Diethyl
(S)-3-(N-benzyl-N-hydroxy)amino-2-
4.3.1. Diethyl (S)-3-(benzyloxyamino)-2-hydroxypropyl-
phosphonate, (S)-8. As described for the racemic com-
pound (Section 4.3), from (S)-6 (0.380g, 1.97mmol, ee
94%), O-benzylhydroxylamine hydrochloride (0.469g,
2.94mmol) and triethylamine (0,408mL, 2.94mmol)
hydroxypropylphosphonate, (S)-10. 31P NMR spectrum
was taken for a solution of (S)-10 (0.030g, 0.095mmol)
and quinine (0.015g, 0,046mmol) in chloroform-d
(0.7mL); d = 31.14 [(S)-10] and 30.39ppm [(R)-10].
in aqueous ethanol (4.0mL) (S)-8 (0.329g, 53%) was
20
D
obtained as a colourless oil. ½aŠ ¼ ꢀ12:8 (c 1.79,
Acknowledgements
CHCl3) (ee 97%). Anal. Calcd for C14H24NO5PÆ1/
3H2O: C, 52.01; H, 7.69; N, 4.33. Found: C, 51.95; H,
7.77; N, 4.81.
We thank Mrs. Małgorzata Pluskota for her skilled
experimental contributions. Financial support from the
´ ´
Medical University of Łodz (503-314-1) is gratefully
acknowledged.
4.3.2. Diethyl (R)-3-(benzyloxyamino)-2-hydroxypropyl-
phosphonate, (R)-8. O-Benzylhydroxylamine hydro-
chloride (0.554g, 3.47mmol) was stirred with 6N
NaOH (1.2mL) for 15min. After addition of water
(5mL) containing ice, the mixture was extracted with
ether (5 · 5mL), combined extracts were dried over
MgSO4 and concentrated. To the oily residue (R)-6
(0.337g, 1.74mmol, ee 52%) was added followed by eth-
anol (ca. 2mL) to get a homogeneous solution, which
was refluxed under argon atmosphere for 24h. Volatiles
were removed in vacuo to leave a crude product
(0.544g), which was purified on a silica gel column with
chloroform/methanol (50:1, v/v) to give (R)-8 (0.463g,
84%, ee 57%) as a colourless oil and dl- and meso-13
(0.039g, 9%) as a viscous colourless oil.
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