Synthesis of enantiomerically pure diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2009.09.005

The synthesis and ee determination of diethyl 3-azido-2-hydroxypropylphosphonates from 2,3-epoxypropylphosphonates have been optimised. Enantiomerically enriched diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates (R)-3a-j and (S)-3a-h

Full text of DOI:10.1016/j.tetasy.2009.09.005

Tetrahedron: Asymmetry 20 (2009) 2270–2278
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Tetrahedron: Asymmetry
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Synthesis of enantiomerically pure diethyl (R)- and
(S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates
*
Iwona E. Głowacka
´
´
´
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódz, 90-151 Łódz, Muszynskiego 1, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2009
Accepted 4 September 2009
Available online 25 September 2009
The synthesis and ee determination of diethyl 3-azido-2-hydroxypropylphosphonates from 2,3-epox-
ypropylphosphonates have been optimised. Enantiomerically enriched diethyl (R)- and (S)-2-hydroxy-
3-(1,2,3-triazol-1-yl)propylphosphonates (R)-3a–j and (S)-3a–h as well as (S)-3j were synthesised from
diethyl (R)- and (S)-2,3-epoxypropylphosphonates in a reaction sequence including azidolysis followed
by 1,3-dipolar cycloaddition with selected alkynes.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
epoxides with trimethylsilyl azide (TMSN3).19,20 It was reasoned
out that the application of this methodology to the opening of epox-
1,2,3-Triazoles are an important class of heterocycle which dis-
play a large range of biological activities and are widely employed
as pharmaceuticals and agrochemicals. Compounds containing the
1,2,3-triazole moiety are known to exhibit antibacterial,1–3 anti-
fungal,4,5 anticancer6,7 and antiviral activity.8,9 They have also been
found to act as b3 adrenergic receptor agonists10 as well as GABA
ide 1 could lead efficiently to diethyl (R)- and (S)-3-azido-2-hydrox-
ypropylphosphonate (R)- and (S)-2, respectively, in one step from
the racemic starting material. To this end racemic diethyl 2,3-epox-
ypropylphosphonate 1 was treated with 1 equiv of TMSN3 in the
presence of 2 mol % (salen)Cr–Cl (R,R)-4a complex at room temper-
aturefor 7 h to afforda 47:45mixtureof (S)-5 and (R)-1, respectively,
as judged by the 31P NMR spectroscopic analysis of the crude reac-
tion product (Scheme 2). The mixture of azidosilyl ether (S)-5 and
the epoxide (R)-1 was subjected to chromatography on a silica gel
column. The epoxide (R)-1 and a more polar diethyl (S)-3-azido-2-
hydroxypropylphosphonate (S)-2 were separated cleanly in 40%
and 41% yield, respectively. This means that on the surface of silica
gel in the presence of methanol desilylation of the trimethylsilyl
group in (S)-5 occurred to afford azidoalcohol (S)-2. Searching for a
quick and reliable way to determine the enantiomeric excesses of
diethyl 3-azido-2-hydroxypropylphosphonates, it was found that
the application of quinine as an enantiodifferentiating reagent is
the method of choice, while the ee of (S)-2 was determined based
on analysis of the 31P NMR spectra. The ee of the azidophosphonate
(S)-2 obtained in the presence of (R,R)-4a was established as only
28%.
The epoxide (R)-1 from the same kinetic resolution experiment
was reacted with sodium azide in the presence of ammonium sul-
fate to provide diethyl (R)-3-azido-2-hydroxypropylphosphonate
(R)-2 in 84% yield. The ee of this material was estimated to be
26% by the same method. The kinetic resolution of the racemic
epoxide 1 with TMSN3 at 4 °C did not improve the enantiomeric
excesses of the azide (S)-2 as well as of the epoxide (R)-1.
For this reason, another approach to 3-azidophosphonates with
high enantiomeric purities was considered. Based on the procedure
described in the literature, enantiomerically enriched diethyl
a
5 subtype inverse agonists.11 These molecules have also found
industrial applications as corrosion inhibitors, photostabilisers12
and herbicides.13
In 2001, Sharpless defined the concept of ‘click chemistry’ and
the criteria for a transformation to be considered as a ‘click’.14
The conventional route to 1,2,3-triazoles relies on the Huisgen
[3+2] cycloaddition between alkynes and organic azides and is
qualified as a ‘click reaction’. Under thermal conditions, this pro-
cess usually affords a mixture of 1,4- and 1,5-disubstitued regioi-
somers.15,16 Since copper(I) has recently been found to be an
efficient and regiospecific catalyst for this transformation,17,18 it
now represents a general and mild approach to the preparation
of 1,4-disubstituted 1,2,3-triazole derivatives.
Herein we report a short synthesis of highly enantiomerically
enriched diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)pro-
pylphosphonates (R)-3a–j and (S)-3a–h as well as (S)-3j; the strat-
egy is outlined in Scheme 1.
2. Results and discussion
Jacobsen has reported (salen)Cr–Cl complex 4a (Fig. 1) as an
effective catalyst for the enantioselective ring opening of racemic
* Tel.: +48 42 677 92 37; fax: +48 42 678 83 98.
E-mail address: iwona.glowacka@umed.lodz.pl
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.005

I. E. Głowacka / Tetrahedron: Asymmetry 20 (2009) 2270–2278
2271
N
N
OH
OH
(EtO)2(O)P
N3
(EtO)2(O)P
(EtO)2(O)P
N
R'
R"
(R)-3a-j
(R)-2
O
(EtO)2(O)P
( )-1
N
OH
OH
N
N
(EtO)2(O)P
N3
R'
R"
(S)-3a-h and (S)-3j
(S)-2
Scheme 1. Retrosynthesis of diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates.
(R)- and (S)-2,3-epoxypropylphosphonate (R)-1 and (S)-1 (ee of
both was 93%) were obtained in 42% and 35% yields, respectively,
via the hydrolytic kinetic resolution (HKR) of the racemic epoxide
1 using (S,S)-4b and (R,R)-4b as catalysts (Fig. 1).21 In preliminary
studies, the epoxide ring opening in (R)-1 was performed with so-
dium azide in the presence of ammonium chloride in refluxing
methanol as described in the literature.22 However, this procedure
led to the formation of a 94:6 mixture of diethyl (R)-3-azido-2-
hydroxypropylphosphonate (R)-2 and diethyl (R)-3-chloro-2-
hydroxypropylphosphonate (R)-621 in ca. 92% total yield (Scheme
3). As expected, the enantiomeric purity of (R)-2 in the crude prod-
uct remained unchanged (93%). Several attempts at separating 3-
chlorophosphonate (R)-6 from 3-azidophosphonate (R)-2 on silica
gel columns failed. However, chromatography allowed us to im-
prove the ee of (R)-2 to 96%.
OH
O
a
N3
(EtO)2(O)P
(EtO)2(O)P
(R)-1
(R)-2
Scheme 4. Reagents and conditions: (a) NaN3, (NH4)2SO4, MeOH, reflux, 4 h, 80%.
methanol for 4 h (Scheme 4) produced diethyl (R)-3-azido-2-
hydroxypropylphosphonate (R)-2 as a single product. After re-
moval of the inorganic salts by filtration through a pad of Celite,
(R)-2 (ee 96%) was obtained in 80% yield and used in the next step
without further purification.
Underthesame conditions, diethyl (S)-3-azido-2-hydroxypropyl-
phosphonate (S)-2 was obtained from epoxide (S)-1. The reaction of
(S)-1 with sodium azide in the presence of ammonium chloride in
refluxing methanol again led to an inseparable 94:6 mixture of
diethyl (S)-3-azido-2-hydroxypropylphosphonate (S)-2 and diethyl
(S)-3-chloro-2-hydroxypropylphosphonate (S)-621 in ca. 89% yield.
However, treatment of epoxide (S)-1 (ee 93%) with sodium azide in
the presence of ammonium sulfate in refluxing methanol for 4 h
afforded diethyl (S)-3-azido-2-hydroxypropylphosphonate (S)-2
(ee 96%) in 83% yield.
H
H
N
O
N
O
M
t-Bu
t-Bu
To check the reactivity of the diethyl 3-azido-2-hydroxypropyl-
phosphonate framework compound (R)-2 (ee 96%) was reacted with
8 different terminal alkynes 7a–h (7a–methyl propiolate, 7b–propar-
gyl benzoate, 7c–phenylacetylene, 7d–1-ethynyl-2-fluorobenzene,
7e–1-ethynyl-3-fluorobenzene, 7f–1-ethynyl-2,4-difluorobenzene,
7g–1-ethynyl-2-pyridine and 7h–5-ethynyl-1-methyl-1H-imidaz-
ole) according to a standard protocol employing Cu(I) as a catalyst
which was generated in situ from CuSO4 and sodium ascorbate.18,23
The corresponding 1,2,3-triazoles 3a–h (ee 92–96%) were formed in
moderate to excellent yields and were finally purified either by col-
umn chromatography on silica gel or by crystallisation (Scheme 5
and Table 1).
t-Bu
t-Bu
(R,R)-4a M = Cr-Cl
(R,R)-4b M = Co-OAc
Figure 1.
To avoid the formation of 3-chlorophosphonate (R)-6, ammo-
nium chloride was replaced with non-nucleophilic ammonium sul-
fate. Thus, the treatment of epoxide (R)-1 (ee 93%) with sodium
azide in the presence of ammonium sulfate (1.8 equiv) in refluxing
OTMS
N3
O
O
(R,R)-4a
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(S)-5
(R)-1
1
Scheme 2.
OH
OH
a
O
(EtO)2(O)P
Cl
(EtO)2(O)P
(EtO)2(O)P
N3
(R)-6
(R)-1
(R)-2
Scheme 3. Reagents and conditions: (a) NaN3, NH4Cl, MeOH, reflux, 4 h.

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I. E. Głowacka / Tetrahedron: Asymmetry 20 (2009) 2270–2278
N
F
OH
OH
N
N
a
(EtO)2(O)P
N3
(EtO)2(O)P
R'
HC
C
R'
(R)-2
7a-h
(R)-3a-h
F
R' =
,
COOCH3
,
CH2OC(O)C6H5
,
,
,
a
b
e
c
d
F
N
H3C
,
N
N
F
,
g
f
h
Scheme 5. Reagents and conditions: (a) CuSO4ꢀ5H2O (0.1 equiv), sodium ascorbate (0.2 equiv), H2O–t-BuOH (2:1), rt, 48–72 h.
Table 1
Conversely, the cycloaddition of (R)-3-azidophosphonate (R)-2
(ee 96%) and dimethyl acetylenedicarboxylate 7j was carried out
at 110 °C according to the standard procedure24 to give crude
(R)-3j (ee 96%) in quantitative yield (Scheme 6). After crystallisa-
tion from an ethyl acetate–petroleum ether mixture enantiomeri-
cally pure (R)-3j (ee 100%) was obtained in 95% yield.
N
N
N
OH
N
OH
N
N
(EtO)2(O)P
R'
(EtO)2(O)P
R'
R"
R"
To prepare phosphonate (R)-3i, the cycloaddition of azi-
dophosphonate (R)-2 and 2-cyanoacetamide should be carried
out. However, this reaction is usually performed in the presence
of potassium carbonate and DMSO.25 To avoid possible dehydra-
tion of diethyl (R)-3-azido-2-hydroxypropylphosphonate (R)-2 to
diethyl 3-azido-1-propenylphosphonate the protection of the hy-
droxy group was deemed necessary. To this end, (R)-2-hydroxy-
phosphonate (R)-2 (ee 96%) was transformed into 2-O-benzyl
derivative (R)-8 which was next subjected to cycloaddition with
2-cyanoacetamide.25 After removal of the benzyl group by hydrog-
enolysis a crude (R)-3i (ee 94%) was obtained (Scheme 7). Chro-
matographic purification on silica gel column followed by
crystallisation of the appropriate fractions gave pure (R)-3i (ee
96%) in 56% overall yield after three steps.
It appeared that phosphonate (R)-3i could also be obtained
without protection of the hydroxy group in (R)-2. Cycloaddition
of diethyl (R)-3-azidophosphonate (R)-2 and 2-cyanoacetamide
performed in the presence of potassium carbonate and DMSO25
gave phosphonate (R)-3i (ee 96%) in 70% yield after column chro-
matography and crystallisation (Scheme 8).
(R)-3a-j
(S)-3a-j
Compounds R0
R00
Yield (%) ee (%)
d
31P NMRa
(R)-3a
(S)-3a
–COOCH3
H
95
95
96
97
28.44
29.07
(R)-3b
(S)-3b
–CH2OC(O)Ph
H
75
70
95
96
28.66
28.79
(R)-3c
(S)-3c
H
H
95
86
96
95
29.03
29.30
F
(R)-3d
(S)-3d
88
95
92
91
28.70
28.90
F
(R)-3e
(S)-3e
H
91
86
96
96
28.41
28.95
Under the same conditions, from azidophosphonate (S)-2 1,2,3-
triazoles (S)-3a–h and (S)-3j were obtained (Scheme 9 and Table 1).
The determination of the enantiomeric excesses of all the phos-
phonates obtained in this paper deserves comment. For 3-azido-
and 3-(1,2,3-triazol-1-yl)-2-hydroxypropylphosphonates, 31P NMR
spectroscopy using quinine was found most efficient. To optimise
the molar 3-azidoalcohol or 1,2,3-triazole to quinine ratio, the 31P
NMR spectra for 1:1, 1:2, 1:3, 1:4 and 1:5 mixtures of racemic com-
pounds with quinine were recorded. In the case of azidoalcohol 2 the
best separation of the 31P NMR signals of (R)- and (S)-2 was observed
for a 4:1 quinine to azidoalcohol ratio. However, for 1,2,3-triazole
derivatives (R)- and (S)-3a-j addition of 1 equiv of quinine was found
to be sufficient. This methodology was extended to establish ee of
(R)- and (S)-2,3-epoxypropylphosphonates obtained by HKR to sim-
plify the methodology already described in the literature,21 which
relied on a two-step procedure [the epoxide ring opening with
dibenzylamine and esterification with (S)-O-methylmandelic acid]
and was time consuming (at least four days to complete both steps).
Since the epoxide ring opening in 1 with azides is complete in 4 h,
this new approach is fast and simple.
F
(R)-3f
(S)-3f
H
H
90
95
96
96
28.73
28.90
F
(R)-3g
(S)-3g
88
91
94
94
29.21
28.44
N
(R)-3h
(S)-3h
H
75
80
92
94
28.60
29.19
H3C
N
N
(R)-3i
(S)-3i
–C(O)NH2
–COOCH3
NH2
70
—
96
—
29.02
29.11
(R)-3j
(S)-3j
–COOCH3 95
80
100
100
29.48
29.98
The 31P NMR chemical shifts observed with 1 equiv of quinine.
a

I. E. Głowacka / Tetrahedron: Asymmetry 20 (2009) 2270–2278
2273
N
N
N
OH
OH
a
(EtO)2(O)P
(EtO)2(O)P
N3
COOCH3
COOCH3
(R)-2
(R)-3j
Scheme 6. Reagents and conditions: (a) H3COOCC„CCOOCH3 7j, toluene, 110 °C, 4 h, 95%.
N
OR
OR
N
N
b
(EtO)2(O)P
(EtO)2(O)P
N3
C(O)NH2
NH2
(R)-2 R = OH
(R)-8 R = OBn
(R)-9i R = OBn
(R)-3i R = OH
c
a
Scheme 7. Reagents and conditions: (a) BnBr, Ag2O, CH2Cl2, rt, 24 h, 87%; (b) 2-cyanoacetamide, DMSO, K2CO3, 5 h, 50 °C, 70%; (c) H2, 10% Pd–C, EtOH, rt, 24 h, 92%.
N
OH
OH
N
N
a
N3
(EtO)2(O)P
(EtO)2(O)P
C(O)NH2
NH2
(R)-2
(R)-3i
Scheme 8. Reagents and conditions: (a) 2-cyanoacetamide, DMSO, K2CO3, 5 h, 50 °C, 70%.
N
N
N
OH
OH
O
a
b
(EtO)2(O)P
N3
(EtO)2(O)P
(EtO)2(O)P
R'
(S)-1
(S)-2
(S)-3a-h
N
OH
N
N
c
(EtO)2(O)P
COOCH3
COOCH3
(S)-3j
Scheme 9. Reagents and conditions: (a) NaN3, (NH4)2SO4, MeOH, reflux, 4 h, 83%; (b) alkynes 7a–h, CuSO4ꢀ5H2O (0.1 equiv), sodium ascorbate (0.2 equiv), H2O–t-BuOH (2:1),
rt, 48–72 h; (c) H3COOCC„CCOOCH3 7j, toluene, 110 °C, 4 h, 80%.
pling constants J in Hz. 13C and 31P NMR spectra were recorded on a
3. Conclusions
Varian Mercury-300 machine at 75.5 and 121.5 MHz, respectively.
IR spectral data were measured on an Infinity MI-60 FT-IR spec-
trometer. Melting points were determined on a Boetius apparatus
and are uncorrected. Elemental analyses were performed by the
Microanalytical Laboratory of this Faculty on a Perkin Elmer PE
2400 CHNS analyzer. Polarimetric measurements were conducted
on an Optical Activity PolAAr 3001 apparatus.
The following absorbents were used: column chromatography,
Merck Silica Gel 60 (70-230 mesh); analytical TLC, Merck TLC plas-
tic sheets Silica Gel 60 F254. TLC plates were developed in chloro-
form–methanol solvent systems. Visualisation of spots was
effected with iodine vapours. All solvents were purified by meth-
ods described in the literature.
The opening of the epoxide ring in racemic 2,3-epoxypropyl-
phosphonate 1 with TMSN3 in the presence of (salen)Cr–Cl as a
catalyst gave (S)-3-azido-2-hydroxyphosphonate (S)-2 and (R)-2,3-
epoxypropylphosphonate (R)-1 in good chemical yields but the prod-
ucts had low enantiomeric purities (ee 28% and 26%, respectively).
The clean transformation of epoxide (R)- and (S)-1 (ee 93%) to
(R)- and (S)-3-azido-2-hydroxypropylphosphonate (R)- and (S)-2
(ee 96%) was accomplished using sodium azide and ammonium
sulfate because in the presence of ammonium chloride, 3-chloro-
2-hydroxyphosphonate 5 (6%) was formed as a by-product.
3-Azidopropylphosphonates 2 easily react with terminal al-
kynes 7a–h in the presence of Cu(I) as a catalyst, withstood reflux-
ing in toluene when treated with dimethyl acetylenedicarboxylate
7j and underwent cycloaddition with 2-cyjanoacetamide in
strongly basic medium.
4.1. Dynamic kinetic resolution of racemic epoxide 1 at room
temperature
The enantiomeric excesses of the (R)- and (S)-epoxide 1, diethyl
(R)- and (S)-3-azido-2-hydroxypropylphosphonates (R)- and (S)-2
and diethyl (R)- and (S)-2-hydroxy(1,2,3-triazol-1-yl)propylphosph-
onate (R)-and (S)-3 were efficiently determined by 31P NMR spectros-
copy using quinine as an enantiodifferentiating reagent.
To racemic epoxide 1 (0.104 g, 0.536 mmol) was added catalyst
(R,R)-4 (6.76 mg, 0.011 mmol, 0.02 equiv). After 5 min. the solution
was cooled to 0 °C and TMSN3 (0.074 mL, 0.56 mmol, 1.05 equiv)
was injected. The reaction mixture was stirred at room tempera-
ture for 7 h, concentrated and purified on a silica gel column with
chloroform-methanol (100:1, v/v) to give azidoalcohol (S)-2
(0.052 g, 41%; ee 28%) and epoxide (R)-1 (0.042 g, 40%; ee 26%).
31P NMR (121.5 MHz, CDCl3): d = 26.65 for (R)-1 and 29.54 for
(S)-2 (fully characterised in 4.4.2).
4. Experimental
1H NMR spectra were recorded with a Varian Mercury-300
spectrometer; chemical shifts d in ppm with respect to TMS; cou-

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I. E. Głowacka / Tetrahedron: Asymmetry 20 (2009) 2270–2278
4.2. Dynamic kinetic resolution of racemic epoxide 1 at 4 °C
(0.2 mmol) and selected alkynes 7a–h (1 mmol). This suspension
was stirred vigorously at room temperature for 48–72 h. The reac-
tion mixture was extracted with chloroform (3 ꢃ 5 mL), dried over
MgSO4, filtered through a layer of Celite and evaporated. The crude
product was purified by column chromatography on the silica gel
or was crystallised to give (R)-3a–h.
To racemic epoxide 1 (0.104 g, 0.536 mmol) was added catalyst
(R,R)-4 (6.76 mg, 0.011 mmol, 0.02 equiv). After 5 min. the solution
was cooled to 0 °C and TMSN3 (0.074 mL, 0.562 mmol, 1.05 equiv)
was injected. The solution was stirred at 4 °C for 7 h, concentrated
and purification on a silica gel column with chloroform-methanol
(100:1, v/v) gave azidoalcohol (S)-2 (0.049 g, 39%; ee 28%) and
epoxide (R)-1 (0.040 g, 40%; ee 26%).
4.5.1. Diethyl (R)-2-hydroxy-3-(4-methoxycarbonyl-1,2,3-
triazol-1-yl)propylphosphonate (R)-3a
From(R)-2(0.266 g,1.120 mmol),methylpropiolate7a(0.100 mL,
1.120 mmol), CuSO4ꢀ5H2O (0.028 g), sodium ascorbate (0.044 g) in a
mixture of t-BuOH (0.5 mL)–H2O (1 mL), phosphonate (R)-3a
(0.343 g, 95%; ee 96%) was obtained as a white solid after crystallisa-
4.3. Hydrolytic kinetic resolution of racemic epoxide 1
A mixture of (S,S)-Salen CoII (0.024 g, 0.040 mmol), toluene
(0.4 mL) and acetic acid (4.6 lL, 0.074 mmol) was stirred in air at
tion from ethyl acetate–petroleum ether. Mp 103–104 °C. ½a D20
ꢁ
¼
room temperature for 1 h. After removal of the solvent, the brown
residue was vacuum dried. The racemic epoxide (3.601 g,
18.6 mmol) was added to the catalyst in one portion and the mix-
ture was cooled in an ice-water bath. Water (0.200 mL, 11.0 mmol,
0.55 equiv) was added over 10 min. After 1 h, the bath was re-
moved and the reaction mixture was stirred at room temperature
for 72 h. Ethyl acetate (6 mL) was added followed by MgSO4 (0.5 g).
After removal of the drying agent and the solvent, the crude prod-
uct was subjected to distillation to give (R)-1 (1.532 g, 42%) as a
ꢂ3:7 (c 5.20, CHCl3), ee 96%; IR (KBr):
m = 3424, 3287, 2986, 2958,
1725, 1548, 1437, 1237, 1029, 965 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d = 1.32 and 1.34 (2t, J = 7.2 Hz, 6H, 2 ꢃ POCH2CH3), 1.78 (ddd,
J = 16.8 Hz, J = 15.3, J = 3.0 Hz, 1H, H-1b), 2.00 (ddd, J = 19.2 Hz,
J = 15.3, J = 9.3 Hz, 1H, H-1a), 2.45 (br s, 1H, OH), 3.93 (s, 3H, COOCH3),
4.04–4.19 (m, 4H, 2 ꢃ POCH2CH3), 4.36–4.51 (m, 2H, H-3b, H-2),
4.59–4.67 (m, 1H, H-3a), 8.31 (s, 1H, HC5 ); 13C NMR (75.5 MHz,
0
CDCl3): d = 16.5 and 16.6 (2d, J = 6.0 Hz, POCC), 30.8 (d, J = 140.4 Hz,
C-1), 52.3 (s, COOCH3), 56.3 (d, J = 17.8 Hz, C-3), 62.2 and 62.4 (2d,
J = 6.6 Hz, 2 ꢃ POC), 65.3 (d, J = 3.8 Hz, C-2), 129.4 (s, HC@C), 139.7
(s, HC@C), 161.1 (s, C@O); 31P NMR (121.5 MHz, CDCl3): d = 29.24.
Anal. Calcd for C11H20N3O6P:C, 41.12; H, 6.28; N, 13.08. Found: C,
41.08; H, 6.17; N, 12.80.
colourless oil (bp 80–82 °C/0.2 mmHg). ½a D20
¼ þ3:1 (c 2.01, etha-
ꢁ
nol); ee 93%. 31P NMR (121.5 MHz, CDCl3): d = 26.82.
4.4. Reaction of epoxide (R)-1 with sodium azide
4.4.1. Reaction of epoxide (R)-1 with sodium azide in the
presence of NH4Cl
4.5.2. Diethyl (R)-3-(4-benzoyloxymethyl-1,2,3-triazol-1-yl)-2-
hydroxypropylphosphonate (R)-3b
A mixture of epoxide (R)-1 (1.53 g, 7.26 mmol), sodium azide
(1.23 g, 18.7 mmol) and ammonium chloride (0.757 g, 14.2 mmol)
in methanol (5 mL) was stirred at 65 °C for 4 h. After evaporation of
solvents the residue was suspended in ethyl acetate (15 mL) and
filtered through a layer of Celite. The solution was concentrated
in vacuo to give a 94:6 mixture of diethyl (R)-3-azido-2-hydrox-
ypropylphosphonate (R)-2 (ee 93%) and diethyl (R)-3-chloro-2-
hydroxypropylphosphonate (R)-6 (1.74 g) in 92% yield. The crude
product was chromatographed on a silica gel column with chloro-
form-methanol mixtures (100:1, v/v) to give a 94:6 mixture of (R)-
2 (ee 96%) and (R)-6 (1.68 g, 90%). 31P NMR (121.5 MHz, CDCl3):
d = 30.18 for 2 and 29.81 for 6.
From (R)-2 (0.103 g, 0.430 mmol), propargyl benzoate 7a
(0.063 mL, 0.430 mmol), CuSO4ꢀ5H2O (0.011 g), sodium ascorbate
(0.017 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phosphonate
(R)-3b (0.129 g, 75%; ee 95%) was obtained as a colourless oil after
purification on a silica gel with chloroform–methanol (50:1, v/v).
½
a 2D0
ꢁ
¼ ꢂ1:3 (c 2.15, CHCl3), ee 95%; IR (film):
m = 3338, 2984, 2910,
1720, 1272, 1027, 836, 714 cmꢂ1 1H NMR (300 MHz, CDCl3): d =
;
1.32 and 1.33 (2t, J = 7.2 Hz, 6H, 2 ꢃ POCH2CH3), 1.82 (ddd,
J = 16.8 Hz, J = 15.3 Hz, J = 9.0 Hz, 1H, H-1b), 2.01 (ddd, J = 19.5 Hz,
J = 15.3 Hz, J = 2.7 Hz, 1H, H-1a), 2.70 (br s, 1H, OH), 4.05–4.20 (m,
4H, 2 ꢃ POCH2CH3), 4.36–4.47 (m, 2H, H-3b, H-2), 4.54–4.61 (m, 1H,
H-3a), 5.49 (s, 2H, CH2OC(O)Ph), 7.40–7.45 (m, 2H, Ar-H), 7.50–7.60
(m, 1H, Ar-H), 7.92 (s, 1H, HC5 ), 8.03–8.07 (m, 2H, Ar-H); 13C NMR
0
4.4.2. Reaction of epoxide (R)-1 with sodium azide in the
presence of (NH4)2SO4
(75.5 MHz, CDCl3): d = 16.5 and 16.6 (2d, J = 6.0 Hz, POCC), 30.8 (d,
J = 140.4 Hz, C-1), 56.0 (d, J = 17.4 Hz, C-3), 58.1 (s, CH2OC(O)Ph),
62.3 and 62.4 (2d, J = 7.3 Hz, 2 ꢃ POC), 65.5 (d, J = 3.8 Hz, C-2), 123.0
(s, HC@C) 128.3, 129.6 (Carom.), 133.1 (s, HC@C), 142.0 (Cipso), 166.2
(s, C@O); 31P-NMR (121.5 MHz, CDCl3): d = 28.85. Anal. Calcd for
C17H24N3O6P: C, 51.39; H, 6.09; N, 10.57. Found: C, 51.26; H, 6.08;
N, 10.50.
A mixture of the epoxide (R)-1 (0.200 g, 1.03 mmol), sodium azide
(0.161 g, 2.47 mmol) and ammonium sulfate (0.245 g, 1.85 mmol) in
methanol (2 mL) was stirred at 65 °C for 4 h. After evaporation of
solvents the residue was suspended in ethyl acetate (5 mL) and filtered
through a layer of Celite. The solution was concentrated in vacuo to
give diethyl (R)-3-azido-2-hydroxypropylphosphonate (R)-2 (0.198 g,
80%; ee 96%) as a yellowish oil. ½a D20
ꢁ
¼ ꢂ4:4 (c 1.45, CHCl3), IR (film):
4.5.3. Diethyl (R)-2-hydroxy-3-(4-phenyl-1,2,3-triazol-1-
yl)propylphosphonate (R)-3c
From (R)-2 (0.116 g, 0.491 mmol), phenylacetylene 7c
(0.054 mL, 0.491 mmol), CuSO4ꢀ5H2O (0.012 g), sodium ascorbate
(0.019 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phospho-
nate (R)-3c (0.158 g, 95%; ee 96%) was obtained as a white solid
m
= 3339, 2985, 2931, 2911, 2105, 1225, 1029 cmꢂ1 1H NMR
;
(300 MHz, C6D6): d = 0.87 and 0.89 (2t, J = 6.8 Hz, 6H, 2 ꢃ POCH2CH3),
1.60 (ddd, J = 19.2 Hz, J = 15.0 Hz, J = 3.3 Hz, 1H, H-1b), 1.81 (ddd,
J = 16.5 Hz, J = 15.0 Hz, J = 9.6 Hz, 1H, H-1a), 2.02 (br s, 1H, OH), 2.87–
2.82 (m, 2H, H-3a, H-3b), 3.91–3.72 (m, 4H, 2 ꢃ POCH2CH3), 4.16–
4.03 (m, 1H, H-2); 13C NMR (75.5 MHz, CDCl3): d = 16.2 (d, J = 6.3 Hz,
POCC), 30.7 (d, J = 139.4 Hz, C-1), 56.5 (d, J = 14.3 Hz, C-3), 61.7 and
61.9 (2d, J = 6.6 Hz, POC), 65.7 (d, J = 2.9 Hz, C-2); 31P NMR
(121.5 MHz, CDCl3): d = 30.18. Anal. Calcd for C7H16N3O4P: C, 35.45;
H, 6.80; N, 17.72. Found: C, 35.26; H, 6.60; N, 17.62.
after purification on
a silica gel with chloroform–methanol
(100:1, v/v) and crystallisation from ethyl acetate–petroleum
ether. Mp 87–89 °C. ½a D20
ꢁ
¼ þ0:7 (c 2.02, CHCl3), ee 96%; IR (KBr):
m
= 3327, 2984, 2908, 1227, 1029, 965 cmꢂ1 1H NMR (300 MHz,
;
CDCl3): d = 1.30 and 1.31 (2t, J = 7.2 Hz, 6H, 2 ꢃ POCH2CH3), 1.85
(ddd, J = 17.1 Hz, J = 15.3 Hz, J = 9.3 Hz, 1H, H-1b), 2.02 (ddd,
J = 18.6 Hz, J = 15.3 Hz, J = 3.3 Hz, 1H, H-1a), 4.02–4.17 (m, 5H,
2 ꢃ POCH2CH3, OH), 4.38–4.50 (m, 2H, H-3b, H-2), 4.56–4.63 (m,
1H, H-3a), 7.29–7.34 (m, 1H, Ar-H), 7.37–7.43 (m, 2H, Ar-H),
4.5. Synthesis of phosphonates (R)-3a–h, general procedure
To a solution of (R)-2 (1 mmol) in t-BuOH (0.5 mL) and H2O
(1 mL) were added CuSO4ꢀ5H2O (0.1 mmol), sodium ascorbate

I. E. Głowacka / Tetrahedron: Asymmetry 20 (2009) 2270–2278
2275
7.79–7.83 (m, 2H, Ar-H), 7.99 (s, 1H, HC5 ); 13C NMR (75.5 MHz,
(300 MHz, CDCl3): d = 1.33 and 1.34 (2t, J = 6.9 Hz, 6H, 2x POCH2CH3),
1.80 (br s, 1H, OH), 1.83 (ddd, J = 16.8 Hz, J = 15.3 Hz, J = 9.3 Hz, 1H, H-
1b), 2.03 (ddd, J = 19.2 Hz, J = 15.3 Hz, J = 3.0 Hz, 1H, H-1a), 4.06–4.21
(m, 4H, 2 ꢃ POCH2CH3),4.40–4.66(m, 3H,H-2, H-3a,H-3b), 6.87–7.03
0
CDCl3): d = 16.4 and 16.5 (2d, J = 6.0 Hz, POCC), 30.8 (d,
J = 139.7 Hz, C-1), 56.1 (d, J = 15.9 Hz, C-3), 62.2 and 62.3 (2d,
J = 7.3 Hz, 2 ꢃ POC), 65.5 (d, J = 3.8 Hz, C-2), 121.5 (s, HC@C),
125.5, 128.0, 128.6 (Carom.), 130.4 (s, Cipso), 147.3 (HC@C); 31PNMR
(121.5 MHz, CDCl3): d = 28.89. Anal. Calcd for C15H22N3O4P: C,
53.09; H, 6.53; N, 12.38. Found: C, 53.19; H, 6.60; N, 12.42.
0
(m, 2H, Ar-H), 7.35–7.42 (m, 1H, Ar-H), 8.09 (d, J = 3.9 Hz, HC5 ), 8.26
(dt, J = 8.4 Hz, J = 6.3 Hz, 1H, Ar-H); 13C NMR (75.5 MHz, CDCl3):
d = 16.5 and 16.6 (2d, J = 6.0 Hz, POCC), 30.9 (d, J = 140.4 Hz, C-1),
56.2 (d, J = 17,4 Hz, C-3), 62.3 and 62.5 (2d, J = 6.8 Hz, POC), 65.6 (d,
J = 3.8 Hz, C-2), 104.1 (t, J = 30.2 Hz, C-3arom.), 112.0 (dd, J = 21.2 Hz,
J = 3.4 Hz, C-1arom.), 115.0 (dd, J = 13.2 Hz, J = 3.7 Hz, C-5arom.), 124.1
(d, J = 12.0 Hz, C-6arom.), 128.6 (dd, J = 9.7 Hz, J = 5.2 Hz, HC@C),
140.4 (s, C@C–Ph), 159.2 (dd, J = 249.2 Hz, J = 12.3 Hz, C-2arom.),
162.4 (dd, J = 249.2 Hz, J = 12.6 Hz, C-4arom.); 31P NMR (121.5 MHz,
CDCl3): d = 29.65. Anal. Calcd for C15H20F2N3O4P: C, 48.00; H, 5.37;
N, 11.20. Found: C, 48.25; H, 5.06; N, 11.14.
4.5.4. Diethyl (R)-3-[4-(2-fluorophenyl)-1,2,3-triazol-1-yl]-2-
hydroxypropylphosphonate (R)-3d
From (R)-2 (0.149 g, 0.628 mmol), 1-ethynyl-2-fluorobenzene 7d
(0.071 mL, 0.628 mmol), CuSO4ꢀ5H2O (0.016 g), sodium ascorbate
(0.025 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phosphonate
(R)-3d (0.196 g, 88%) was obtained as a colourless oil after purifica-
tion on
¼ þ0:6 (c 1.48, CHCl3), ee 92%; IR (film):
1478, 1221, 1028, 967, 818, 762 cmꢂ1 1H NMR (300 MHz, CDCl3):
a
silica gel with chloroform–methanol (100:1, v/v).
½
a 2D0
ꢁ
m
= 3339, 2984, 2911,
;
4.5.7. Diethyl (R)-2-hydroxy-3-[4-(2-pyridinyl)-1,2,3-triazol-1-
yl]propylphosphonate (R)-3g
d = 1.33 and 1.34 (2t, J = 6.9 Hz, 6H, 2 ꢃ POCH2CH3), 1.83 (ddd,
J = 16.5 Hz, J = 15.3 Hz, J = 9.3 Hz, 1H, H-1b), 1.80 (br s, 1H, OH),
2.03 (ddd, J = 18.6 Hz, J = 15.3 Hz, J = 3.3 Hz, 1H, H-1a), 4.06–4.21
(m, 4H, 2 ꢃ CH3CH2OP), 4.41–4.66 (m, 3H, H-2, H-3a, H-3b), 7.14
(ddd, J = 10.8 Hz, J = 7.8 Hz, J = 1.2 Hz, 1H, Ar-H), 7.22–7.35 (m, 2H,
From (R)-2 (0.225 g, 0.95 mmol), 1-ethynyl-2-pyridine 7g
(0.096 mL, 0.95 mmol), CuSO4ꢀ5H2O (0.024 g), sodium ascorbate
(0.038 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phospho-
nate (R)-3e (0.285 g, 88%) was obtained as a yellowish oil after
purification on a silica gel with chloroform–methanol (100:1, v/
0
Ar-H), 8.14 (d, J = 3.6 Hz, HC5 ), 8.28 (dt, J = 7.5 Hz, J = 1.8 Hz, 1H,
Ar-H); 13C NMR (75.5 MHz, CDCl3): d = 16.4 and 16.5 (2d,
J = 6.8 Hz, POCC), 31.0 (d, J = 140.3 Hz, C-1), 56.2 (d, J = 16.9 Hz, C-
3), 62.3 and 62.4 (2d, J = 6.6 Hz, POC), 65.6 (d, J = 3.1 Hz C-2), 115.7
(d, J = 21.8 Hz, C-3arom.), 118.5 (d, J = 12.9 Hz, C-1arom.), 124.6 (d,
J = 12.6 Hz, Carom.), 124.6 (d, J = 3.4 Hz, Carom.), 127.6 (d, J = 3.4 Hz,
HC@C), 129.2 (d, J = 8.6 Hz, C-4arom.), 141.0 (s, C@CH), 159.1 (d,
J = 247.6 Hz, C–F); 31P NMR (121.5 MHz, CDCl3): d = 28.91. Anal.
Calcd for C15H21FN3O4P: C, 50.42; H, 5.92; N, 11.76. Found: C,
50.44; H, 5.96; N, 11.62.
v). ½a 2D0
ꢁ
¼ ꢂ2:3 (c 1.82, CHCl3), ee 94%; IR (film):
m
= 3339, 3104,
2925, 2851, 1636, 1612, 1226, 1163, 1080, 786 cmꢂ1
;
1H NMR
(300 MHz, CDCl3): d = 1.34 and 1.37 (2t, J = 7.0 Hz, 6H, 2 ꢃ
POCH2CH3), 1.91–2.22 (m, 2H, H-1b, H-1a), 4.05–4.21 (m, 4H,
2 ꢃ POCH2CH3), 4.21–4.59 (m, 3H, H-2, H-3b, OH), 4.61 (dd,
J = 14.2 Hz, J = 4.0 Hz, 1H, H-3a), 7.22–7.26 (m, 1H, Ar-H), 7.80 (dt,
J = 7.8 Hz, J = 1.8 Hz, 1H, Ar-H), 8.16 (d, J = 7.8 Hz, 1H, Ar-H), 8.38
(s, 1H, HC5 ), 8.37–8.60 (m 1H, Ar-H); 13C NMR (75.5 MHz, CDCl3):
0
d = 16.6 and 16.7 (2d, J = 6.0 Hz, POCC), 31.0 (d, J = 140.4 Hz, C-1),
56.3 (d, J = 17.4 Hz, C-3), 62.3 and 62.5 (2d, J = 6.0 Hz, POC), 65.7
(d, J = 3.7 Hz C-2), 120.4 (s, Carom.), 123.0 (s, HC@C), 124.0, 137.2
(s, Carom.), 147.9 (s, C@CH), 149.2, 150.1 (s, Carom.); 31P NMR
(121.5 MHz, CDCl3): d = 29.52. Anal. Calcd for C14H21N4O4P: C,
49.41; H, 6.22; N, 16.46. Found: C, 49.26; H, 6.34; N, 16.41.
4.5.5. Diethyl (R)-3-[4-(3-fluorophenyl)-1,2,3-triazol-1-yl]-2-
hydroxypropylphosphonate (R)-3e
From (R)-2 (0.239 g, 1.01 mmol), 1-ethynyl-3-fluorobenzene 7e
(0.116 mL, 1.01 mmol), CuSO4ꢀ5H2O (0.025 g), sodium ascorbate
(0.040 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phosphonate
(R)-3e (0.328 g, 91%) was obtained as a colourless oil after purifica-
4.5.8. Diethyl (R)-2-hydroxy-3-[4-(1-methyl-1H-imidazol-5-yl)-
1,2,3-triazol-1-yl]propylphosphonate (R)-3h
tion on
¼ þ0:6 (c 2.06, CHCl3), ee 96%; IR (film):
2911, 1466, 1229, 1030, 967, 866, 787 cmꢂ1
a silica gel with chloroform–methanol (100:1, v/v).
From (R)-2 (0.206 g, 0.87 mmol), 5-ethynyl-1-methyl-1H-imid-
azole 7h (0.088 mL, 0.87 mmol), CuSO4ꢀ5H2O (0.022 g), sodium
ascorbate (0.034 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL),
phosphonate (R)-3h (0.225 g, 75%) was obtained as a white solid
after purification on a silica gel with chloroform–methanol (100:1,
½
a 2D0
ꢁ
m
;
= 3326, 3141, 2985,
1H NMR (300 MHz,
CDCl3): d = 1.33 and 1.35 (2t, J = 6.9 Hz, 6H, 2 ꢃ POCH2CH3), 1.80
(ddd, J = 16.8 Hz, J = 15.3 Hz, J = 9.6 Hz, 1H, H-1b), 1.85 (br s, 1H,
OH), 1.97–2.09 (m, 1H, H-1a), 4.05–4.21 (m, 4H, 2 ꢃ POCH2CH3),
4.39–4.51 (m, 2H, H-2, H-3b), 4.56–4.66 (m, 1H, H-3b), 6.99–7.06
(m, 1H, Ar-H), 7.35–7.42 (m, 1H, Ar-H), 7.55–7.62 (m, 2H, Ar-H),
v/v). ½a 2D0
ꢁ
¼ ꢂ2:4 (c 1.82, CHCl3), ee 92%; IR (KBr):
m
= 3392, 2985,
2911, 1656, 1629, 1510, 1230, 1029, 966, 833 cmꢂ1
;
1H NMR
(300 MHz, CDCl3): d = 1.34 and 1.35 (2t, J = 6.9 Hz, 6H, 2 ꢃ POCH2-
CH3), 1.84–2.12 (m, 2H, H-1a, H-1b), 3.05 (br s, 1H, OH), 3.91 (s,
3H, CH3–N), 4.07–4.21 (m, 4H, 2 ꢃ POCH2CH3), 4.39–4.51 (m, 2H,
H-2, H-3b), 4.60–4.68 (m, 1H, H-3a), 7.20 (br s, 1H, Himid), 7.56 (br
8.01 (s, 1H, HC5 ); 13C NMR (75.5 MHz, CDCl3): d = 16.5 and 16.6
0
(2d, J = 6.0 Hz, POCC), 30.9 (d, J = 140.0 Hz, C-1), 56.2 (d, J = 17.2 Hz,
C-3), 62.4 and 62.5 (2d, J = 6.9 Hz, POC), 65.6 (d, J = 3.7 Hz C-2),
112.7 (d, J = 22.9 Hz, C-2arom.), 114.9 (d, J = 21.2 Hz, Carom.), 121.3
(d, J = 2.9 Hz, Carom.), 122.1 (s, HC@C) 130.5 (d, J = 8.3 Hz, Carom.),
146.4 (s, C@CH), 163.1 (d, J = 245.1 Hz, C–F); 31P NMR (121.5 MHz,
CDCl3): d = 28.93. Anal. Calcd for C15H21FN3O4P: C, 50.42; H, 5.92;
N, 11.76. Found: C, 50.28; H, 5.89; N, 11.64.
s, 1H, Himid), 7.94 (s, 1H, HC5 ); 13C NMR (75.5 MHz, CDCl3):
0
d = 16.5 and 16.6 (2d, J = 6.0 Hz, POCC), 31.3 (d, J = 140.0 Hz, C-1),
33.8 (s, CH3–N), 56.4 (d, J = 16.0 Hz, C-3), 62.2 and 62.4 (2d,
J = 6.6 Hz, POC), 65.4 (d, J = 3.1 Hz C-2), 122.7, 123.6, 127.8 (s, HC@C),
137.9 (s, HC@C), 139.1 (s, N–CH–N); 31P NMR (121.5 MHz, CDCl3):
d = 28.70. Anal. Calcd for C13H22N5O4P: C, 45.48; H, 6.46; N, 20.40.
Found: C, 45.64; H, 6.54; N, 20.48.
4.5.6. Diethyl (R)-3-[4-(2,4-difluorophenyl)-1,2,3-triazol-1-yl]-
2-hydroxypropylphosphonate (R)-3f
From (R)-2 (0.250 g, 1.05 mmol), 1-ethynyl-2,4-difluorobenzene
7f (0.145 g, 1.05 mmol), CuSO4ꢀ5H2O (0.026 g), sodium ascorbate
(0.040 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phosphonate
(R)-3f(0.356 g, 90%) wasobtainedasa white solid aftercrystallisation
4.6. Diethyl (R)-3-(5-amino-4-carbamoyl-1,2,3-triazol-1-yl) 2-
hydroxypropylphosphonate (R)-3i
4.6.1. Synthesis of diethyl (R)-3-azido-2-
benzyloxypropylphosphonate (R)-8
A suspension of (R)-2 (0.645 g, 2.72 mmol), benzyl bromide
(0.502 mL, 4.35 mmol), Ag2O (1.01 g, 4.35 mmol) and powdered
from ethyl acetate–petroleum ether. Mp 93–94 °C. ½a D20
¼ ꢂ1:0
ꢁ
(c 3.51, CHCl3), ee 96%; IR (KBr):
m = 3286, 3136, 2988, 2907, 1628,
1600, 1561, 1493, 1196, 1072, 1036, 979, 826 cmꢂ1 1H NMR
;

2276
I. E. Głowacka / Tetrahedron: Asymmetry 20 (2009) 2270–2278
molecular sieves 4 Å was stirred at room temperature for 4 h. After
filtration through a pad of Celite, the solvent was evaporated and
the crude product was purified on a silica gel column with chloro-
form–methanol (100:1, v/v) to give (R)-8 (0.773 g, 87%) as a colour-
d = 29.87. Anal. Calcd for C10H20N5O5P: C, 37.39; H, 6.28; N,
21.80. Found: C, 37.44; H, 6.33; N, 21.88.
4.6.4. Diethyl (R)-3-(5-amino-4-carbamoyl-1,2,3-triazol-1-yl)-
2-hydroxypropylphosphonate (R)-3i
less oil. ½a 2D0
ꢁ
¼ ꢂ6:6 (c 3.07, CHCl3); IR (film):
m
;
= 3429, 2983, 2930,
2871, 2104, 1245, 1052, 964, 740, 700 cmꢂ1
1H NMR (300 MHz,
To a solution of 2-cyanoacetamide (0.102 g, 1.21 mmol) in DMSO
(0.5 mL) was added K2CO3 (0.167 g, 1.21 mmol) at room tempera-
ture under an argon atmosphere. The mixture was stirred at the
same temperature for 30 min. After the addition of diethyl (R)-3-azi-
do-2-hydroxypropylphosphonate (R)-2 (0.143 g, 0.603 mmol) in
DMSO (0.5 mL), stirring was continued for 5 h at 50 °C. After evapo-
ration of the solvent, the residue was purified by silica gel column
chromatography with chloroform–methanol (200:1, 100:1, 50:1,
20:1 v/v) and the appropriate fractions were crystallised from meth-
anol–diethyl etherto give(R)-3i (0.136 g, 70%)as a white amorphous
CDCl3): d = 1.28 and 1.31 (2t, J = 6.8 Hz, 6H, 2 ꢃ POCH2CH3), 2.07
(ddd, J = 18.2 Hz, J = 15.6 Hz, J = 7.5 Hz, 1H, H-1b), 2.18 (ddd,
J = 19.5 Hz, J = 15.6 Hz, J = 5.7 Hz, 1H, H-1a), 3.38 (dd, J = 13.2 Hz,
J = 5.7 Hz, 1H, H-3b), 3.54 (dd, J = 13.2 Hz, J = 3.6 Hz, 1H, H-3a),
3.91–4.00 (m, 1H, H-2), 4.03–4.16 (m, 4H, 2 ꢃ POCH2CH3), 4.64
(AB, JAB = 12.9 Hz, 2H, HaHbC–Ph), 7.25–7.42 (m, 5H, Ar-H); 13C
NMR (75.5 MHz, CDCl3): d = 16.5 (d, J = 6.3 Hz, POCC), 29.1 (d,
J = 139.2 Hz, C-1), 54.1 (d, J = 7.7 Hz, C-3), 61.8 and 61.9 (2d,
J = 6.6 Hz, POC), 71.9 (s, CH2Ph), 73.7 (s, C-2), 127.8, 127.8, 128.3
(Carom.); 31P NMR (121.5 MHz, CDCl3): d = 27.64. Anal. Calcd for
C14H22N3O4P:C, 51.37; H, 6.77; N, 12.84. Found: C, 51.16; H, 6.64;
N, 11.94.
solid. Mp 153–154 °C. ½a D20
¼ ꢂ1:0 (c 3.52, CH3OH), ee 96%; IR (KBr):
ꢁ
m
= 3486, 3366, 3193, 2956, 2911, 1665, 1638, 1239, 1030, 949 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d = 1.33 and 1.35 (2t, J = 6.9 Hz, 6H,
2 ꢃ POCH2CH3), 1.81 (ddd, J = 16.2 Hz, J = 15.3 Hz, J = 10.5 Hz, 1H,
H-1b), 2.02 (ddd, J = 19.2 Hz, J = 15.3 Hz, J = 3.0 Hz, 1H, H-1a), 2.70
(br s, 1H, OH), 4.05–4.42 (m, 4H, 2 ꢃ POCH2CH3), 4.26 (dd,
J = 14.4 Hz, J = 5.1 Hz, H-3b), 4.35–4.50 (m, 2H, H-2, H-3a), 5.79 (br
s, 2H, C(O)NH2), 5.48 and 6.74 (2 ꢃ br s, 2H, NH2); 13C NMR
(75.5 MHz, CDCl3): d = 16.6 and 16.7 (2d, J = 6.0 Hz, POCC), 30.3 (d,
J = 139.7 Hz, C-1), 52.6 (d, J = 17.4 Hz, C-3), 62.7 and 62.8 (2d,
J = 6.8 Hz, 2 ꢃ POC), 67.0 (d, J = 3.0 Hz, C-2), 123.0 (s, HC@C), 146.5
(s, HC@C), 164.6 (s, C@O); 31P NMR (121.5 MHz, CDCl3): d = 29.87.
Anal. Calcd for C10H20N5O5P: C, 37.39; H, 6.28; N, 21.80. Found: C,
37.44; H, 6.33; N, 21.88.
4.6.2. Synthesis of diethyl (R)-3-(5-amino-4-carbamoyl-1,2,3-
triazol-1-yl)-2-benzyloxypropylphosphonate (R)-9i
To a solution of 2-cyanoacetamide (0.227 g, 2.68 mmol) in DMSO
(2 mL) was added K2CO3 (0.371 g, 2.68 mmol) at room temperature
under an argon atmosphere. The mixture was stirred at the same
temperature for 30 min. After the addition of diethyl (R)-2-benzyl-
oxy-3-azidopropylphosphonate (R)-8 (0.439 g, 1.34 mmol) in DMSO
(1 mL), the stirring was continued for 5 h at 50 °C. After evaporation
of the solvent, the residue was purified by silica gel column chroma-
tography with chloroform–methanol (200:1, v/v) to give (R)-9i
(0.386 g, 70%) as a colourless oil. ½a D20
¼ ꢂ3:2 (c 2.01, CHCl3); IR
ꢁ
(film):
m
= 3414, 3319, 3180, 2986, 2922, 2864, 1658, 1244, 1025,
4.7. Diethyl (R)-2-hydroxy-3-(4,5-dimetoxycarbonyl-1,2,3-
triazol-1-yl)propylphosphonate (R)-3j
966, 698 cmꢂ1 1H NMR (300 MHz, CDCl3): d = 1.31 (t, J = 6.9 Hz,
;
6H, 2 ꢃ POCH2CH3), 2.02–2.16 (m, 2H, H-1a, H-1b), 4.06–4.25 (m,
5H, 2 ꢃ POCH2CH3, H-2), 4.38 (dd, J = 14.7 Hz, J = 6.6 Hz, 1H, H-3b),
4.55 (AB, JAB = 11.4 Hz, 2H, HaHbC–Ph), 4.58 (dd, J = 14.7 Hz,
J = 3.6 Hz, 1H, H-3a), 5.69 (br s, 2H, C(O)NH2), 5.46 and 6.84 (2 ꢃ br
s, 2H, NH2), 7.22–7.46 (m, 5H, Ar-H); 13C NMR (75.5 MHz, CDCl3):
d = 16.6 (d, J = 6.0 Hz, POCC), 28.3 (d, J = 138.2 Hz, C-1), 50.2 (d,
J = 5.4 Hz, C-3), 62.2 and 62.4 (2d, J = 6.0 Hz, 2 ꢃ POC), 72.1 (s,
CH2Ph), 73.5 (s, C-2), 122.3 (s, C–NH2), 128.0, 128.2, 128.5, 136.5
(Carom.), 145.7, 164.8 (s, C@O); 31P NMR (121.5 MHz, CDCl3):
d = 27.97. Anal. Calcd for C17H26N5O5P: C, 49.63; H, 6.37; N, 17.02.
Found: C, 49.44; H, 6.18; N, 17.08.
A solution of azide (R)-2 (0.346 g, 1.46 mmol) and dimethyl acet-
ylenedicarboxylate 7j (0.179 mL, 1.46 mmol) in toluene (2 mL) was
refluxed for 4 h. The mixture was concentrated to dryness to leave a
yellow solid (0.549 g), which was chromatographed on a silica gel
column with chloroform–methanol (100:1, v/v) and was later crys-
tallised from ethyl acetate–petroleum ether to give enantiomeri-
cally pure (R)-3j (0.523 g, 95%) as a white solid. Mp 76–78 °C.
½
a 2D0
ꢁ
¼ ꢂ3:7 (c 1.82, CHCl3); IR (KBr):
m
= 3302, 2986, 2957, 2911,
1737, 1468, 1440, 1224, 1025, 963, 826, 754 cmꢂ1
;
1H NMR
(300 MHz, CDCl3): d = 1.33 and 1.34 (2t, J = 7.2 Hz, 6H,
2 ꢃ POCH2CH3), 1.80 (ddd, J = 16.5 Hz, J = 15.3 Hz, J = 9.9 Hz, 1H, H-
1a), 2.04 (ddd, J = 19.8 Hz, J = 15.3 Hz, J = 3.0 Hz, 1H, H-1b), 2.15 (br
s, 1H, OH), 3.98 (s, 3H, COOCH3), 3.99 (s, 3H, COOCH3), 4.05–4.24
(m, 4H, 2 ꢃ POCH2CH3), 4.39 (ddddd, J = 11.4 Hz, J = 9.9 Hz,
J = 6.3 Hz, J = 3.9 Hz, J = 3.0 Hz, 1H, H-2), 4.70 (d, J = 13.8 Hz,
J = 6.3 Hz, 1H, H-3a), 4.82 (ddd, J = 13.8 Hz, J = 3.9, J = 1.5 Hz, 1H, H-
3b); 13C NMR (75.5 MHz, CDCl3): d = 16.5 and 16.6 (2d, J = 6.0 Hz,
POCC), 30.9 (d, J = 140.4 Hz, C-1), 52.8 (s, COOCH3), 56.3 (s, COOCH3),
55.3 (d, J = 18.9 Hz, C-3), 62.4 and 62.6 (2d, J = 6.8 Hz, 2 ꢃ POC), 65.6
(d, J = 3.8 Hz, C-2), 132.1 (s, HC@C), 139.2 (s, HC@C), 159.3 (s, C@O),
160.3 (s, C@O); 31P NMR (121.5 MHz, CDCl3): d = 29.21. Anal. Calcd
for C13H22N3O8P: C, 41.16; H, 5.84; N, 11.08. Found: C, 41.41; H,
5.76; N, 10.93.
4.6.3. Diethyl (R)-3-(5-amino-4-carbamoyl-1,2,3-triazol-1-yl)-
2-hydroxypropylphosphonate (R)-3i
A solution of (R)-9i (0.317 g, 0.77 mmol) in ethanol (3 mL) was
kept under a hydrogen atmosphere over palladium catalyst [20%
Pd(OH)2] (10 mg) at room temperature for 24 h. The suspension
was filtered through a pad of Celite and washed with methanol.
After evaporation of the solvent, the residue was chromatographed
on a silica gel column with chloroform–methanol (20:1, v/v) and
the appropriate fractions were crystallised from methanol–diethyl
ether to give (R)-3i (0.229 g, 92%) as a white amorphous solid. Mp
153–154 °C.
½
a 2D0
ꢁ
¼ ꢂ1:0 (c 3.52, CH3OH), ee 96%; IR (KBr):
m
= 3486, 3366, 3193, 2956, 2911, 1665, 1638, 1239, 1030,
949 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d = 1.33 and 1.35 (2t,
J = 6.9 Hz, 6H, 2 ꢃ POCH2CH3), 1.81 (ddd, J = 16.2 Hz, J = 15.3 Hz,
J = 10.5 Hz, 1H, H-1b), 2.02 (ddd, J = 19.2 Hz, J = 15.3 Hz, J = 3.0 Hz,
1H, H-1a), 2.70 (br s, 1H, OH), 4.05–4.42 (m, 4H, 2 ꢃ POCH2CH3),
4.26 (dd, J = 14.4 Hz, J = 5.1 Hz, H-3b), 4.35–4.50 (m, 2H, H-2, H-
3a), 5.79 (br s, 2H, C(O)NH2), 5.48 and 6.74 (2 ꢃ br s, 2H, NH2);
13C NMR (75.5 MHz, CDCl3): d = 16.6 and 16.7 (2d, J = 6.0 Hz, POCC),
30.3 (d, J = 139.7 Hz, C-1), 52.6 (d, J = 17.4 Hz, C-3), 62.7 and 62.8
(2d, J = 6.8 Hz, 2 ꢃ POC), 67.0 (d, J = 3.0 Hz, C-2), 123.0 (s, HC@C),
146.5 (s, HC@C), 164.6 (s, C@O); 31P NMR (121.5 MHz, CDCl3):
4.8. Hydrolytic kinetic resolution of racemic 1
A mixture of (R,R)-Salen CoII (0.024 g, 0.040 mmol), toluene
(0.4 mL) and acetic acid (4.6 ll, 0.074 mmol) was stirred in air at
room temperature for 1 h. After removal of the solvent, the brown
residue was vacuum dried. The racemic epoxide (3.601 g,
18.6 mmol) was added to the catalyst in one portion and the mix-
ture was cooled in an ice-water bath. Water (0.200 mL, 11.0 mmol,
0.55 equiv) was added over 10 min. After 1 h, the bath was re-

I. E. Głowacka / Tetrahedron: Asymmetry 20 (2009) 2270–2278
2277
moved and the reaction mixture was stirred at room temperature
4.10.3. Diethyl (S)-2-hydroxy-3-(4-phenyl-1,2,3-triazol-1-
yl)propylphosphonate (S)-3c
for 72 h. Ethyl acetate (6 mL) was added followed by MgSO4 (0.5 g).
After removal of the drying agent and the solvent, the crude prod-
uct was subjected to distillation to give (S)-1 (1.266 g, 35%) as a
From (S)-2 (0.160 g, 0.675 mmol), phenylacetylene 7c (0.074 mL,
0.675 mmol), CuSO4ꢀ5H2O (0.017 g), sodium ascorbate (0.027 g) in a
mixture of t-BuOH (0.5 mL)–H2O (1 mL), phosphonate (S)-3c
(0.198 g, 86%) was obtained as a colourless oil after purification on
colourless oil (bp 79–84 °C/0.3 mmHg). ½aꢁD ¼ ꢂ3:0 (c 1.25, etha-
nol) ee 93%. 31P NMR (121.5 MHz, CDCl3): d = 26.82.
4.9. Reaction of epoxide (S)-1 with sodium azide
a silica gel with chloroform–methanol (100:1, v/v). ½a D20
¼ ꢂ0:8 (c
ꢁ
1.93, CHCl3), ee 95%. Anal. Calcd for C15H22N3O4P: C, 53.09; H,
6.53; N, 12.38. Found: C, 53.16; H, 6.70; N, 12.28.
4.9.1. Reaction of epoxide (S)-1 with sodium azide in the
presence of NH4Cl
4.10.4. Diethyl (S)-3-[4-(2-fluorophenyl)-1,2,3-triazol-1-yl]-2-
hydroxypropylphosphonate (S)-3d
A mixture of epoxide (S)-1 (0.868 g, 4.47 mmol), sodium azide
(0.697 g, 10.7 mmol) and ammonium chloride (0.359 g, 6.71
mmol) in methanol (5 mL) was stirred at 65 °C for 4 h. After evap-
oration of solvents, the residue was suspended in ethyl acetate
(10 mL) and filtered through a layer of Celite. The solution was
concentrated in vacuo to give a 94:6 mixture of diethyl (S)-3-azi-
do-2-hydroxypropylphosphonate (S)-2 (ee 93%) and diethyl (S)-3-
chloro-2-hydroxypropylphosphonate (S)-6 (1.043 g) in 98% yield.
The crude product was chromatographed on a silica gel column
with chloroform-methanol (100:1, v/v) to give a 96:4 mixture of
(S)-2 (ee 96%) and (S)-6 (0.943 g, 89%). 31P NMR (121.5 MHz,
CDCl3): d = 30.18 for (S)-2 and 29.81 for (S)-6.
From (S)-2 (0.195 g, 0.822 mmol), 1-ethynyl-2-fluorobenzene
7d (0.093 mL, 0.822 mmol), CuSO4ꢀ5H2O (0.021 g), sodium
ascorbate (0.033 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL),
phosphonate (S)-3d (0.281 g, 95%) was obtained as a white
solid after purification on silica gel with chloroform–methanol
(100:1, v/v) and crystallisation from diethyl ether–petroleum
ether.
½
a 2D0
ꢁ
¼ 0:6 (c 2.08, CHCl3), ee 91%. Anal. Calcd for
C15H21FN3O4P: C, 50.42; H, 5.92; N, 11.76. Found: C, 50.51; H,
6.04; N, 11.52.
4.10.5. Diethyl (S)-3-[4-(3-fluorophenyl)-1,2,3-triazol-1-yl]-2-
hydroxypropylphosphonate (S)-3e
4.9.2. Reaction of epoxide (S)-1 with sodium azide in the
presence of (NH4)2SO4
From (S)-2 (0.201 g, 0.847 mmol), 1-ethynyl-3-fluorobenzene
7e (0.098 mL, 0.847 mmol), CuSO4ꢀ5H2O (0.021 g), sodium ascor-
bate (0.034 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phos-
phonate (S)-3e (0.262 g, 86%) was obtained as a colourless oil
after purification on silica gel with chloroform–methanol (100:1,
A mixture of the epoxide (S)-1 (0.200 g, 1.03 mmol), sodium
azide (0.161 g, 2.47 mmol) and ammonium sulfate (0.245 g,
1.85 mmol) in methanol (2 mL) was stirred at 65 °C for 4 h. After
evaporation of solvents the residue was suspended of ethyl acetate
(5 mL) and filtered through a layer of Celite. The solution was con-
centrated in vacuo to give of diethyl (S)-3-azido-2-hydrox-
ypropylphosphonate (S)-2 (0.206 g, 83%; ee 96%) as a yellowish
50:1 v/v). ½a 2D0
¼ ꢂ0:7 (c 2.22, CHCl3), ee 96%. Anal. Calcd for
ꢁ
C15H21FN3O4P: C15H21FN3O4P: C, 50.42; H, 5.92; N, 11.76. Found:
C, 50.61; H, 6.10; N, 11.84.
oil. ½a 2D0
ꢁ
¼ þ4:1 (c 1.63, CHCl3).
4.10.6. Diethyl (S)-3-[4-(2,4-difluorophenyl)-1,2,3-triazol-1-yl]-
2-hydroxypropylphosphonate (S)-3f
4.10. Synthesis of phosphonates (S)-3a–h, general procedure
From (S)-2 (0.190 g, 0.801 mmol), 1-ethynyl-2,4-difluoroben-
zene 7f (0.111 g, 0.801 mmol), CuSO4ꢀ5H2O (0.020 g), sodium
ascorbate (0.032 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL),
phosphonate (S)-3f (0.286 g, 95%) was obtained as a white solid
after crystallisation from ethyl acetate–petroleum ether. Mp 92–
To a solution of (S)-2 (1 mmol) in t-BuOH (0.5 mL) and H2O
(1 mL) were added CuSO4ꢀ5H2O (0.1 mmol), sodium ascorbate
(0.2 mmol) and selected alkynes 7a–h (1 mmol). This suspension
was stirred vigorously at room temperature for 48–72 h. The reac-
tion mixture was extracted with chloroform (3 ꢃ 5 mL), dried over
MgSO4, filtered through Celite and evaporated. The crude product
was purified by column chromatography on silica gel or crystal-
lised to give (S)-3a–h.
93 °C.
½
a 2D0
ꢁ
¼ þ1:0 (c 4.23, CHCl3), ee 96%. Anal. Calcd for
C15H20F2N3O4P: C, 48.00; H, 5.37; N, 11.20. Found: C, 48.11; H,
5.40; N, 11.31.
4.10.7. Diethyl (S)-2-hydroxy-3-[4-(2-pyridinyl)-1,2,3-triazol-1-
yl]propylphosphonate (S)-3g
4.10.1. Diethyl (S)-2-hydroxy-3-(4-methoxycarbonyl-1,2,3-
triazol-1-yl)propylphosphonate (S)-3a
From (S)-2 (0.170 g, 0.717 mmol), 1-ethynyl-2-pyridine 7g
(0.072 mL, 0.717 mmol), CuSO4ꢀ5H2O (0.018 g), sodium ascorbate
(0.028 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phospho-
From (R)-2 (0.191 g, 0.81 mmol), methyl propiolate 7a
(0.072 mL, 0.81 mmol), CuSO4ꢀ5H2O (0.020 g), sodium ascorbate
(0.032 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phospho-
nate (S)-3a (0.247 g, 95%) was obtained as a white solid after crys-
tallisation from ethyl acetate–diethyl ether. Mp 103–104 °C.
nate (S)-3e (0.223 g, 91%) was obtained as
after purification on a silica gel with chloroform–methanol (50:1,
v/v).
a yellowish oil
½
a 2D0
ꢁ
¼ þ2:2 (c 2.01, CHCl3), ee 94%. Anal. Calcd for
C14H21N4O4P ꢃ H2O: C, 46.92; H, 6.47; N, 15.64. Found: C, 47.06;
½
a 2D0
ꢁ
¼ þ3:9 (c 2.35, CHCl3), ee 97%. Anal. Calcd for C11H20N3O6P:
H, 6.54; N, 15.77.
C, 41.12; H, 6.28; N, 13.08. Found: C, 41.20; H, 6.46; N, 13.28.
4.10.8. Diethyl (S)-2-hydroxy-3-[4-(1-methyl-1H-imidazol-5-
yl)-1,2,3-triazol-1-yl]propylphosphonate (S)-3h
4.10.2. Diethyl (S)-3-(4-benzoyloxymethyl-1,2,3-triazol-1-yl)-2-
hydroxypropylphosphonate (S)-3b
From (S)-2 (0.154 g, 0.649 mmol), 5-ethynyl-1-methyl-1H-
imidazole 7h (0.066 mL, 0.649 mmol), CuSO4ꢀ5H2O (0.016 g),
sodium ascorbate (0.026 g) in a mixture of t-BuOH (0.5 mL)–H2O
(1 mL), phosphonate (S)-3h (0.179 g, 80%) was obtained as a
colourless oil after purification on a silica gel with chloroform–
From (S)-2 (0.169 g, 0.713 mmol), propargyl benzoate 7b
(0.103 mL, 0.713 mmol), CuSO4ꢀ5H2O (0.018 g), sodium ascorbate
(0.028 g) in a mixture of t-BuOH (0.5 mL)–H2O (1 mL), phosphonate
(S)-3b (0.196 g, 70%) was obtained as a colourless oil after purifica-
tion on a silica gel with chloroform–methanol (100:1, 50:1, 20:1 v/
methanol (20:1, v/v). ½a D20
¼ þ2:5 (c 2.15, CHCl3), ee 94%. Anal.
ꢁ
v). ½a 2D0
ꢁ
¼ þ1:5 (c 2.30, CHCl3), ee 96%. Anal. Calcd for C17H24N3O6P:
Calcd for C13H22N5O4P: C, 45.48; H, 6.46; N, 20.40. Found: C,
45.44; H, 6.21; N, 20.61.
C, 51.39; H, 6.09; N, 10.57. Found: C, 51.16; H, 6.18; N, 10.48.

2278
I. E. Głowacka / Tetrahedron: Asymmetry 20 (2009) 2270–2278
4.11. Diethyl (S)-2-hydroxy-3-(4,5-dimetoxycarbonyl-1,2,3-
triazol-1-yl)propylphosphonate (S)-3j
References
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Acknowledgements
The author is grateful to Professor Andrzej E. Wróblewski for
discussions and helpful suggestions during preparation of this
manuscript. Mrs. Małgorzata Pluskota is acknowledged for her
excellent technical assistance. Preliminary experiments in this
project were conducted by Tomasz Matusiak. This work was
´
supported by the Medical University of Łódz internal fund (503-
3014-1).