Synthesis of four enantiomerically pure 4-(4-carbamoyl-1,2,3-triazol-1-yl)- 2,3-dihydroxy-1-methoxybutylphosphonic acids

Article abstract of DOI:10.1016/j.tetasy.2005.11.010

CuCl-catalysed cycloaddition of methyl propiolate to O,O-diisopropyl (1S,2R,3S)- and (1R,2R,3S)-, or O,O-dibenzyl (1S,2R,3S)-, (1R,2R,3S)-, (1S,2R,3R)- and (1R,2R,3R)-4-azido-1,2,3-trihydroxy-2,3-O- isopropylidenebutylphosphonates followed by methylation

Full text of DOI:10.1016/j.tetasy.2005.11.010

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 4056–4064
Synthesis of four enantiomerically pure
4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-
methoxybutylphosphonic acids
*
´
Andrzej E. Wroblewski and Iwona E. Głowacka
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ło´dz´, Muszyn´skiego 1, 90-151 Ło´dz´, Poland
Received 13 October 2005; accepted 10 November 2005
Abstract—CuCl-catalysed cycloaddition of methyl propiolate to O,O-diisopropyl (1S,2R,3S)- and (1R,2R,3S)-, or O,O-dibenzyl
(1S,2R,3S)-, (1R,2R,3S)-, (1S,2R,3R)- and (1R,2R,3R)-4-azido-1,2,3-trihydroxy-2,3-O-isopropylidenebutylphosphonates followed
by methylation of HO–C-1, ammonolysis of methoxycarbonyl groups and hydrolysis of isopropylidene acetals led to diisopropyl
(1S,2R,3S)- and (1R,2R,3S)-4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonates or, after hydrogenolytic
removal of benzyl groups, to (1S,2R,3S)-, (1R,2R,3S)-, (1S,2R,3R)- and (1R,2R,3R)-4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihy-
droxy-1-methoxybutylphosphonic acids.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
logues of ribavirin29 2 was described.30 In the meantime
several 4-(1,2,3-triazole)carboxamide nucleoside ana-
logues (Fig. 1) have been prepared.31–33
Recent interest in 1,3-dipolar cycloadditions of azides
and alkynes was stimulated by the discovery of the cat-
alytic properties of Cu(I) salts, which allows complete
control of regioselectivity in the synthesis of 1,2,3-tri-
azoles from unsymmetrical alkynes.1,2 This regioselective
and quantitative transformation, classified among click
reactions,3 has found numerous applications in the syn-
thesis of novel compounds, for example, water-soluble
calixarenes,4 triazole-linked glycoconjugates,5 neoglyco-
conjugate6 and glycopeptides,7,8 peptides1 and cyclic
peptides,9 enzyme inhibitors,10–12 1,2,3-triazole-modi-
fied nucleic acids,13 vitamin D analogues,14,15 1,2,3-tri-
azole dendrimers,16,17 nucleoside analogues18,19 and
fluorescence coumarin dyes.20 Several compounds con-
taining a 1,2,3-triazole moiety have exhibited biological
activities including anti-allergic,21 anti-bacterial,22,23
anti-HIV24,25 and anti-epileptic.26 They were also found
acting as b3 selective adrenergic receptor agonists27 as
well as GABA-A a5 subtype inverse agonists.28
As the spatial separation of the 1,2,3-triazole ring mim-
icking a nucleobase and the phosphonate group as well
as absolute stereochemistries at secondary hydroxyl
functions may have played an important role in the
biological activity, we extended our studies to include
a functionalised butylphosphonate scaffold. Herein,
we report on the synthesis of enantiomerically pure
(1S,2R,3S)-, (1R,2R,3S)-, (1S,2R,3R)- and (1R,2R,3R)-
4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-meth-
oxybutylphosphonic acids.
2. Results and discussion
A thermal cycloaddition of methyl propiolate and diiso-
propyl 4-azido-1,2,3-trihydroxy-2,3-O-isopropylidene-
butylphosphonates,34 (1S,2R,3S)-3 or (1R,2R,3S)-5 led to
the formation of mixtures of regioisomeric 1,2,3-tri-
hydroxy-2,3-O-isopropylidene-4-[(4- and 5-methoxycar-
bonyl)-1,2,3-triazol-1-yl]butylphosphonates (1S,2R,3S)-4a
and (1S,2R,3S)-4b (Scheme 1) and phosphonates
(1R,2R,3S)-6a and (1R,2R,3S)-6b (Scheme 2) in both
cases in a 4:1 ratio (Table 1). The same ratios of the
regioisomers were observed for the dibenzyl esters
In our recent contribution to this area, the synthesis of
(1R,2S)- and (1S,2S)-3-(4-carbamoyl-1,2,3-triazol-1-yl)-
1,2-dihydroxypropylphosphonates 1 as acyclic ana-
*
Corresponding author. Fax: +48 42 678 83 98; e-mail: aewplld@
ich.pharm.am.lodz.pl
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.11.010

A. E. Wro´blewski, I. E. Głowacka / Tetrahedron: Asymmetry 16 (2005) 4056–4064
4057
CONH2
N
CONH2
N
N
R'
N
R
N
HO
N
O
MeO(O)P
OH OH
R=H, R'=OH (1S,2S)-1
R=OH, R'=H (1R,2S)-1
OH OH
2
CONH2
CONH2
CONH2
N
N
N
N
O
O
P
O-
N
N
-O
O
PO
-O
N
(HO)2(O)P
N
HO
N
O
O
O
OH
OH
OH
Figure 1.
COOMe
P(O)(OR)2
N
N
OH
O
a
N
N
COOMe
O
N
O
N
O
(RO)2(O)P
(RO)2(O)P
N3
OH
O
OH O
R=i-Pr (1S,2R,3S)-3
R=Bn (1S,2R,3S)-7
(1S,2R,3S)-4a (59%)
(1S,2R,3S)-4b
(1S,2R,3S)-8b
(36%)
(1S,2R,3S)-8a
Scheme 1. Reagents and conditions: (a) HC„CCOOMe, toluene, reflux, 4 h.
COOMe
P(O)(OR)2
N
N
N
HO
a
N
O
COOMe
O
N
O
N
O
(RO)2(O)P
(RO)2(O)P
N3
OH
O
OH O
R=i-Pr (1R,2R,3S)-5
R=Bn (1R,2R,3S)-9
(1R,2R,3S)-6a (46%)
(1R,2R,3S)-10a (47%)
(1R,2R,3S)-6b
(1R,2R,3S)-10b
Scheme 2. Reagents and conditions: (a) HC„CCOOMe, toluene, reflux, 4 h.
Table 1. Thermal versus CuCl-catalysed [2+3] cycloadditions of
methyl propiolate and the azides 3, 5, 7, 9, 11 and 12
However, pure major products 4a, 6a, 8a and 10a were
isolated by crystallisation. Structural assignments in
regioisomers a are based on the observation that in ther-
mal [2+3] cycloadditions of azides and propiolates, the
4-alkoxycarbonyl-1,2,3-triazoles were always formed as
major isomers,35–39 but primarily on our results in CuCl-
catalysed cycloadditions, when 4-methoxycarbonyl-
1,2,3-triazoles (1S,2R,3S)-4a or (1R,2R,3S)-6a (Scheme
3) and (1S,2R,3S)-8a or (1R,2R,3S)-10a (Scheme 4)
were produced as single isomers. Yields (Table 1) of
the purified products obtained in the catalysed reactions
were significantly higher (94–99%) in comparison to
yields of the major isomers from thermal processes
(36–59%).
Entry Azide CuCl
(mol %)
1,2,3-Triazoles
Yield
(%)
4-COOMe 5-COOMe
1
2
3
4
3
5
7
9
0a
4a (75)
4a (100)
6a (75)
6a (100)
8a (75)
8a (100)
10a (75)
10a (100)
13 (100)
14 (100)
4b (25)
4b (0)
6b (25)
6b (0)
8b (25)
8b (0)
10b (25)
10b (0)
4a (59)
4a (94)
6a (46)
6a (99)
8a (36)
8a (94)
10a (47)
10a (99)
13 (98)
14 (92)
10b
0a
10b
0a
10b
0a
10b
10b
10b
5
6
11
12
a In toluene at reflux, 4 h.
b In water at room temperature, 4 days.
Dibenzyl 4-azido-1,2,3-trihydroxy-2,3-O-isopropylidene-
butylphosphonates34 (1S,2R,3R)-11 and (1R,2R,3R)-
12 cleanly reacted with methyl propiolate in CuCl-
catalysed reactions to produce only the respective
4-methoxycarbonyl-1,2,3-triazoles (1S,2R,3R)-13 and
(1R,2R,3R)-14, which were separated in very high yields
(Scheme 5).
(1S,2R,3S)-8a and (1S,2R,3S)-8b (Scheme 1) and
(1R,2R,3S)-10a and (1R,2R,3S)-10b (Scheme 2).
Attempts at separating mixtures of regioisomeric 1,2,3-
triazoles a and b proved unsuccessful in all four cases.

4058
A. E. Wro´blewski, I. E. Głowacka / Tetrahedron: Asymmetry 16 (2005) 4056–4064
COOMe
N
(1S,2R,3S)-3
(1R,2R,3S)-5
(1S,2R,3S)-4a
(1R,2R,3S)-6a
a
N
b
c
O
N
(i-PrO)2(O)P
R' R"
O
(85%)
(63%)
R'=H, R"=OMe (1S,2R,3S)-15
R'=OMe, R"=H (1R,2R,3S)-16
CONH2
N
CONH2
N
N
N
N
d
O
OH
N
(i-PrO)2(O)P
(i-PrO)2(O)P
R' R"
R' R"
O
OH
(85%)
(51%)
(52%)
(77%)
(1S,2R,3S)-21
(1R,2R,3S)-22
R'=H, R"=OMe
R'=MeO, R"=H
(1S,2R,3S)-23
(1R,2R,3S)-24
Scheme 3. Reagents and conditions: (a) HC„CCOOMe, CuCl, water, rt, 4 days, yields: (1S,2R,3S)-4a—94% and (1R,2R,3S)-6a—99%; (b) MeI,
Ag2O, rt, 4 days; (c) 25% ammonia, rt, 5 days; (d) H2O, Dowex 50W · 8 H+, 75 ꢁC, 2.5 h.
(1S,2R,3S)-7
(1R,2R,3S)-9
COOMe
c, d, e
CONH2
a
N
N
(1S,2R,3S)-8a
(1R,2R,3S)-10a
N
N
b
O
N
OH
N
(BnO)2(O)P
(HO)2(O)P
R' R"
R' R"
O
OH
(97%)
(51%)
(26%)
(82%)
R'=H, R"=OMe (1S,2R,3S)-17
R'=MeO, R"=H (1R,2R,3S)-18
(1S,2R,3S)-25
(1R,2R,3S)-26
Scheme 4. Reagents and conditions: (a) HC„CCOOMe, CuCl, water, rt, 4 days, yields: (1S,2R,3S)-8a—94% and (1R,2R,3S)-10a—99%; (b) MeI,
Ag2O, rt, 4 days; (c) 25% ammonia, rt, 5 days; (d) H2O, Dowex 50W · 8 H+, 75 ꢁC, 2.5 h; (e) H2, 10 % Pd–C, aqueous methanol, 48 h.
COOMe
P(O)(OBn)2
N
R'
R"
O
a
b
N
O
N
O
(BnO)2(O)P
N3
R' R"
O
(1S,2R,3R)-11
(1R,2R,3R)-12
R'=H, R"=OH
R'=OH, R"=H
(1S,2R,3R)-13 (98%)
(1R,2R,3R)-14 (92%)
COOMe
CONH2
N
N
N
N
c, d, e
O
N
OH
N
(BnO)2(O)P
(HO)2(O)P
R' R"
R' R"
O
OH
R'=H, R"=OMe (1S,2R,3R)-19 (83%)
(1R,2R,3R)-20 (77%)
(42%)
(1S,2R,3R)-27
(1R,2R,3R)-28 (39%)
R'=MeO, R"=H
Scheme 5. Reagents and conditions: (a) HC„CCOOMe, CuCl, water, rt, 4 days; (b) MeI, Ag2O, rt, 4 days; (c) 25% ammonia, rt, 5 days; (d) H2O,
Dowex 50W · 8 H+, 75 ꢁC, 2.5 h; (e) H2, 10% Pd–C, aqueous methanol, 48 h.
Due to our previous experience in the decomposition of
a-hydroxyphosphonates during ammonolysis of alkoxy-
carbonyl groups,30 the protection of HO–C-1 groups in
phosphonates 4a, 6a, 8a 10a, 13 and 14 was necessary.
We were disappointed with the failure of benzylation
and unsuccessful attempts at introducing the methoxy-
ethoxymethyl (MEM) group. However, acetylation of
HO–C-1 went smoothly and we concluded that the steric

A. E. Wro´blewski, I. E. Głowacka / Tetrahedron: Asymmetry 16 (2005) 4056–4064
4059
bulkiness of the O,O-diisopropyl(dibenzyl)phosphoryl
and isopropylidene groups prevented benzylation at
HO–C-1. Finally, methylation of this group was accom-
plished in satisfactory yields to provide 1-meth-
oxyphosphonates (1S,2R,3S)-15 and (1R,2R,3S)-16
(Scheme 3), (1S,2R,3S)-17 and (1R,2R,3S)-18 (Scheme
4) as well as (1S,2R,3R)-19 and (1R,2R,3R)-20 (Scheme
5).
propiolate followed by a methylation of the HO–C-1
groups, ammonolysis and the removal of the protective
groups by hydrolysis and hydrogenolysis.
Diisopropyl 4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihy-
droxy-1-methoxybutylphosphonates (1S,2R,3S)-23 and
(1R,2R,3S)-24 were obtained from diisopropyl 4-azido-
1,2,3-trihydroxy-2,3-O-isopropylidenebutylphosphonates
3 and 5 by a similar sequence of reactions.
The ammonolysis of the 4-methoxycarbonyl group in
diisopropyl esters 15 and 16 was carried out in the pres-
ence of 25% ammonia and led to the formation of O,O-
diisopropyl 4-(4-carbamoyl-1,2,3-triazole)phoshonates
(1S,2R,3S)-21 and (1R,2R,3S)-22 in good yields
(Scheme 3). When O,O-dibenzyl esters (1S,2R,3S)-17
and (1R,2R,3S)-18 (Scheme 4) and (1S,2R,3R)-19 and
(1R,2R,3R)-20 (Scheme 5) were similarly treated with
ammonia, complex reaction mixtures were produced as
judged from 31P NMR spectra. However, the ammonol-
ysis was complete as evidenced by disappearance of the
4. Experimental
1H NMR spectra were recorded with a Varian Mercury-
300 spectrometer; chemical shifts d in parts per million
with respect to TMS, coupling constants J in hertz.
13C and 31P NMR spectra were recorded on a Varian
Mercury-300 machine at 75.5 and 121.5 MHz, respec-
tively. However, 13C NMR spectra in D2O were taken
on a Bruker DPX spectrometer at 62.9 MHz. IR spec-
tral data were measured on an Infinity MI-60 FT-IR
spectrometer. Melting points were determined on a Boe-
tius apparatus and are uncorrected. Elemental analyses
were performed by the Microanalytical Laboratory of
this Faculty on a Perkin Elmer PE 2400 CHNS analyser.
Polarimetric measurements were conducted on a Perkin
Elmer 241 MC apparatus.
1
MeOOC resonances in H NMR spectra. Opposite to
O,O-diisopropyl esters 15 and 16, but similar to O,O-
dimethyl esters30 in the presence of 25% ammonia,
partial debenzylation of O,O-dibenzyl esters 17–20 took
place. We were able to isolate O-benzyl (1S,2R,3S)-4-(4-
carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxy-
butylphosphonic acid 29 by treating the crude product
after the ammonolysis of (1S,2R,3S)-17 with Dowex
(H+).
The following absorbents were used: column chroma-
tography, Merck silica gel 60 (70–230 mesh) or Kieselgel
60 silanisiert (70–230 mesh) (Merck Art. 7719); analy-
CONH2
tical TLC, Merck TLC plastic sheets silica gel 60 F254
.
N
N
4.1. Reaction of diisopropyl and dibenzyl 4-azido-1,2,3-
trihydroxy-2,3-O-isopropylidenebutylphosphonates (1S,2R,
3S)-3 and (1R,2R,3S)-5, and (1S,2R,3S)-7 and (1R,2R,
3S)-9 with methyl propiolate in refluxing toluene (general
procedure)
OH
N
(HO)(BnO)(O)P
OMe OH
(1S,2R,3S)-29
Removal of the isopropylidene protecting groups from
phosphonates 21 and 22 cleanly gave pure diisopropyl
4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-meth-
oxybutylphosphonates (1S,2R,3S)-23 and (1R,2R,3S)-
24 (Scheme 3).
A solution of azidophosphonate (1.00 mmol) and
methyl propiolate (2.00 mmol) in toluene (10 mL) was
refluxed for 4 h. The reaction mixture was concentrated
in vacuo and the residue was crystallised to give pure
major regioisomers.
The crude products obtained after ammonolysis of O,O-
dibenzyl esters 17–20 (Schemes 4 and 5) were subjected
to hydrolysis followed by catalytic hydrogenolysis of
the benzyl groups to afford 4-(4-carbamoyl-1,2,3-triazol-
1-yl)-2,3-dihydroxy-1-methoxybutylphosphonic acids (1S,
2R,3S)-25 and (1R,2R,3S)-26 (Scheme 4), as well as
(1S,2R,3R)-27 and (1R,2R,3R)-28 (Scheme 5).
4.1.1. Diisopropyl (1S,2R,3S)-1,2,3-trihydroxy-2,3-O-iso-
propylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]but-
ylphosphonate, (1S,2R,3S)-4a. From (1S,2R,3S)-3
(0.301 g, 0.860 mmol) and methyl propiolate (0.163 mL,
1.72 mmol) in toluene (2.0 mL), phosphonate (1S,2R,
3S)-4a (0.221 g, 59%) was obtained as a white amor-
phous solid after crystallisation from ethyl acetate–chlo-
20
roform, mp 212–213 ꢁC; ½aꢀD ¼ ꢁ29:6 (c 1.06, CHCl3).
IR (KBr): m = 3274, 2980, 2953, 1732, 1245, 1220,
1
3. Conclusions
1001 cmꢁ1. H NMR (CDCl3): d = 8.31 (s, 1H), 4.92
(dd, J = 14.4, 2.7 Hz, 1H), 4.90–4.76 (m, 2H), 4.72
(dd, J = 14.4, 6.0 Hz, 1H), 4.54 (ddd, J = 7.2, 6.0,
2.7 Hz, 1H), 4.13–4.03 (m, 2H), 3.96 (s, 3H), 1.42–1.35
(m, 15H), 1.28 (s, 3H). 13C NMR (CDCl3): d = 161.3,
139.9, 129.4, 110.4, 77.0 (d, J = 6.6 Hz), 75.7 (d,
J = 6.0 Hz), 72.8 and 72.5 (2d, J = 7.0 Hz), 68.3 (d,
J = 163.8 Hz), 52.6, 52.4, 27.3, 27.1, 24.5 and 24.4 and
24.3 and 24.2 (4d, J = 5.3 Hz). 31P NMR (CDCl3):
Enantiomerically pure 4-(4-carbamoyl-1,2,3-triazol-1-
yl)-2,3-dihydroxy-1-methoxybutylphosphonic acids (1S,
2R,3S)-25, (1R,2R,3S)-26, (1S,2R,3R)-27 and (1R,
2R,3R)-28 were synthesised from the respective dibenzyl
4-azido-1,2,3-trihydroxy-2,3-O-isopropylidenebutylphos-
phonates 7, 9, 11 and 12 in a sequence of reactions
involving the CuCl-catalysed cycloaddition of methyl

4060
A. E. Wro´blewski, I. E. Głowacka / Tetrahedron: Asymmetry 16 (2005) 4056–4064
d = 19.55. Anal. Calcd for C17H30N3O8P: C, 46.89; H,
6.95; N, 9.65. Found: C, 46.83; H, 6.99; N, 9.42.
d = 160.9, 139.7, 136.0 and 135.9 (2d, J = 7.6 Hz),
129.0, 128.5, 128.5, 128.4 128.4, 128.0, 127.9, 110.8,
77.2, 74.7 (d, J = 10.6 Hz), 68.7 and 68.4 (2d,
J = 7.2 Hz), 66.7 (d, J = 163.1 Hz), 52.3, 51.8, 27.2,
26.9. 31P NMR (CDCl3): d = 22.08. Anal. Calcd for
C25H30N3O8P: C, 56.50; H, 5.69; N, 7.91. Found: C,
56.49; H, 5.75; N, 7.98.
4.1.2. Diisopropyl (1R,2R,3S)-1,2,3-trihydroxy-2,3-O-
isopropylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]-
butylphosphonate, (1R,2R,3S)-6a. From (1R,2R,3S)-5
(0.171 g, 0.492 mmol) and methyl propiolate (0.097 mL,
0.98 mmol) in toluene (2.0 mL), phosphonate (1R,2R,
3S)-6a (0.098 g, 46%) was obtained as a white amor-
4.2. Reaction of diisopropyl and dibenzyl 4-azido-1,2,3-
trihydroxy-2,3-O-isopropylidenebutylphosphonates (1S,2R,
3S)-3 and (1R,2R,3S)-5, and (1S,2R,3S)-7 and (1R,2R,
3S)-9 with methyl propiolate in the presence of CuCl
(general procedure)
phous solid after crystallisation from chloroform–
20
hexane, mp 157–158 ꢁC; ½aꢀD ¼ ꢁ29:7 (c 1.23, CHCl3).
IR (KBr): m = 3227, 2986, 2937, 1725, 1236, 1032,
1
1009 cmꢁ1. H NMR (CDCl3): d = 8.29 (s, 1H), 4.90–
4.70 (m, 2H), 4.79 (dd, J = 14.4, 2.7 Hz, 1H), 4.61 (dd,
J = 14.4, 6.3 Hz, 1H), 4.45 (ddd, J = 7.5, 6.3, 2.7 Hz,
1H), 4.08 (ddd, J = 7.5, 4.5, 4.2 Hz, 1H), 3.96 (s, 3H),
3.84 (dd, J = 11.4, 4.2 Hz, 1H), 2.5–1.7 (br s, 1H) 1.42
(s, 3H), 1.39–1.35 (m, 12H), 1.33 (s, 3H). 13C NMR
(CDCl3): d = 161.2, 140.0, 129.2, 110.8, 77.3, 75.2 (d,
J = 9.2 Hz), 72.6 and 72.3 (2d, J = 7.0 Hz), 67.5 (d,
J = 163.2 Hz), 52.4, 51.8, 27.3, 27.1, 24.5 and 24.4 (2d,
J = 9.0 Hz), 24.2 and 24.1 (2d, J = 6.0 Hz). 31P NMR
(CDCl3): d = 19.14. Anal. Calcd for C17H30N3O8P: C,
46.89; H, 6.95; N, 9.65. Found: C, 46.70; H, 6.85; N,
9.47.
A suspension of azidophosphonate (1.00 mmol), methyl
propiolate (1.00 mmol) and CuCl (0.10 mmol) in water
(10 mL) was stirred vigorously at room temperature
for 4 days. The reaction mixture was extracted with
methylene chloride (3 · 10 mL), dried over MgSO4, fil-
tered through a layer of Celite or short pad of silica
gel, concentrated and the residue was crystallised to give
pure products.
4.2.1. Diisopropyl (1S,2R,3S)-1,2,3-trihydroxy-2,3-O-iso-
propylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]-
butylphosphonate, (1S,2R,3S)-4a. From (1S,2R,3S)-3
(0.100 g, 0.281 mmol), methyl propiolate (0.023 g,
0.28 mmol) and CuCl (3 mg, 0.03 mmol) in water
(2.5 mL), phosphonate (1S,2R,3S)-4a (0.116 g, 94%)
was obtained after crystallisation from ethyl acetate–
chloroform.
4.1.3. Dibenzyl (1S,2R,3S)-1,2,3-trihydroxy-2,3-O-iso-
propylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]-
butylphosphonate, (1S,2R,3S)-8a. From (1S,2R,3S)-7
(1.346 g, 3.008 mmol) and methyl propiolate (0.535 mL,
6.02 mmol) in toluene (10.0 mL), phosphonate (1S,2R,
3S)-8a (0.575 g, 36%) was obtained as a white amor-
phous solid after crystallisation from methanol, mp
4.2.2. Diisopropyl (1R,2R,3S)-1,2,3-trihydroxy-2,3-O-
isopropylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]-
butylphosphonate, (1R,2R,3S)-6a. From (1R,2R,3S)-5
(0.285 g, 0.811 mmol), methyl propiolate (0.068 g,
0.81 mmol) and CuCl (8 mg, 0.08 mmol) in water
(6.0 mL), phosphonate (1R,2R,3S)-6a (0.348 g, 99%)
was obtained after crystallisation from chloroform–
hexane.
20
186.5–187 ꢁC; ½aꢀD ¼ ꢁ16:7 (c 1.08, CHCl3). IR (KBr):
1
m = 3266, 2986, 2980, 1725, 1237, 1056, 1039 cmꢁ1. H
NMR (CDCl3): d = 8.21 (s, 1H), 7.39–7.26 (m, 10H),
5.19–5.02 (m, 4H), 4.81 (dd, J = 14.1, 2.4 Hz, 1H),
4.59 (dd, J = 14.1, 6.6 Hz, 1H), 4.48 (ddd, J = 7.5, 6.6,
2.4 Hz, 1H), 4.14 (dd, J = 8.1, 5.4 Hz, 1H), 4.03 (ddd,
J = 7.5, 5.4, 4.5 Hz, 1H), 3.95 (s, 3H), 3.7–3.5 (br s,
1H), 1.35 (s, 3H), 1.27 (s, 3H). 13C NMR (CDCl3):
d = 161.3, 139.9, 135.9, 135.8, 129.2, 128.8, 128.8,
128.7 128.4, 128.2, 110.7, 76.7, 76.4 (d, J = 8.6 Hz),
69.0 and 68.9 (2d, J = 7.2 Hz), 68.6 (d, J = 161.9 Hz),
52.6, 52.4, 27.3, 27.0. 31P NMR (CDCl3): d = 22.48.
Anal. Calcd for C25H30N3O8P: C, 56.50; H, 5.69; N,
7.91. Found: C, 56.48; H, 5.53; N, 7.85.
4.2.3. Dibenzyl (1S,2R,3S)-1,2,3-trihydroxy-2,3-O-iso-
propylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]-
butylphosphonate, (1S,2R,3S)-8a. From (1S,2R,3S)-7
(0.220 g, 0.501 mmol), methyl propiolate (0.045 mL,
0.50 mmol) and CuCl (5 mg, 0.05 mmol) in water
(2.0 mL), phosphonate (1S,2R,3S)-8a (0.246 g, 94%)
was obtained after crystallisation from ethyl acetate–
petroleum ether.
4.1.4. Dibenzyl (1R,2R,3S)-1,2,3-trihydroxy-2,3-O-iso-
propylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]-
butylphosphonate, (1R,2R,3S)-10a. From (1R,2R,3S)-9
(0.343 g, 0.767 mmol) and methyl propiolate (0.136 mL,
1.53 mmol) in toluene (5.0 mL), phosphonate (1R,2R,
3S)-10a (0.193 g, 47%) was obtained as a white amor-
4.2.4. Dibenzyl (1R,2R,3S)-1,2,3-trihydroxy-2,3-O-iso-
propylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]-
butylphosphonate, (1R,2R,3S)-10a. From (1R,2R,3S)-9
(0.138 g, 0.308 mmol), methyl propiolate (0.027 mL,
0.31 mmol) and CuCl (3 mg, 0.03 mmol) in water
(1.0 mL), phosphonate (1R,2R,3S)-10a (0.162 g, 99%)
was obtained after crystallisation from ethyl acetate.
phous solid after crystallisation from ethyl acetate, mp
20
152.7–153.9 ꢁC; ½aꢀD ¼ ꢁ27:7 (c 2.33, CHCl3). IR (KBr):
1
m = 3262, 3126, 2986, 1726, 1237, 1055, 1040 cmꢁ1. H
NMR (CDCl3): d = 8.23 (s, 1H), 7.38–7.26 (m, 10H),
5.18–5.03 (m, 4H), 4.69 (dd, J = 14.1, 2.4 Hz, 1H),
4.49 (dd, J = 14.1, 6.6 Hz, 1H), 4.42 (ddd, J = 7.8, 6.6,
2.4 Hz, 1H), 4.08 (ddd, J = 7.8, 4.4, 3.6 Hz, 1H), 3.96
(s, 3H), 3.94 (dd, J = 11.0, 3.6 Hz, 1H), 3.3–2.5 (br s,
1H), 1.36 (s, 3H), 1.32 (s, 3H). 13C NMR (CDCl3):
4.2.5. Dibenzyl (1S,2R,3R)-1,2,3-trihydroxy-2,3-O-iso-
propylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]-
butylphosphonate, (1S,2R,3R)-13. From (1S,2R,3R)-11
(0.316 g, 0.706 mmol), methyl propiolate (0.063 mL,
0.71 mmol) and CuCl (7 mg, 0.07 mmol) in water

A. E. Wro´blewski, I. E. Głowacka / Tetrahedron: Asymmetry 16 (2005) 4056–4064
4061
(6.0 mL), phosphonate (1S,2R,3R)-13 (0.368 g, 98%)
110.0, 77.6 (d, J = 13.6 Hz), 77.5 (d, J = 166.9 Hz),
74.2 (d, J = 1.4 Hz), 72.4 and 72.3 (2d, J = 7.5 Hz),
62.9 (d, J = 4.3 Hz), 52.3, 52.1, 27.3, 26.7, 24.5 (d,
J = 3.8 Hz), 24.2 and 24.2 (2d, J = 4.5 Hz). 31P NMR
(CDCl3): d = 17.75. Anal. Calcd for C18H32N3O8P: C,
48.10; H, 7.18; N, 9.35. Found: C, 48.35; H, 7.23; N,
9.16.
was obtained as a white amorphous solid after crystalli-
20
sation from ethyl acetate, mp 178–179 ꢁC; ½aꢀD ¼ þ31:2
(c 1.26, CHCl3). IR (KBr): m = 3282, 3110, 2992, 1730,
1
1225, 1034, 992 cmꢁ1. H NMR (CDCl3): d = 8.16 (s,
1H), 7.38–7.26 (m, 10H), 5.18–5.00 (m, 5H), 4.56–4.45
(m, 2H), 4.37 (dd, J = 14.1, 9.6 Hz, 1H), 4.12 (dd,
J = 8.7, 5.7, Hz, 1H), 3.95 (s, 3H), 1.43 (s, 3H), 1.28
(s, 3H). 13C NMR (CDCl3): d = 161.3, 139.9, 136.0
and 136.0 (2d, J = 7.6, Hz), 128.8, 128.7, 128.7 128.6,
128.1, 128.0, 110.3, 76.4 (d, J = 12.1 Hz), 75.6 (d,
J = 2.3 Hz), 68.9 and 68.7 (2d, J = 7.6 Hz), 66.6 (d,
J = 162.3 Hz), 52.3, 51.2, 28.2, 25.7. 31P NMR (CDCl3):
d = 23.56. Anal. Calcd for C25H30N3O8P: C, 56.50; H,
5.69; N, 7.91. Found: C, 56.44; H, 5.57; N, 7.87.
4.3.2. Diisopropyl (1R,2R,3S)-2,3-dihydroxy-2,3-O-iso-
propylidene-1-methoxy-4-[(4-methoxycarbonyl)-1,2,3-tri-
azol-1-yl]butylphosphonate, (1R,2R,3S)-16. From (1R,
2R,3S)-6a (0.186 g, 0.432 mmol), phosphonate (1R,2R,
3S)-16 (0.120 g, 63%) was obtained as a white amor-
phous solid after chromatography with chloroform–
20
methanol (150:1, v/v), mp 75–76 ꢁC; ½aꢀD ¼ ꢁ26:5 (c
1.40, CHCl3). IR (KBr): m = 3136, 2984, 2926, 1731,
1
4.2.6. Dibenzyl (1R,2R,3R)-1,2,3-trihydroxy-2,3-O-iso-
propylidene-4-[(4-methoxycarbonyl)-1,2,3-triazol-1-yl]-
butylphosphonate, (1R,2R,3R)-14. From (1R,2R,3R)-
12 (0.248 g, 0.554 mmol), methyl propiolate (0.049 mL,
0.55 mmol) and CuCl (6 mg, 0.06 mmol) in water
(5.0 mL), phosphonate (1R,2R,3R)-14 (0.271 g, 92%)
was obtained as a white amorphous solid after crystalli-
1237, 998 cmꢁ1. H NMR (CDCl3): d = 8.31 (s, 1H),
4.87 (dd, J = 14.4, 2.7 Hz, 1H), 4.91–4.78 (m, 2H),
4.60 (dd, J = 14.4, 6.3 Hz, 1H), 4.49 (ddd, J = 7.5, 6.3,
2.7 Hz, 1H), 4.06 (ddd, J = 7.5, 6.6, 6.6 Hz, 1H), 3.96
(s, 3H), 3.61 (s, 3H), 3.47 (dd, J = 9.9, 6.6 Hz, 1H), 1.41
(s, 3H), 1.40–1.35 (m, 12H), 1.34 (s, 3H). 13C NMR
(CDCl3): d = 161.2, 139.9, 129.2, 110.8, 79.1 (d, J =
158.6 Hz), 77.9 (d, J = 2.6 Hz), 75.6 (d, J = 3.0 Hz),
72.6 and 72.2 (2d, J = 6.8 Hz), 61.8 (d, J = 4.5 Hz),
52.5, 52.4, 27.3, 27.1, 24.5 (d, J = 3.0 Hz), 24.3 (d,
J = 4.5 Hz), 24.2 (d, J = 5.3 Hz). 31P NMR (CDCl3):
d = 18.24. Anal. Calcd for C18H32N3O8P: C, 48.10; H,
7.18; N, 9.35. Found: C, 48.27; H, 7.25; N, 9.53.
sation from chloroform–petroleum ether, mp 171.6–
20
173 ꢁC; ½aꢀD ¼ þ15:3 (c 1.65, CHCl3). IR (KBr):
1
m = 3288, 3109, 2989, 1728, 1222, 1038, 994 cmꢁ1. H
NMR (CDCl3): d = 8.18 (s, 1H), 7.39–7.26 (m, 10H),
5.19–5.03 (m, 4H), 4.74 (dd, J = 13.5, 1.8 Hz, 1H),
4.66–4.46 (m, 3H), 4.03 (ddd, J = 13.5, 9.9, 1.8 Hz,
1H), 3.95 (s, 3H), 2.96 (dd, J = 9.9, 4.8 Hz, 1H), 1.52
(s, 3H), 1.31 (s, 3H). 13C NMR (CDCl3): d = 161.2,
140.0, 136.1 and 135.8 (2d, J = 5.7 Hz), 128.7, 128.2,
110.0, 76.2 (d, J = 14.0 Hz), 74.9, 68.9 and 68.6 (2d,
J = 7.1 Hz), 66.8 (d, J = 160.9 Hz), 52.4, 52.0, 27.3,
24.9. 31P NMR (CDCl3): d = 22.05. Anal. Calcd for
C25H30N3O8P: C, 56.50; H, 5.69; N, 7.91. Found: C,
56.77; H, 5.49; N, 7.90.
4.3.3. Dibenzyl (1S,2R,3S)-2,3-dihydroxy-2,3-O-isoprop-
ylidene-1-methoxy-4-[(4-methoxycarbonyl)-1,2,3-triazol-
1-yl]butylphosphonate, (1S,2R,3S)-17. From (1S,2R,
3S)-8a (0.119 g, 0.224 mmol), phosphonate (1S,2R,3S)-
17 (0.118 g, 97%) was obtained as a colourless oil after
chromatography with chloroform–methanol (100:1,
20
v/v); ½aꢀD ¼ ꢁ13:4 (c 2.68, CHCl3). IR (film): m = 3129,
1
2989, 2952, 1723, 1240, 1009 cmꢁ1. H NMR (CDCl3):
4.3. Methylation of 1-hydroxyphosphonates with MeI in
the presence of Ag2O (general procedure)
d = 8.18 (s, 1H), 7.39–7.26 (m, 10H), 5.19–5.01 (m,
4H), 4.74 (dd, J = 14.4, 3.6 Hz, 1H), 4.70 (dd,
J = 14.4, 5.1 Hz, 1H), 4.54 (ddd, J = 7.8, 5.1, 3.6 Hz,
1H), 4.04 (ddd, J = 7.8, 3.0, 2.4 Hz, 1H), 3.96 (s, 3H),
3.78 (dd, J = 12.0, 3.0 Hz, 1H), 3.55 (d, J = 1.0 Hz,
3H), 1.38 (s, 3H), 1.25 (s, 3H). 13C NMR (CDCl3):
d = 161.2, 139.7, 135.9 (d, J = 5.7 Hz), 135.8 (d,
J = 5.4 Hz), 129.2, 128.8, 128.7, 128.7, 128.5, 128.3,
110.2, 77.6 (d, J = 166.1 Hz), 77.2 (d, J = 13.6 Hz),
74.5 (d, J = 3.0 Hz), 68.8 and 68.7 (2d, J = 6.8 Hz),
62.7 (d, J = 4.5 Hz), 52.3, 52.0, 27.2, 26.7. 31P NMR
(CDCl3): d = 21.13. Anal. Calcd for C26H32N3O8P: C,
57.25; H, 5.91; N, 7.70. Found: C, 57.38; H, 5.70; N,
7.71.
A suspension of 1-hydroxyphosphonates (1.00 mmol),
methyl iodide (10 mmol) and silver(I) oxide (1.60 mmol)
in chloroform (6 mL) was stirred vigorously at room
temperature for 4 days. The reaction mixture was fil-
tered through a layer of Celite, concentrated and the
crude product was chromatographed on silica gel.
4.3.1. Diisopropyl (1S,2R,3S)-2,3-dihydroxy-2,3-O-iso-
propylidene-1-methoxy-4-[(4-methoxycarbonyl)-1,2,3-tri-
azol-1-yl]butylphosphonate, (1S,2R,3S)-15. From (1S,
2R,3S)-4a (0.822 g, 1.89 mmol), phosphonate (1S,2R,
3S)-15 (0.724 g, 85%) was obtained as a white amor-
phous solid after chromatography with chloroform–
4.3.4. Dibenzyl (1R,2R,3S)-2,3-dihydroxy-2,3-O-isoprop-
ylidene-1-methoxy-4-[(4-methoxycarbonyl)-1,2,3-triazol-
1-yl]butylphosphonate, (1R,2R,3S)-18. From (1R,2R,
3S)-10a (0.235 g, 0.442 mmol), phosphonate (1R,2R,
3S)-18 (0.122 g, 51%) was obtained as a colourless oil
20
methanol (150:1, v/v), mp 96–97.5 ꢁC; ½aꢀD ¼ ꢁ28:4 (c
1.43, CHCl3). IR (KBr): m = 3133, 2982, 2928, 1723,
1
1241, 997 cmꢁ1. H NMR (CDCl3): d = 8.30 (s, 1H),
4.89 (dd, J = 14.4, 2.7 Hz, 1H), 4.89–4.78 (m, 2H),
4.78 (dd, J = 14.4, 5.7 Hz, 1H), 4.59 (ddd, J = 7.8, 5.7,
2.7 Hz, 1H), 4.10 (ddd, J = 7.8, 2.6, 1.1 Hz, 1H), 3.95
(s, 3H), 3.74 (dd, J = 13.2, 2.6 Hz, 1H), 3.62 (d,
J = 0.8 Hz, 3H), 1.42 (s, 3H), 1.40–1.36 (m, 12H), 1.27
(s, 3H). 13C NMR (CDCl3): d = 161.3, 139.7, 129.4,
after chromatography with chloroform–methanol
20
(100:1, v/v); ½aꢀD ¼ ꢁ8:3 (c 1.53, CHCl3). IR (film):
1
m = 3138, 2988, 2950, 1730, 1236, 1017 cmꢁ1. H NMR
(CDCl3): d = 8.21 (s, 1H), 7.39–7.31 (m, 10H), 5.16–
5.01 (m, 4H), 4.79–4.68 (m, 1H), 4.56–4.43 (m, 2H),

4062
A. E. Wro´blewski, I. E. Głowacka / Tetrahedron: Asymmetry 16 (2005) 4056–4064
4.12–4.02 (m, 1H), 3.96 (s, 3H), 3.55 (dd, J = 9.6,
6.0 Hz, 1H), 3.54 (d, J = 0.6 Hz, 3H), 1.35 (s, 3H),
1.31 (s, 3H). 13C NMR (CDCl3): d = 161.2, 140.0,
136.0 (d, J = 5.4 Hz), 135.9 (d, J = 5.7 Hz), 129.1,
128.7, 128.4, 128.3, 110.6, 78.6 (d, J = 158.0 Hz), 77.5
(d, J = 11.3 Hz), 75.3 (d, J = 4.5 Hz), 69.0 and 68.3
(2d, J = 6.9 Hz), 61.8 (d, J = 4.0 Hz), 52.4, 52.3, 27.3,
27.0. 31P NMR (CDCl3): d = 21.14. Anal. Calcd for
C26H32N3O8P · 0.5H2O: C, 56.32; H, 6.00; N, 7.58.
Found: C, 56.51; H, 6.04; N, 7.56.
form–methanol (50:1, v/v) to give (1S,2R,3S)-21
(0.489 g, 85%) as a white powder after crystallisation
20
from ethyl acetate–hexane, mp 106–107 ꢁC; ½aꢀD
¼
ꢁ26:3 (c 2.51, CHCl3). IR (KBr): m = 3437, 3245,
3199, 2987, 2933, 1692, 1657, 1248, 1006, 979 cmꢁ1
.
1H NMR (CDCl3): d = 8.31 (s, 1H), 7.07 and 5.70
(2 · br s, 2H), 4.94 (dd, J = 13.8, 2.4 Hz, 1H), 4.91–
4.79 (m, 2H), 4.66 (dd, J = 13.8, 6.6 Hz, 1H), 4.58
(ddd, J = 7.5, 6.6, 2.4 Hz, 1H), 4.12 (ddd, J = 7.5, 2.4,
1.2 Hz, 1H), 3.74 (dd, J = 12.6, 2.4 Hz, 1H), 3.63 (d,
J = 1.0 Hz, 3H), 1.41 (s, 3H), 1.41–1.36 (m, 12H), 1.31
(s, 3H). 13C NMR (CDCl3): d = 162.4, 142.5, 127.5,
110.1, 77.8 (d, J = 15.8 Hz), 77.5 (d, J = 166.9 Hz),
74.4 (d, J = 2.0 Hz), 72.3 and 72.2 (2d, J = 7.6 Hz),
62.7 (d, J = 5.3 Hz), 52.5, 27.3, 26.7, 24.5 (d,
J = 3.8 Hz), 24.4 (d, J = 3.5 Hz), 24.2 and 24.1 (2 · d,
J = 5.4 Hz). 31P NMR (CDCl3): d = 18.41. Anal. Calcd
for C17H31N4O7P: C, 46.99; H, 7.20; N, 12.90. Found:
C, 46.82; H, 7.23; N, 13.06.
4.3.5. Dibenzyl (1S,2R,3R)-2,3-dihydroxy-2,3-O-isoprop-
ylidene-1-methoxy-4-[(4-methoxycarbonyl)-1,2,3-triazol-
1-yl]butylphosphonate, (1S,2R,3R)-19. From (1S,2R,
3R)-13 (0.368 g, 0.692 mmol), phosphonate (1S,2R,
3R)-19 (0.316 g, 83%) was obtained as a white powder
after chromatography with chloroform–methanol (50/
1, v/v) followed by crystallisation from ethyl acetate–
20
petroleum ether, mp 106.4–106.6 ꢁC; ½aꢀD ¼ þ54:4 (c
1.19, CHCl3). IR (KBr): m = 3131, 2990, 2952, 1726,
1
1230, 1010 cmꢁ1. H NMR (CDCl3): d = 8.01 (s, 1H),
4.4.1. Diisopropyl (1R,2R,3S)-4-(4-carbamoyl-1,2,3-tri-
azol-1-yl)-2,3-dihydroxy-2,3-O-isopropylidene-1-methoxy-
butylphosphonate, (1R,2R,3S)-22. In a similar method
as described in Section 4.4. from (1R,2R,3S)-16
(0.120 g, 0.270 mmol) dissolved in methanol (4 mL) con-
taining ammonia (6 mL), phosphonate (1R,2R,3S)-22
(0.059 g, 51%) was obtained as a white powder after
7.40–7.26 (m, 10H), 5.18–4.92 (m, 5H), 4.46–4.32 (m,
3H), 3.95 (s, 3H), 3.90 (dd, J = 12.0, 3.9 Hz, 1H), 3.55
(d, J = 1.0 Hz, 3H), 1.50 (s, 3H), 1.26 (s, 3H). 13C
NMR (CDCl3): d = 161.3, 139.9, 135.8 (d, J = 5.3 Hz),
128.9, 128.8, 128.8, 128.5, 128.5, 128.3, 109.3, 76.9 (d,
J = 165.2 Hz), 76.3 (d, J = 3.7 Hz), 76.1 (d, J =
12.3 Hz), 68.7 and 68.6 (2d, J = 7.2 Hz), 62.1 (d,
J = 4.5 Hz), 52.3, 52.3, 28.3, 25.7. 31P NMR (CDCl3):
d = 21.81. Anal. Calcd for C26H32N3O8P: C, 57.25; H,
5.91; N, 7.70. Found: C, 57.09; H, 5.76; N, 7.78.
crystallisation from ethyl acetate–hexane, mp 140–
20
141 ꢁC; ½aꢀD ¼ ꢁ34:0 (c 1.1, CHCl3). IR (KBr):
m = 3443, 3197, 3098, 2982, 2936, 1631, 1242, 1027,
996 cmꢁ1 1H NMR (CDCl3): d = 8.31 (s, 1H), 7.06
.
and 5.68 (2 · br s, 2H), 4.88 (dd, J = 13.8, 2.1 Hz,
1H), 4.85–4.77 (m, 2H), 4.55 (dd, J = 13.8, 6.9 Hz,
1H), 4.48 (ddd, J = 7.5, 6.9, 1.8 Hz, 1H), 4.08 (ddd,
J = 7.5, 6.6, 6.3 Hz, 1H), 3.62 (d, J = 1.0 Hz, 3H), 3.47
(dd, J = 9.6, 6.6 Hz, 1H), 1.41 (s, 3H), 1.40–1.35 (m,
12H), 1.35 (s, 3H). 13C NMR (CDCl3): d = 162.2,
142.7, 127.4, 110.4, 78.9 (d, J = 163.8 Hz), 78.1 (d,
J = 9.1 Hz), 75.5 (d, J = 3.8 Hz), 72.4 and 72.0 (2 · d,
J = 7.2 Hz), 61.7 (d, J = 4.5 Hz), 52.6, 27.3, 27.1, 24.4
(d, J = 3.0 Hz), 24.3 (d, J = 4.5 Hz), 24.1 (d,
J = 5.3 Hz). 31P NMR (CDCl3): d = 18.29. Anal. Calcd
for C17H31N4O7P: C, 46.99; H, 7.20; N, 12.90. Found:
C, 46.79; H, 6.89; N, 12.76.
4.3.6. Dibenzyl (1R,2R,3R)-2,3-dihydroxy-2,3-O-isoprop-
ylidene-1-methoxy-4-[(4-methoxycarbonyl)-1,2,3-triazol-
1-yl]butylphosphonate, (1R,2R,3R)-20. From (1R,2R,
3R)-14 (0.204 g, 0.384 mmol), phosphonate (1R,2R,
3R)-20 (0.162 g, 77%) was obtained as a colourless oil
after chromatography with chloroform–methanol
20
(100:1, v/v); ½aꢀD ¼ þ27:3 (c 3.8, CHCl3). IR (film):
1
m = 3201, 2992, 2954, 1734, 1241, 1008 cmꢁ1. H NMR
(CDCl3): d = 8.08 (s, 1H), 7.42–7.26 (m, 10H), 5.20–
5.04 (m, 4H), 4.67 (dd, J = 12.6, 1.5 Hz, 1H), 4.57
(ddd, J = 10.2, 5.7, 4.5Hz, 1H), 4.47 (dd, J = 12.6,
9.6 Hz, 1H), 4.40 (ddd, J = 9.6, 4.5, 1.5 Hz, 1H), 3.96
(s, 3H), 3.72 (dd, J = 8.4, 5.7 Hz, 1H), 3.58 (d,
J = 1.2 Hz, 3H), 1.53 (s, 3H), 1.31 (s, 3H). 13C NMR
(CDCl3): d = 161.2, 140.0, 135.9 (d, J = 5.3 Hz), 135.8
(d, J = 5.7 Hz), 128.8, 128.7, 128.5, 128.4, 128.3, 110.0,
76.5 (d, J = 160.9 Hz), 76.1 (d, J = 6.9 Hz), 75.8 (d,
J = 7.7 Hz), 68.9 and 68.5 (2d, J = 6.9 Hz), 60.9 (d,
J = 2.6 Hz), 52.3, 51.7, 27.9, 25.6. 31P NMR (CDCl3):
d = 21.40. Anal. Calcd for C26H32N3O8P: C, 57.25; H,
5.91; N, 7.70. Found: C, 57.04; H, 5.90; N, 7.47.
4.5. Diisopropyl (1S,2R,3S)-4-(4-carbamoyl-1,2,3-triazol-
1-yl)-2,3-dihydroxy-1-methoxybutylphosphonate,
(1S,2R,3S)-23
A solution of phosphonate (1S,2R,3S)-21 (0.229 g,
0.987 mmol) in aqueous dioxane (20 mL, 3:1, v/v) was
stirred with Dowex 50W · 8 H+ (1.0 g) at 75 ꢁC for
1.5 h. After filtration, the solution was concentrated in
vacuo and the residue chromatographed on a silica gel
column with chloroform–methanol (25:1, v/v) to give
4.4. Diisopropyl (1S,2R,3S)-4-(4-carbamoyl-1,2,3-triazol-
1-yl)-2,3-dihydroxy-2,3-O-isopropylidene-1-methoxybutyl-
phosphonate, (1S,2R,3S)-21
(1S,2R,3S)-23 (0.109 g, 52%) as a white amorphous
20
solid, mp 169–170 ꢁC; ½aꢀD ¼ +6.8 (c 1.1, CH3OH). IR
(KBr): m = 3484, 3299, 3093, 2984, 2939, 1649, 1620,
1
A solution of phosphonate (1S,2R,3S)-15 (0.750 g,
1.67 mmol) in methanol (3 mL) containing 25% ammo-
nia (10 mL) was left at room temperature for 5 days.
All volatiles were removed in vacuo and the residue
chromatographed on a silica gel column with chloro-
1223, 998 cmꢁ1. H NMR (CD3OD): d = 8.41 (s, 1H),
4.82–4.70 (m, 2H), 4.62 (dd, J = 13.8, 4.8 Hz, 1H),
4.54 (dd, J = 13.8, 8.7 Hz, 1H), 4.20 (ddd, J = 8.7, 4.8,
1.5 Hz, 1H), 3.75 (ddd, J = 9.0, 9.0, 1.5 Hz, 1H), 3.59
(dd, J = 9.0, 3.9 Hz, 1H), 3.52 (d, J = 1.0 Hz, 3H),

A. E. Wro´blewski, I. E. Głowacka / Tetrahedron: Asymmetry 16 (2005) 4056–4064
4063
1.36 (d, J = 6.9 Hz, 9H), 1.33 (d, J = 6.9 Hz, 3H). 13C
NMR (CD3OD): d = 164.7, 143.5, 128.7, 79.0 (d,
J = 166.6 Hz), 73.2 and 73.2 (2 · d, J = 7.2 Hz), 71.7
(d, J = 4.5 Hz), 70.2 (d, J = 10.6 Hz), 61.6 (d,
J = 2.3 Hz), 54.9, 24.7 and 24.7 (2 · d, J = 3.8 Hz),
24.4 and 24.4 (2 · d, J = 3.0 Hz). 31P NMR (CD3OD):
d = 22.47. Anal. Calcd for C14H27N4O7P · 0.25 H2O:
C, 42.16; H, 6.95; N, 14.05. Found: C, 42.30; H, 6.93;
N, 13.83.
(D2O): d = 18.64. Anal. Calcd for C8H15N4O7P · 3
H2O: C, 26.39; H, 5.81; N, 15.38. Found: C, 26.21; H,
5.90; N, 15.09.
4.6.2. (1R,2R,3S)-4-(4-Carbamoyl-1,2,3-triazol-1-yl)-2,3-
dihydroxy-1-methoxybutylphosphonic acid, (1R,2R,3S)-
26. From (1R,2R,3S)-18 (0.113 g, 0.207 mmol), phos-
phonic acid (1R,2R,3S)-26 (0.053 g, 82%) was obtained
as a white powder after crystallisation from aqueous
ethanol,
which
½aꢀD ¼ ꢁ19:6 (c 1.01, water). IR (KBr): m = 3358, 2961,
2914, 1647, 1239, 1045 cmꢁ1 1H NMR (D2O):
decomposed
above
230 ꢁC;
20
4.5.1. Diisopropyl (1R,2R,3S)-4-(4-carbamoyl-1,2,3-tria-
zol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonate, (1R,
2R,3S)-24. In a similar method as described in Section
4.5. from (1R,2R,3S)-22 (0.127 g, 0.290 mmol), phos-
.
d = 8.46 (s, 1H), 4.80–4.50 (m, 2H), 4.45–4.30 (m, 1H),
3.95–3.80 (m, 1H), 3.60–3.45 (m, 1H), 3.54 (s, 3H). 13C
NMR (69.5 MHz, D2O): d = 162.5, 139.6, 126.2, 77.3
(d, J = 150.8 Hz), 69.7, 68.3, 58.6, 51.6. 31P NMR
(D2O): d = 17.60. Anal. Calcd for C8H15N4O7P · 3
H2O: C, 26.39; H, 5.81; N, 15.38. Found: C, 26.29; H,
6.01; N, 15.13.
phonate (1R,2R,3S)-24 (0.088 g, 77%) was obtained as
20
a white powder, mp 163–164 ꢁC; ½aꢀD ¼ ꢁ1:1 (c 1.8,
CHCl3). IR (KBr): m = 3405, 3205, 2978, 2928, 1636,
1
1212, 1108, 993 cmꢁ1. H NMR (CDCl3): d = 8.30 (s,
1H), 7.05 and 5.96 (2 · br s, 2H), 4.85–4.72 (m, 2H),
4.66 (dd, J = 13.8, 3.9 Hz, 1H), 4.54 (dd, J = 13.8,
8.1 Hz, 1H), 4.36 (ddd, J = 8.1, 3.6, 2.4 Hz, 1H), 3.83
(ddd, J = 15.3, 6.0, 2.4 Hz, 1H), 3.65 (dd, J = 8.1,
6.0 Hz, 1H), 3.58 (s, 3H), 3.2–2.8 (br s, 2H), 1.36 (d,
J = 6.3 Hz, 9H), 1.34 (d, J = 6.3 Hz, 3H). 13C NMR
(CDCl3): d = 168.3, 143.3, 127.6, 78.8 (d, J =
163.1 Hz), 72.7 and 72.2 (2 · d, J = 7.6 Hz), 70.7 (d,
J = 6.0 Hz), 69.6 (d, J = 5.3 Hz), 61.3 (d, J = 3.8 Hz),
53.8, 24.5 and 24.4 and 24.3 and 24.2 (4 · d,
J = 4.9 Hz). 31P NMR (CDCl3): d = 20.55. Anal. Calcd
for C14H27N4O7P: C, 42.64; H, 6.90; N, 14.21. Found:
C, 42.80; H, 6.62; N, 13.93.
4.6.3. (1S,2R,3R)-4-(4-Carbamoyl-1,2,3-triazol-1-yl)-2,3-
dihydroxy-1-methoxybutylphosphonic acid, (1S,2R,3R)-
27. From (1S,2R,3R)-19 (0.501 g, 0.918 mmol), phos-
phonic acid (1S,2R,3R)-27 (0.119 g, 42%) was obtained
as a white powder after crystallisation from aqueous
ethanol,
which
½aꢀD ¼ þ12:4 (c 0.84, water). IR (KBr): m = 3363, 2958,
2927, 1655, 1242, 1054 cmꢁ1 1H NMR (D2O):
decomposed
above
230 ꢁC;
20
.
d = 8.42 (s, 1H), 4.85–4.75 (m, 1H), 4.55 (dd, J = 14.3,
8.6 Hz, 1H), 4.34 (ddd, J = 8.6, 5.7, 3.4 Hz, 1H), 3.92
(ddd, J = 9.9, 5.7, 4.4 Hz, 1H), 3.58 (dd, J = 10.9,
4.4 Hz, 1H), 3.51 (s, 3H). 13C NMR (69.5 MHz, D2O):
d = 162.6, 139.6, 126.3, 78.2 (d, J = 151.7 Hz), 70.5 (d,
J = 6.4 Hz), 68.3, 58.5, 51.2. 31P NMR (D2O):
d = 16.52. Anal. Calcd for C8H15N4O7P · H2O: C,
29.27; H, 5.22; N, 17.07. Found: C, 29.10; H, 5.27; N,
17.36.
4.6. 4-(4-Carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-
1-methoxybutylphosphonic acids 25, 26, 27 and 28
(general procedure)
A solution of phosphonate (17–20, 1.00 mmol) in meth-
anol (2 mL) containing 25% ammonia (7 mL) was left at
room temperature for 5 days. All volatiles were removed
in vacuo and the residue dissolved in aqueous methanol
(20 mL, 1:3, v/v) and stirred with Dowex 50W · 8 H+
(1.0 g) at 75 ꢁC for 1.5 h. After filtration, the solution
was concentrated in vacuo and the residue was dissolved
in methanol (30 mL). After addition of water (15 mL)
and 10% Pd–C (12 mg) the suspension was stirred under
hydrogen atmosphere for 24 h. Removal of the catalyst
by filtration through a layer of Celite and concentration
of the solution gave crude products, which were chro-
matographed on silanised silica gel using water and
finally crystallised.
4.6.4.
(1R,2R,3R)-4-(4-Carbamoyl-1,2,3-triazol-1-yl)-
2,3-dihydroxy-1-methoxybutylphosphonic acid, (1R,2R,
3R)-28. From (1R,2R,3R)-20 (0.162 g, 0.297 mmol),
phosphonic acid (1R,2R,3R)-28 (0.036 g, 39%) was
obtained as a white powder after crystallisation from
aqueous acetone, which decomposed above 230 ꢁC;
20
½aꢀD ¼ þ7:7 (c 0.83, water). IR (KBr): m = 3360, 2973,
2920, 1659, 1228, 1049 cmꢁ1 1H NMR (D2O): d =
.
8.46 (s, 1H), 4.90–4.75 (m, 1H), 4.56 (dd, J = 14.2,
7.8 Hz, 1H), 4.12 (dd, J = 8.4, 7.8 Hz, 1H), 3.79 (d,
J = 8.4, Hz, 1H), 3.68 (d, J = 9.3, Hz, 1H), 3.53 (s,
3H). 13C NMR (69.5 MHz, D2O): d = 162.6, 139.6,
126.4, 75.3 (d, J = 151.0 Hz), 70.2, 67.3 (d, J =
9.4 Hz), 59.0, 51.8. 31P NMR (D2O): d = 18.76. Anal.
Calcd for C8H15N4O7P · 1.25 H2O: C, 28.89; H, 5.45;
N, 16.83. Found: C, 28.95; H, 5.16; N, 16.82.
4.6.1. (1S,2R,3S)-4-(4-Carbamoyl-1,2,3-triazol-1-yl)-2,3-
dihydroxy-1-methoxybutylphosphonic acid, (1S,2R,3S)-
25. From (1S,2R,3S)-17 (0.337 g, 0.618 mmol),
phosphonic acid (1S,2R,3S)-25 (0.050 g, 26%) was
obtained as a white powder after crystallisation from
aqueous ethanol, which decomposed above 230 ꢁC;
4.7. O-Benzyl (1S,2R,3S)-4-(4-carbamoyl-1,2,3-triazol-
1-yl)-2,3-dihydroxy-1-methoxybutylphosphonic acid,
(1S,2R,3S)-29
20
½aꢀD ¼ ꢁ64:6 (c 0.89, water). IR (KBr): m = 3365, 2967,
2923, 1653, 1233, 1050 cmꢁ1
.
1H NMR (D2O):
d = 8.46 (s, 1H), 4.80–4.60 (m, 2H), 4.35–4.25 (m, 1H),
3.90–3.80 (m, 1H), 3.60–3.45 (m, 1H), 3.50 (s, 3H). 13C
NMR (69.5 MHz, D2O): d = 162.5, 139.6, 126.2, 76.4
(d, J = 154.9 Hz), 68.6, 67.1, 58.6, 52.1. 31P NMR
Phosphonate (1S,2R,3S)-17 (0.337 g, 0.579 mmol) was
treated with 25% ammonia (4 mL) as described in Sec-
tion 4.6. After hydrolysis of the isopropylidene group

4064
A. E. Wro´blewski, I. E. Głowacka / Tetrahedron: Asymmetry 16 (2005) 4056–4064
K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2004, 43, 3928–
3932.
(Section 4.6.), the crude product was crystallised from
methanol–chloroform to give (1S,2R,3S)-29 (0.108 g,
´
17. Helms, B.; Mynar, J. L.; Hawker, C. J.; Frechet, J. M. J.
48%) as a white amorphous solid, mp 170.6–171.5 ꢁC;
20
J. Am. Chem. Soc. 2004, 126, 15020–15021.
18. Al-Masoudi, N. A.; Al-Soud, Y. A.; Abdul-Zahra, A.
Heteroat. Chem. 2004, 15, 380–387.
½aꢀD ¼ ꢁ8:5 (c 1.01, DMSO). IR (KBr): m = 3413,
3210, 2958, 2921, 1654, 1108, 996 cmꢁ1 1H NMR
.
(CD3OD): d = 8.40 (s, 1H), 7.44–7.27 (m, 5H), 5.12 (d,
J = 7.2 Hz, 2H), 4.62 (dd, J = 13.8, 4.8 Hz, 1H), 4.56
(dd, J = 13.8, 8.4 Hz, 1H), 4.22 (dd, J = 8.4, 4.8 Hz,
1H), 3.80 (dd, J = 9.0, 9.0 Hz, 1H), 3.65 (dd, J = 9.0,
3.9 Hz, 1H), 3.51 (s, 3H). 13C NMR (CD3SOCD3):
d = 161.5, 142.4, 137.6 (d, J = 6.3 Hz), 128.1, 127.5,
127.2, 127.2, 76.9 (d, J = 158.3 Hz), 70.1 (d,
J = 3.0 Hz), 68.7 (d, J = 10.3 Hz), 66.2 (d, J = 6.0 Hz),
59.9 (d, J = 2.3 Hz), 53.3. 31P NMR (CD3OD):
d = 23.53. Anal. Calcd for C15H21N4O7P · 0.5 H2O:
C, 44.01; H, 5.41; N, 13.69. Found: C, 43.80; H, 5.12;
N, 13.41.
19. Sallam, M. A. E.; Louis, F. F. Chirality 2004, 16, 331–335.
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Acknowledgements
´
25. Velazquez, S.; Alvarez, R.; Perez, C.; Gago, F.; De Clercq,
´ ´
Financial support from the Medical University of Łodz
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(503-314-1 and 502-13-853) is gratefully acknowledged.
The authors wish to express their gratitude to Mrs.
Jolanta Płocka for her excellent technical assistance.
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M. R.; Cascieri, M. A.; Colwell, L. F.; Deng, L.; Feeney,
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