Synthesis of (1R,2S)- and (1S,2S)-3-(4-carbamoyl-1,2,3-triazol-1-yl)-1,2- dihydroxypropylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2004.03.025

Good regioselectivity (86:14 and 80:20) was observed in the 1,3-dipolar cycloaddition of methyl propiolate to diastereoisomeric dimethyl (1R,2S)- and (1S,2S)-3-azido-2-benzyloxy-1-hydroxypropylphosphonates. The major 4-methoxycarbonyl regioisomers were transformed into O-methyl (1R,2S)- and (1S,2S)-3-(4-carbamoyl-1,2,3-triazol-1-yl)-1,2-dihydroxypropylphosphonic acids, structural analogues of ribavirin.

Full text of DOI:10.1016/j.tetasy.2004.03.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1457–1464
Synthesis of (1R,2S)- and (1S,2S)-3-(4-carbamoyl-
1,2,3-triazol-1-yl)-1,2-dihydroxypropylphosphonates
*
ꢀ
Andrzej E. Wroblewski and Iwona E. Głowacka
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łꢀodꢀz, 90-151 Łꢀodꢀz, Muszyꢀnskiego 1, Poland
Received 12 February 2004; accepted 18 March 2004
Available online 15 April 2004
Abstract—Good regioselectivity (86:14 and 80:20) was observed in the 1,3-dipolar cycloaddition of methyl propiolate to diaste-
reoisomeric dimethyl (1R,2S)- and (1S,2S)-3-azido-2-benzyloxy-1-hydroxypropylphosphonates. The major 4-methoxycarbonyl
regioisomers were transformed into O-methyl (1R,2S)- and (1S,2S)-3-(4-carbamoyl-1,2,3-triazol-1-yl)-1,2-dihydroxy-
propylphosphonic acids, structural analogues of ribavirin.
ꢀ 2004 Elsevier Ltd. All rights reserved.
CONH2
1. Introduction
N
N
In the search for more effective antiviral and antitumour
agents, various modifications of nucleotides have been
proposed.1 For over three decades, many nucleotide
analogues have been studied, in which nucleobases were
replaced by heterocyclic moieties of diverse degree of
stereo and electronic similarities to those found in
Nature. Subsequently, the sugar portion of the nucleo-
tide has also been the subject of intensive studies leading
to an array of modified structures having acyclic, car-
bocyclic and other saturated heterocyclic systems in-
stead of the ribofuranoside ring. These studies led to the
discovery of several drugs effective against HIV and
other viruses.
N
HO
O
OH
OH
1
Substituted 1,2,3-triazoles, easily available from organic
azides and acetylenic compounds via [2 þ 3] cycloaddi-
tion,5 have enjoyed a continuous interest due to several
applications in industry and medicine.6–22 Syntheses of
N-glycosides or other sugar derivatives having substi-
tuted 1,2,3-triazole ring instead of nucleobases have
been especially an active area of research, since they may
act as nucleoside mimics.6;13–22
Among these nucleosides mimics, ribavirin 1 plays a
special role, since it contains an unusual 3-carbamoyl-
1,2,4-triazole group.2 This compound is a synthetic
nucleoside structurally related to inosine and guanosine,
which has been used against various viral infections
since its approval by FDA in 1986. Detailed studies
proved that intracellular conversion of ribavirin into
50-O-triphosphate is required to obtain the active form
of the drug.3 Other 1,2,4-triazole derivatives have
recently been shown to act as nonnucleoside reverse
transcriptase inhibitors.4
Combining the ideas of unnatural nucleobases, acyclic
replacements for the furanose ring and the introduction
of a nonhydrolysable C–P bond23 instead of the O–P
phosphate linkage, we designed molecules of general
formula 2.
N
X
N
OH
N
(RO)2P
O
OH
n
≥
n 1
2
Recent papers on 4-(1,2,3-triazole)carboxamide nucleo-
side analogues 313, 414 and especially 515 (Fig. 1) have
* Corresponding
aewplld@ich.pharm.am.lodz.pl
author.
Fax:
+48-42-678-83-98;
e-mail:
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.03.025

1458
A. E. Wrꢀoblewski, I. E. Głowacka / Tetrahedron: Asymmetry 15 (2004) 1457–1464
CONH2
CONH2
HO
CONH2
N
N
N
O
P
O
N
N
N
O-
N
N
(HO)2P(O)
N
O
PO
O-
O-
O
O
O
OH
OH
OH
3
4
5
Figure 1. Recent examples of 4-(1,2,3-triazole)carboxamide nucleoside analogues.
prompted us to report the synthesis of enantiomerically
pure 1,2-dihydroxypropylphosphonates substituted at
C(3) with a 1,2,3-triazole ring functionalised with the
methoxycarbonyl and carbamoyl groups.
carbonyl-1,2,3-triazoles were always formed as major
isomers.20;22;25–27
The regioselectivity of the cycloadditions shown on
Schemes 1, 2 and 5 was primarily rationalised by the
comparison of the steric interactions of alkoxycarbonyl
groups of acetylenic compounds and carbon framework
of azides21;27 and later on refined by employing the
frontier molecular orbital theory.12;29;30
2. Results and discussion
A [2 þ 3] cycloaddition of 3-azidophosphonates (1S,2S)-
6 and (1R,2S)-624 and methyl propiolate was carried out
at 110 ꢁC according to the standard procedure (Schemes
1 and 2).20 Examination of the crude products by 31P
NMR revealed the formation of regioisomeric pairs
(1S,2S)-7 and (1S,2S)-8, and (1R,2S)-7 and (1R,2S)-8 in
80:20 and 86:14 ratios, respectively. The mixtures were
separated on silica gel to give pure products in good
yields.
The transformation of the major isomers (1S,2S)-7 and
(1R,2S)-7 into the 4-carbamoyl-1,2,3-triazoles (1S,2S)-
12 and (1R,2S)-12 is illustrated in Schemes 3 and 4,
respectively. From the preliminary experiment, we
learned that the protection of the C(1) hydroxyl group
in phosphonates 7 was necessary. When (1S,2S)-7 was
treated with 25% aqueous ammonia at room temper-
ature for 5 days, cleavage of the C–P bond occurred.
1
In the H and 31P NMR spectra of the crude product,
1
signals (d1H ¼ 6:67 ppm; JHP ¼ 613 Hz and d31P ¼
COOMe
5:9 ppm) that are characteristic of ammonium O-me-
thyl phosphonate (over 60% of the mixture) were
found.
N
N
P(OMe)
OH
(O)
2
N
N
COOMe
a
OH
N
OH
N
+
BnO
(MeO)2P
O
(MeO)2P
O
CH2N3
Thus, hydrogenolysis of the benzyl protecting groups led
to diols (1S,2S)-9 and (1R,2S)-9 in excellent yields. The
1,2-diols 9 were then treated with 2,2-dimethoxypropane
to give the isopropylidene derivatives (1S,2S)-10 and
(1R,2S)-10. The protected phosphonates 10 were left
with 25% aqueous ammonia at room temperature.
Under these conditions, quantitative amidation of the
methoxycarbonyl group was complete in less than 1 h.
As a much slower process hydrolysis of a phosphonate
ester took place leading to the formation of mono-
ammonium salts (1S,2S)-11 and (1R,2S)-11 in about one
week. The isopropylidene protecting groups were
quantitatively hydrolysed in the presence of a Dowex
Hþ resin at 75 ꢁC leaving monoacids (1R,2S)-12 and
(1S,2S)-12 in 86% and 76% yield, respectively, after
purification on silanised silica gel.
OBn
(1S,2S)-7
OBn
(1S,2S)-8
(1S,2S)-6
Scheme 1. Reagents and conditions: (a) HCBCCOOMe, toluene,
110 ꢁC, 4 h.
COOMe
N
N
P(OMe)
CH2N3
(O)
HO
BnO
2
N
N
COOMe
a
OH
N
OH
N
+
(MeO)2P
O
(MeO)2P
O
OBn
(1R,2S)-7
OBn
(1R,2S)-8
(1R,2S)-6
Scheme 2. Reagents and conditions: (a) HCBCCOOMe, toluene,
110 ꢁC, 4 h.
An alternative approach to the synthesis of the phos-
phonates (1S,2S)-7 and (1R,2S)-7 is shown in Schemes 5
and 6. The known (2S,3S)-4-azido-3-benzyloxy-1,2-O-
isopropylidene-1,2-butanediol 1324 was reacted with
methyl propiolate under standard conditions20 to give
an 80:20 mixture of (2S,3S)-14 and (2S,3S)-15 quanti-
tatively. The major product, which was identified as a
4-methoxycarbonyl regioisomer, was separated by
crystallisation in 62% yield. After hydrolysis of the iso-
propylidene group, diol (2S,3S)-16 was transformed into
the very unstable aldehyde (2S)-18, quantitatively. Tri-
ethylamine-catalysed additions of dimethyl or diethyl
Structural assignment of (1S,2S)-8 as a 5-methoxycar-
bonyl substituted 1,2,3-triazole was based on the de-
shielding of HaHbCN protons in the 1H NMR spectrum of
this compound (by ca. 0.4 ppm) in comparison with the
4-methoxycarbonyl isomer (1S,2S)-7. The same rela-
tionship was also noticed for (1R,2S)-7 and (1R,2S)-8
isomers. The deshielding effect of the carbonyl group has
frequently been applied to structural studies on the
related 1,2,3-triazoles.20;22;25–29 Furthermore, in [2 þ 3]
cycloadditions of azides to propiolates, the 4-alkoxy-

A. E. Wrꢀoblewski, I. E. Głowacka / Tetrahedron: Asymmetry 15 (2004) 1457–1464
1459
COOMe
COOMe
COOMe
c
N
N
N
N
N
N
N
N
O
N
HO
(MeO)2(O)P
HO
(MeO)2(O)P
a
b
(MeO)2(O)P
O
OH
OBn
(1S,2S)-10
(1S,2S)-7
(1S,2S)-9
CONH2
CONH2
N
N
N
N
N
O
d
N
HO
MeO(O)P
OH
MeO(O)P
+
O
-
NH4
O
OH
(1S,2S)-11
(1S,2S)-12
Scheme 3. Reagents and conditions: (a) H2–Pd/C, rt, 5 days; (b) Me2C(OMe)2; cat. p-TosOH, rt, 20 h; (c) 25% NH3, 7 days; (d) H2O, Dowex 50W · 4,
Hþ, 75 ꢁC, 1.5 h.
COOMe
COOMe
a
COOMe
c
N
N
N
N
N
N
N
HO
N
HO
(MeO)2(O)P
O
N
b
(MeO)2(O)P
(MeO)2(O)P
O
OH
OBn
(1R,2S)-10
(1R,2S)-7
(1R,2S)-9
CONH2
CONH2
N
N
N
N
N
O
d
N
HO
MeO(O)P
OH
MeO(O)P
+
-
O
NH4
O
OH
(1R,2S)-11
(1R,2S)-12
Scheme 4. Reagents and conditions: (a) H2–Pd/C, rt, 7 days; (b) Me2C(OMe)2; cat. p-TosOH, rt, 20 h; (c) 25% NH3, 7 days; (d) H2O, Dowex 50W · 4,
Hþ, 75 ꢁC, 1.5 h.
(and 5-)methoxycarbonyl-1,2,3-triazol-1-yl]propylphos-
phonates (1R,2S)-7 and (1R,2S)-8, respectively. Simi-
larly, from (1S,2S)-6 an 80:20 mixture of regioisomers
(1S,2S)-7 and (1S,2S)-8 was obtained. The major 4-
methoxycarbonyl isomers (1R,2S)-7 and (1S,2S)-7 were
transformed in a four step reaction sequence into O-
methyl (1R,2S)- and (1S,2S)-3-(4-carbamoyl-1,2,3-tria-
zol-1-yl)-1,2-dihydroxypropylphosphonic acids 12.
OR'
OR'
OR"
OR"
O
O
BnO
BnO
a, b
+
CH2
CH2
BnO
N
N
COOMe
N3
N
N
N
N
COOMe
(2S,3S)-15 (R'/R" = CMe2)
(2S,3S)-17 (R' = R" = H)
(2S,3S)-13
(2S,3S)-14 (R'/R" = CMe2)
(2S,3S)-16 (R' = R" = H)
The alternative strategy to phosphonates 7 (cycloaddi-
tion proceeds phosphonylation) employing (2S,3S)-4-
azido-3-benzyloxy-1,2-O-isopropylidene-1,2-butanediol
as a starting material failed, because mixtures of dia-
stereoisomeric phosphonates (1R,2S)-7 and (1S,2S)-7,
which were formed in a 1:1 ratio, could not be separated.
Scheme 5. Reagents and conditions: (a) HCBCCOOMe, toluene,
110 ꢁC, 4 h; (b) 1 M HCl, dioxane, rt, 24 h.
phosphites led to 1:1 mixtures of the respective phos-
phonates, which could not be separated on silica gel.
3. Conclusions
4. Experimental
Dimethyl (1R,2S)-3-azido-2-benzyloxy-1-hydroxyprop-
ylphosphonate (1R,2S)-6 underwent [2 þ 3] cycloaddi-
tion with methyl propiolate to give an 86:14 mixture of
regioisomeric dimethyl 2-benzyloxy-1-hydroxy-3-[4-
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

1460
A. E. Wrꢀoblewski, I. E. Głowacka / Tetrahedron: Asymmetry 15 (2004) 1457–1464
COOMe
COOMe
CHO
N
N
BnO
N
N
OH
N
OH
N
CH2
N
a
b
+
(2S,3S)-16
(RO)2P
O
(RO)2P
N
OH
O
OH
N
COOMe
(1R,2S)-7 R = Me
(1R,2S)-19 R = Et
(1S,2S)-7 R = Me
(1S,2S)-19 R = Et
(2S)-18
Scheme 6. Reagents and conditions: (a) NaIO4, H2O, NaHCO3, 40 ꢁC, 3 h; (b) (RO)2P(O)H, NEt3, rt, 16 h.
spectra were recorded on a Varian Mercury-300
machine at 75.5 and 121.5 MHz, respectively. However,
13C NMR spectra in D2O were taken on a Bruker DPX
spectrometer at 62.9 MHz. IR spectral data were mea-
sured on an Infinity MI-60 FT-IR spectrometer. 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 analyser. Polarimetric measure-
ments were conducted on a Perkin Elmer 241 MC
apparatus.
CDCl3): d ¼ 24:06 ppm. Anal. Calcd for C16H22N3O7P:
C, 48.12; H, 5.55; N, 10.52. Found: C, 48.35; H, 5.43; N,
10.68.
4.1.2. Dimethyl (1S,2S)-2-benzyloxy-1-hydroxy-3-(5-
methoxycarbonyl-1,2,3-triazol-1-yl)propylphosphonate,
20
D
(1S,2S)-8. Colourless oil. ½aꢀ ¼ ꢁ20:1 (c 3.22, CHCl3).
IR (film): m ¼ 3277, 2956, 2922, 2853, 1732, 1454, 1318,
1259, 1054 cmꢁ1. 1H NMR (300 MHz, CDCl3): d ¼ 3:08
(br s, 1H, OH), 3.77 and 3.79 (2d, J ¼ 10:7 Hz, 6H,
CH3OPOCH3), 3.88 (s, 3H, CH3OOC), 3.97 (dd,
J ¼ 11:8, 2.4 Hz, 1H, HCP), 4.34 (dddd, J ¼ 6:5, 6.2,
5.3, 2.4 Hz, 1H, HCCP), 4.43 (d, J ¼ 10:9 Hz, 1H,
HaCHbPh), 4.68 (d, J ¼ 10:9 Hz, 1H, HaCHbPh), 4.96
(dd, J ¼ 13:5, 6.2 Hz, 1H, HaCHbN), 5.14 (ddd,
J ¼ 13:5, 6.5, 1.8 Hz, 1H, HaCHbN), 7.23–7.33 (m, 5H,
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); analyti-
cal TLC, Merck TLC plastic sheets silica gel 60 F254
.
C6H5), 8.09 (s, 1H, HC4 ). 13C NMR (75.5 MHz,
0
4.1. Reaction of (1S,2S)-6 with methyl propiolate
CDCl3): d ¼ 49:9 (d, J ¼ 12:9 Hz, CCCP), 52.8, 53.3
and 53.9 (2d, J ¼ 7:1 Hz, CH3OPOCH3), 67.9 (d,
J ¼ 162:6 Hz, CP), 73.8, 76.8 (d, J ¼ 2:3 Hz, CCP),
128.0, 128.3, 128.4, 128.6, 137.0, 137.9, 158.9. 31P NMR
(121.5 MHz, CDCl3): d ¼ 24:76 ppm. Anal. Calcd for
C16H22N3O7P: C, 48.12; H, 5.55; N, 10.52. Found: C,
47.97; H, 5.60; N, 10.21.
A solution of (1S,2S)-6 (213 mg, 0.676 mmol) and
methyl propiolate (114 mg, 1.36 mmol) in toluene (2 mL)
was refluxed for 4 h. The mixture was concentrated to
dryness to leave a white solid (266 mg), which was
chromatographed on a silica gel column with chloro-
form/methanol (100:1, v/v). The appropriate fractions
were collected to give (1S,2S)-7 (138 mg, 52%), a mix-
ture of (1S,2S)-7 and (1S,2S)-8 (74 mg, 28%) and
(1S,2S)-8 (54 mg, 20%).
4.2. Reaction of (1R,2S)-6 with methyl propiolate
In
a
similar manner, from (1R,2S)-6 (156 mg,
0.495 mmol) and methyl propiolate (88 lL, 0.99 mmol)
in toluene (1 mL), a colourless oil (202 mg) was ob-
tained. After chromatography on a silica gel column
with chloroform/methanol (100:1, v/v), (1R,2S)-7
(142 mg, 71%), a mixture of (1R,2S)-7 and (1R,2S)-8
(35 mg, 18%) and (1R,2S)-8 (24 mg, 11%) were obtained.
4.1.1. Dimethyl (1S,2S)-2-benzyloxy-1-hydroxy-3-(4-
methoxycarbonyl-1,2,3-triazol-1-yl)propylphosphonate,
(1S,2S)-7. The material obtained after chromatography
was recrystallised from ethyl acetate/hexanes to afford a
20
D
white amorphous solid (136 mg, 52%). ½aꢀ ¼ ꢁ32:1 (c
1.37, CHCl3). Mp 120.5–121.5 ꢁC. IR (KBr): m ¼ 3200,
2953, 2923, 2853, 1746, 1222, 1204, 1047, 1021 cmꢁ1. 1H
NMR (300 MHz, CDCl3): d ¼ 3:57 (br t, J ¼ 8:9 Hz,
1H, OH), 3.82 and 3.83 (2d, J ¼ 10:5 Hz, 6H,
CH3OPOCH3), 3.93 (ddd, J ¼ 11:9, 8.9, 3.2 Hz, 1H,
HCP), 3.95 (s, 3H, CH3OOC), 4.30 (d, J ¼ 10:9 Hz, 1H,
HaCHbPh), 4.31 (dddd, J ¼ 7:5, 7.4, 5.5, 3.2 Hz, 1H,
HCCP), 4.57 (dd, J ¼ 11:9, 7.5 Hz, 1H, HaCHbN), 4.69
(d, J ¼ 10:9 Hz, 1H, HaCHbPh), 4.72 (dd, J ¼ 11:9,
5.5 Hz, 1H, HaCHbN), 7.20–7.31 (m, 5H, C6H5), 8.09 (s,
4.2.1. Dimethyl (1R,2S)-2-benzyloxy-1-hydroxy-3-(4-
methoxycarbonyl-1,2,3-triazol-1-yl)propylphosphonate,
20
D
(1R,2S)-7. Colourless very thick oil. ½aꢀ ¼ ꢁ21:2
(c 1.08, CH3OH). IR (film): m ¼ 3296, 2956, 2922, 2854,
1738, 1232, 1042 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d ¼ 3:79 and 3.81 (2d, J ¼ 10:5 Hz, 6H, CH3OPOCH3),
3.87 (dd, J ¼ 10:9, 5.8 Hz, 1H, OH), 3.96 (s, 3H,
CH3OOC), 3.99 (ddd, J ¼ 9:1, 5.8, 5.5 Hz, 1H, HCP),
4.19 (dddd, J ¼ 9:1, 6.9, 5.8, 3.4 Hz, 1H, HCCP), 4.41
(d, J ¼ 11:1 Hz, 1H, HaCHbPh), 4.56 (d, J ¼ 11:1 Hz,
1H, HaCHbPh), 4.69 (dd, J ¼ 14:5, 6.9 Hz, 1H,
HaCHbN), 4.82 (dd, J ¼ 14:5, 3.4 Hz, 1H, HaCHbN),
1H, HC5 ). 13C NMR (75.5 MHz, CDCl3): d ¼ 51:1 (d,
0
J ¼ 10:6 Hz, CCCP), 52.3, 53.6 and 53.8 (2d,
J ¼ 7:0 Hz, CH3OPOCH3), 67.6 (d, J ¼ 163:8 Hz, CP),
74.1, 77.4 (d, J ¼ 2:3 Hz, CCP), 128.2, 128.4, 128.5,
129.2, 136.7, 139.6, 160.9. 31P NMR (121.5 MHz,
7.18–7.33 (m, 5H, C6H5), 8.13 (s, 1H, HC5 ). 13C NMR
0

A. E. Wrꢀoblewski, I. E. Głowacka / Tetrahedron: Asymmetry 15 (2004) 1457–1464
1461
(75.5 MHz, CDCl3): d ¼ 50:7 (d, J ¼ 7:6 Hz, CCCP),
52.4, 53.9 and 53.9 (2d, J ¼ 7:5 Hz, CH3OPOCH3), 67.2
(d, J ¼ 162:5 Hz, CP), 73.1, 77.5 (d, J ¼ 5:3 Hz, CCP),
128.3, 128.4, 128.5, 129.4, 136.6, 139.7, 161.1. 31P NMR
(121.5 MHz, CDCl3): d ¼ 24:84 ppm. Anal. Calcd for
C16H22N3O7P: C, 48.12; H, 5.55; N, 10.52. Found: C,
47.81; H, 5.72; N, 10.40.
column with chloroform/methanol (50:1 and 25:1, v/v)
and gave (1R,2S)-9 (328 mg, 91%) as a colourless oil.
20
D
½aꢀ ¼ ꢁ2:6 (c 2.7, CH3OH). IR (film): m ¼ 3348, 2959,
2855, 1729, 1230, 1042 cmꢁ1
.
1H NMR (300 MHz,
CD3OD): d ¼ 3:80 and 3.85 (2d, J ¼ 10:5 Hz, 6H,
CH3OPOCH3), 3.92 (s, 3H, CH3OOC), 3.93 (dd,
J ¼ 7:9, 6.5 Hz, 1H, HCP), 4.21 (dddd, J ¼ 8:5, 8.3, 6.5,
2.9 Hz, 1H, HCCP), 4.57 (dd, J ¼ 14:1, 8.3 Hz, 1H,
HaCHbN), 4.74 (dd, J ¼ 14:1, 2.9 Hz, 1H, HaCHbN),
8.50 (s, 1H, HC5 ). 13C NMR (75.5 MHz, CD3OD):
0
4.2.2. Dimethyl (1R,2S)-2-benzyloxy-1-hydroxy-3-(5-
methoxycarbonyl-1,2,3-triazol-1-yl)propylphosphonate,
d ¼ 52:7, 54.0 and 54.5 (2d, J ¼ 7:2 Hz, CH3OPOCH3),
54.4 (d, J ¼ 9:5 Hz, CCCP), 70.5 (d, J ¼ 163:2 Hz, CP),
71.2 (d, J ¼ 5:7 Hz, CCP), 130.9, 140.1, 162.4. 31P NMR
(121.5 MHz, CD3OD): d ¼ 26:75 ppm. Anal. Calcd for
C9H16N3O7P: C, 34.96; H, 5.22; N, 13.58. Found: C,
35.15; H, 5.23; N, 13.26.
(1R,2S)-8. A white amorphous solid. Mp 119–120 ꢁC.
20
½aꢀ ¼ ꢁ36:3 (c 0.91, CHCl3). IR (KBr): m ¼ 3227, 3029,
D
2961, 2855, 1737, 1535, 1454, 1322, 1263, 1208,
1
1052 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 3:55–3.90
(br d, J ¼ 5:9 Hz, 1H, OH), 3.76 (s, 3H, CH3OOC), 3.78
and 3.82 (2d, J ¼ 10:5 Hz, 6H, CH3OPOCH3), 4.05
(ddd, J ¼ 9:9, 6.0, 5.9 Hz, 1H, HCP), 4.26 (dddd,
J ¼ 10:2, 6.6, 6.0, 3.8 Hz, 1H, HCCP), 4.36 (d,
J ¼ 10:9 Hz, 1H, HaCHbPh), 4.53 (d, J ¼ 10:9 Hz, 1H,
HaCHbPh), 5.16 (dd, J ¼ 14:1, 6.6 Hz, 1H, HaCHbN),
5.23 (dd, J ¼ 14:1, 3.8 Hz, 1H, HaCHbN), 7.10–7.27 (m,
4.4. Dimethyl (1S,2S)-1,2-dihydroxy-1,2-O-isopropylid-
ene-3-(4-methoxycarbonyl-1,2,3-triazol-1-yl)propyl-
phosphonate, (1S,2S)-10
5H, C6H5), 8.08 (s, 1H, HC4 ). 13C NMR (75.5 MHz,
A mixture of (1S,2S)-9 (161 mg, 0.521 mmol) and 2,2-
dimethoxypropane (128 lL, 1.04 mmol) in methylene
chloride (10 mL) containing p-toluenesulfonic acid
(1 mg) was left at room temperature for 20 h. The
reaction mixture was neutralised with triethylamine and
concentrated in vacuo. The residue (198 mg) was chro-
matographed on a silica gel column with methylene
chloride/methanol (50:1, v/v) to give (1S,2S)-10 as a
0
CDCl3): d ¼ 49:5 (d, J ¼ 6:9 Hz, CCCP), 52.6, 53.6 and
54.0 (2d, J ¼ 6:9 Hz, CH3OPOCH3), 67.7 (d,
J ¼ 163:5 Hz, CP), 73.0, 77.7 (d, J ¼ 4:3 Hz, CCP),
128.0, 128.0, 128.4, 129.0, 137.1, 137.8, 158.9. 31P NMR
(121.5 MHz, CDCl3): d ¼ 24:75 ppm. Anal. Calcd for
C16H22N3O7P: C, 48.12; H, 5.55; N, 10.52. Found: C,
48.24; H, 5.41; N, 10.58.
white amorphous solid (174 mg, 96%). Mp 61–62.5 ꢁC.
20
½aꢀ ¼ ꢁ26:5 (c 1.09, CHCl3). IR (KBr): m ¼ 3544, 3476,
D
4.3. Dimethyl (1S,2S)-1,2-dihydroxy-3-(4-methoxycar-
bonyl-1,2,3-triazol-1-yl)propylphosphonate, (1S,2S)-9
3125, 2964, 1733, 1542, 1248, 1020 cmꢁ1
.
1H NMR
(300 MHz, CDCl3): d ¼ 1:30 and 1.45 (2s, 6H,
CH3CCH3), 3.87 and 3.88 (2d, J ¼ 10:8 Hz, 6H,
CH3OPOCH3), 3.90 (dd, J ¼ 9:1, 1.1 Hz, 1H, HCP),
3.97 (s, 3H, CH3OOC), 4.55–4.67 (m, 2H, HCCP,
HaCHbN), 4.78–4.87 (m, 1H, HaCHbN), 8.26 (s, 1H,
A suspension of (1S,2S)-7 (114 mg, 0.285 mmol) and
Pd–C (10%, 6 mg) in methanol (15 mL) was stirred
under hydrogen for 5 days. The catalyst was filtered off
through a layer of Celite, the solution concentrated in
vacuo and the residue chromatographed on silica gel
HC5 ). 13C NMR (75.5 MHz, CDCl3): d ¼ 26:3 and 26.6
0
(2s, CH3CCH3), 51.0 (d, J ¼ 3:7 Hz, CCCP), 52.4, 53.9
and 54.2 (2d, J ¼ 6:9 Hz, CH3OPOCH3), 71.8 (d,
J ¼ 173:2 Hz, CP), 75.3 (d, J ¼ 4:9 Hz, CCP), 112.5 (d,
J ¼ 10:6 Hz, CH3CCH3), 129.4, 140.0, 161.0. 31P NMR
(121.5 MHz, CDCl3): d ¼ 21:37 ppm. Anal. Calcd for
C12H20N3O7P: C, 41.26; H, 5.77; N, 12.03. Found: C,
41.27; H, 5.80; N, 11.74.
with methylene chloride/methanol (20:1, v/v) to give
20
D
(1S,2S)-9 as a colourless oil (85 mg, 97%). ½aꢀ ¼ ꢁ6:7
(c 1.22, CHCl3). IR (film): m ¼ 3292, 2959, 2920, 2854,
1732, 1222, 1044 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d ¼ 3:81 and 3.86 (2d, J ¼ 10:7 Hz, 6H, CH3OPOCH3),
3.93 (ddd, J ¼ 12:0, 6.1, 2.3 Hz, 1H, HCP), 3.94 (s, 3H,
CH3OOC), 4.34–4.44 (m, 1H, HCCP), 4.60 (dd,
J ¼ 14:1, 7.8 Hz, 1H, HaCHbN), 4.69 (dd, J ¼ 14:1,
4.8 Hz, 1H, HaCHbN), 4.63–4.75 (br s, 2H, OH), 8.29 (s,
4.4.1. Dimethyl (1R,2S)-1,2-dihydroxy-1,2-O-isopropyl-
idene-3-(4-methoxycarbonyl-1,2,3-triazol-1-yl)propylphos-
phonate, (1R,2S)-10. In a similar manner from (1R,2S)-9
(287 mg, 0.928 mmol) the phosphonate (1R,2S)-10
1H, HC5 ). 13C NMR (75.5 MHz, CDCl3): d ¼ 52:4, 53.0
0
(d, J ¼ 14:3 Hz, CCCP), 53.8 and 54.3 (2d, J ¼ 7:2 Hz,
CH3OPOCH3), 68.7 (d, J ¼ 162:9 Hz, CP), 69.7 (d,
J ¼ 2:6 Hz, CCP), 129.3, 139.5, 161.1. 31P NMR
(121.5 MHz, CDCl3): d ¼ 25:21 ppm. Anal. Calcd for
C9H16N3O7P: C, 34.96; H, 5.22; N, 13.58. Found: C,
35.19; H, 5.39; N, 13.35.
(281 mg, 87%) was obtained as a white amorphous solid.
20
D
Mp 88–89 ꢁC. ½aꢀ ¼ ꢁ29:6 (c 1.25, CHCl3). IR (KBr):
m ¼ 3101, 3068, 2994, 2960, 1720, 1546, 1255, 1045 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d ¼ 1:33 and 1.61 (2s, 6H,
CH3CCH3), 3.86 and 3.91 (2d, J ¼ 10:6 Hz, 6H,
CH3OPOCH3), 3.96 (s, 3H, CH3OOC), 4.48 (dd,
J ¼ 7:1, 1.9 Hz, 1H, HCP), 4.63 (dd, J ¼ 13:7, 10.1 Hz,
1H, HaCHbN), 4.73 (dddd, J ¼ 10:1, 9.9, 7.1, 2.1 Hz, 1H,
HCCP), 5.01 (dd, J ¼ 13:7, 2.1 Hz, 1H, HaCHbN), 8.25
4.3.1. Dimethyl (1R,2S)-1,2-dihydroxy-3-(4-methoxycar-
bonyl-1,2,3-triazol-1-yl)propylphosphonate, (1R,2S)-9. In
a similar way from (1R,2S)-7 (464 mg, 1.16 mmol) the
crude phosphonate (1R,2S)-9 (430 mg) was obtained
after 7 days. The purification took place on a silica gel
(s, 1H, HC5 ). 13C NMR (75.5 MHz, CDCl3): d ¼ 24:7
0
and 27.0 (2s, CH3CCH3), 51.5 (d, J ¼ 4:0 Hz, CCCP),

1462
A. E. Wrꢀoblewski, I. E. Głowacka / Tetrahedron: Asymmetry 15 (2004) 1457–1464
52.0, 53.1 and 54.2 (2d, J ¼ 7:0 Hz, CH3OPOCH3), 71.8
(d, J ¼ 172:1 Hz, CP), 76.8, 111.7 (d, J ¼ 8:9 Hz,
CH3CCH3), 128.7, 139.6, 160.9. 31P NMR (121.5 MHz,
CDCl3): d ¼ 19:82 ppm. Anal. Calcd for C12H20N3O7P:
C, 41.26; H, 5.77; N, 12.03. Found: C, 41.28; H, 6.00; N,
12.12.
until washings were neutral. The aqueous solution was
concentrated in vacuo to leave a solid (0.125 g), which
was chromatographed on a silanised silica gel column
with distilled water to give phosphonate (1S,2S)-12
(0.105 g, 76%) as a white amorphous solid. Mp 187–
20
D
3137, 3095, 2958, 2924, 2555, 1619, 1571, 1240, 1197,
189 ꢁC. ½aꢀ ¼ ꢁ21:1 (c 1.1, H2O). IR (KBr): m ¼ 3394,
1052 cmꢁ1
.
1H NMR (300 MHz, D2O): d ¼ 3:65 (d,
4.5. Ammonium O-methyl (1S,2S)-3-(4-carbamoyl-1,2,3-
triazol-1-yl)-1,2-dihydroxy-1,2-O-isopropylidene-
propylphosphonate, (1S,2S)-11
J ¼ 10:5 Hz, 3H, CH3OP), 3.86 (dd, J ¼ 10:8, 3.9 Hz,
1H, HCP), 4.32 (dddd, J ¼ 9:6, 5.4, 3.9, 2.7 Hz, 1H,
HCCP), 4.58 (dd, J ¼ 14:1, 9.6 Hz, 1H, HaCHbN), 4.75
0
(dd, J ¼ 14:1, 2.7 Hz, 1H, HaCHbN), 8.48 (s, 1H, HC5 ).
A mixture of (1S,2S)-10 (360 mg, 1.03 mmol) and
aqueous ammonia (25%) (8 mL) was diluted with
methanol (2 mL) and left at room temperature for
6 days. Volatiles were removed in vacuo and the residue
13C NMR (62.9 MHz, D2O): d ¼ 52:2 (d, J ¼ 6:3 Hz,
CH3OP), 52.9 (d, J ¼ 11:8 Hz, CCCP), 67.5 (d,
J ¼ 159:6 Hz, CP), 69.2 (d, J ¼ 3:5 Hz, CCP), 127.7,
141.1, 163.9. 31P NMR (121.5 MHz, D2O):
1
recrystallised from methanol/diethyl ether to give
(1S,2S)-11 as a white powder (258 mg, 74%). Mp 141–
d ¼ 21:19 ppm. Anal. Calcd for C7H13N4O6P · H2O: C,
29.53; H, 4.62; N, 19.68. Found: C, 29.80; H,44.71; N,
19.43.
20
D
142 ꢁC. ½aꢀ ¼ ꢁ37:7 (c 1.55, CH3OH). IR (KBr):
m ¼ 3439, 3207, 3103, 2980, 2926, 1632, 1240, 1212,
1047 cmꢁ1. 1H NMR (300 MHz, CD3OD): d ¼ 1:24 and
1.40 (2s, 6H, CH3CCH3), 3.70 (d, J ¼ 10:1 Hz, 3H,
CH3OP), 3.84 (dd, J ¼ 9:5, 1.2 Hz, 1H, HCP), 4.48
(dddd, J ¼ 9:5, 9.4, 6.7, 2.8 Hz, 1H, HCCP), 4.67 (dd,
J ¼ 14:3, 6.7 Hz, 1H, HaCHbN), 4.90 (dd, J ¼ 14:3,
4.6.1. O-Methyl (1R,2S)-3-(4-carbamoyl-1,2,3-triazol-1-
yl)-1,2-dihydroxypropylphosphonic acid, (1R,2S)-12. In a
similar manner, from (1R,2S)-11 (98 mg, 0.29 mmol)
phosphonate (1R,2S)-12 (70 mg, 86%) was obtained as a
20
D
2.8 Hz, 1H, HaCHbN), 8.42 (s, 1H, HC5 ). 13C NMR
white amorphous solid. Mp 165–167 ꢁC. ½aꢀ ¼ ꢁ12:9 (c
0
(75.5 MHz, CD3OD): d ¼ 26:9 and 27.2 (2s, CH3CCH3),
53.2 (CCCP), 53.4 (d, J ¼ 6:3 Hz, CH3OP), 75.2 (d,
J ¼ 163:1 Hz, CP), 77.9 (d, J ¼ 7:3 Hz, CCP), 112.0 (d,
J ¼ 10:9 Hz, CH3CCH3), 129.0, 143.5, 164.7. 31P NMR
(121.5 MHz, CD3OD): d ¼ 14:78 ppm. Anal. Calcd for
C10H20N5O6P: C, 35.61; H, 5.97; N, 20.76. Found: C,
35.71; H, 5.65; N, 21.16.
1.0, H2O). IR (KBr): m ¼ 3377, 2961, 2924, 2853, 1655,
1
1255, 1051 cmꢁ1. H NMR (300 MHz, D2O): d ¼ 3:66
(d, J ¼ 10:3 Hz, 3H, CH3OP), 3.93 (dd, J ¼ 9:8, 5.8 Hz,
1H, HCP), 4.20–4.39 (m, 1H, HCCP), 4.59 (dd,
J ¼ 14:2, 8.8 Hz, 1H, HaCHbN), 4.79–4.88 (m, 1H,
HaCHbN), 8.46 (s, 1H, HC5 ). 13C NMR (62.9 MHz,
0
D2O): d ¼ 52:3 (d, J ¼ 6:5 Hz, CH3OP), 52.4 (d,
J ¼ 6:8 Hz, CCCP), 68.3 (d, J ¼ 150:1 Hz, CP), 69.6 (d,
J ¼ 1:8 Hz, CCP), 127.8, 141.0, 163.7. 31P NMR
(121.5 MHz, D2O): d ¼ 20:72 ppm. Anal. Calcd for
4.5.1. Ammonium O-methyl (1R,2S)-3-(4-carbamoyl-
1,2,3-triazol-1-yl)-1,2-dihydroxy-1,2-O-isopropylideneprop-
ylphosphonate, (1R,2S)-11. In a similar manner from
(1R,2S)-10 (57 mg, 0.16 mmol) the phosphonate
1
C7H13N4O6P · 4H2O: C, 29.53; H, 4.62; N, 19.68.
Found: C, 29.73; H, 4.78; N, 19.35.
(1R,2S)-11 (40 mg, 73%) was obtained as white plates.
20
D
Mp 186–188 ꢁC. ½aꢀ ¼ ꢁ76:3 (c 1.2, CH3OH). IR
4.7. Reaction of (2S,3S)-13 with methyl propiolate
(KBr): m ¼ 3425, 3274, 3084, 2993, 2953, 2827, 1648,
1210, 1029 cmꢁ1
.
1H NMR (300 MHz, CD3OD):
A solution of azide 13 (2.01 g, 7.24 mmol) and methyl
propiolate (1.29 mL, 14.5 mmol) in toluene (10 mL) was
refluxed for 4 h. The mixture was concentrated to dry-
ness to leave a white solid (2.62 g), which was recrys-
tallised from ethyl acetate/n-heptane to give (2S, 3S)-14
(1.535 g) as a white powder. The residue was chroma-
tographed on a silica gel column with methylene chlo-
ride/methanol (150:1, v/v). The appropriate fractions
were collected to give (2S, 3S)-14 (85 mg), a mixture of
(2S,3S)-14 and (2S,3S)-15 (614 mg, 23%) and (2S,3S)-15
(386 mg, 15%).
d ¼ 1:31 and 1.58 (2s, 6H, CH3CCH3), 3.73 (d,
J ¼ 10:1 Hz, 3H, CH3OP), 4.42 (dd, J ¼ 6:8, 5.5 Hz, 1H,
HCP), 4.58–4.69 (m, 2H, HCCP, HaCHbN), 4.89–5.00
(m, 1H, HaCHbN), 8.41 (s, 1H, HC5 ). 13C NMR
(75.5 MHz, CD3OD): d ¼ 25:3 and 28.2 (2s, CH3CCH3),
53.3 (d, J ¼ 6:0 Hz, CH3OP), 54.2 (d, J ¼ 3:0 Hz,
CCCP), 74.7 (d, J ¼ 160:1 Hz, CP), 77.5 (d, J ¼ 1:5 Hz,
CCP), 111.8 (d, J ¼ 12:6 Hz, CH3CCH3), 128.3, 143.4,
164.8. 31P NMR (121.5 MHz, CD3OD): d ¼ 13:37 ppm.
Anal. Calcd for C10H20N5O6P: C, 35.61; H, 5.97; N,
20.76. Found: C, 35.70; H, 6.13; N, 20.40.
0
4.7.1. (2S,3S)-3-Benzyloxy-1,2-O-isopropylidene-4-(4-meth-
oxycarbonyl-1,2,3-triazol-1-yl)-1,2-butanediol, (2S,3S)-
4.6. O-Methyl (1S,2S)-3-(4-carbamoyl-1,2,3-triazol-1-
yl)-1,2-dihydroxypropylphosphonic acid, (1S,2S)-12
14. Total yield (1.62 g, 62%). Mp 89–90 ꢁC.
20
½aꢀ ¼ ꢁ10:9 (c 1.1, CHCl3). IR (KBr): m ¼ 3121, 1719,
D
1
An aqueous (4 mL) solution of the phosphonate
(1S,2S)-11 (168 mg, 4.98 mmol) containing Dowex
50W · 4 (Hþ) (0.95 g) was maintained at 75 ꢁC for 1.5 h.
The resin was filtered off and washed with distilled water
1238 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 1:36 and
1.47 (2s, 6H, CH3CCH3), 3.93 (dd, J ¼ 8:6, 6.0 Hz, 1H,
HaHbCO), 3.96 (s, 3H, CH3OOC), 3.96 (ddd, J ¼ 8:4,
5.0, 3.4 Hz, 1H, HCOBn), 4.07 (dd, J ¼ 8:6, 6.5 Hz, 1H,

A. E. Wrꢀoblewski, I. E. Głowacka / Tetrahedron: Asymmetry 15 (2004) 1457–1464
1463
HaHbCO), 4.18 (ddd, J ¼ 6:5, 6.0, 5.0 Hz, 1H, HCO),
4.34 (d, J ¼ 11:7 Hz, 1H, HaHbCPh), 4.37 (dd, J ¼ 14:1,
8.4 Hz, 1H, HaCHbN), 4.53 (d, J ¼ 11:7 Hz, 1H,
HaHbCPh), 4.63 (dd, J ¼ 14:1, 3.4 Hz, 1H, HaCHbN),
7.14–7.17 (m, 2H, C6H5), 7.27–7.31 (m, 3H, C6H5), 8.10
17 (159 mg, 50%) was obtained as a yellowish oil.
20
½aꢀ ¼ ꢁ5:25 (c 2.02, CHCl3). IR (film): m ¼ 3397, 2927,
D
1731, 1075 cmꢁ1. 1H NMR (300 MHz, CDCl3): d ¼ 2:22
(br s, 1H, HOCH2), 2.79 (d, J ¼ 6:3 Hz, 1H, HOCH),
3.62–3.87 (m, 3H, HCOH and H2COH), 3.88 (s, 3H,
CH3OOC), 4.01 (ddd, J ¼ 6:9, 5.4, 3.4 Hz, 1H,
HCOBn), 4.40 (s, 2H, H2CPh), 4.99 (dd, J ¼ 13:7,
5.4 Hz, 1H, HaCHbN), 5.07 (dd, J ¼ 13:7, 6.9 Hz, 1H,
HaCHbN), 7.17–7.21 (m, 2H, C6H5), 7.27–7.34 (m, 3H,
(s, 1H, HC5 ). 13C NMR (75.5 MHz, CDCl3): d ¼ 25:2,
0
26.5, 51.4, 52.4, 65.2, 73.9, 75.3, 77.8, 110.1, 128.2,
128.2, 128.6, 129.2, 137.0, 139.8, 161.0. Anal. Calcd for
C18H23N3O5: C, 59.82; H, 6.41; N, 11.62. Found: C,
59.62; H, 6.25; N, 11.59.
C6H5), 8.10 (s, 1H, HC4 ). 13C NMR (75.5 MHz,
0
CDCl3): d ¼ 50:4, 52.8, 63.4, 71.5, 73.5, 77.7, 128.2,
128.3, 128.4, 128.6, 137.1, 137.9, 159.0. Anal. Calcd for
C15H19N3O5 · 0.5H2O: C, 55.00; H, 5.91; N, 13.30.
Found: C, 55.28; H, 5.96; N, 13.27.
4.7.2. (2S,3S)-3-Benzyloxy-1,2-O-isopropylidene-4-(5-meth-
oxycarbonyl-1,2,3-triazol-1-yl)-1,2-butanediol, (2S,3S)-15.
20
Yellowish oil. ½aꢀ ¼ ꢁ43:9 (c 1.51, CHCl3). IR (film):
D
m ¼ 2987, 1732, 1261cmꢁ1. 1H NMR (300 MHz, CDCl3):
d ¼ 1:37 and 1.47 (2s, 6H, CH3CCH3), 3.82 (s, 3H,
CH3OOC), 3.98 (dd, J ¼ 8:7, 6.0 Hz, 1H, HaHbCO), 3.98
(ddd, J ¼ 9:0, 5.3, 3.7 Hz, 1H, HCOBn), 4.08 (dd, J ¼ 8:7,
6.8 Hz, 1H, HaHbCO), 4.26 (ddd, J ¼ 6:8, 6.0, 5.3Hz, 1H,
HCO), 4.28 (d, J ¼ 11:7 Hz, 1H, HaHbCPh), 4.45 (d,
J ¼ 11:7 Hz, 1H, HaHbCPh), 4.81 (dd, J ¼ 13:7, 3.7 Hz,
1H, HaCHbN), 4.95 (dd, J ¼ 13:7, 9.0 Hz, 1H, HaCHbN),
7.05–7.08 (m, 2H, C6H5), 7.22–7.27 (m, 3H, C6H5), 8.05 (s,
4.9. A mixture of phosphonates (1R,2S)- and (1S,2S)-7
from the diol (2S,3S)-16
Solutions of (2S,3S)-16 (400 mg, 1.24 mmol) in chloro-
form (20 mL) and of NaIO4 (319 mg, 1.49 mmol) in
water (10 mL) were vigorously stirred for 5 min and
solid NaHCO3 (7.5 mg) then added. After 3 h at 40 ꢁC,
the aqueous layer was saturated with NaCl. The organic
phase was separated and the aqueous layer extracted
with chloroform (5 · 5 mL). The organic extracts were
collected, dried over MgSO4 and concentrated in vacuo
to leave crude (2S)-18 (360 mg, 100%) as a yellowish oil.
1H, HC4 ). 13C NMR (75.5MHz, CDCl3): d ¼ 25:2, 26.6,
0
50.4, 52.6, 65.3, 73.4, 75.8, 77.4, 109.9, 127.8, 128.1, 128.4,
128.5, 137.4, 137.8, 158.9. Anal. Calcd for C18H23N3O5: C,
59.82; H, 6.41; N, 11.62. Found: C, 59.62; H, 6.01; N,
11.55.
1
IR (film): m ¼ 3427, 3140, 1714, 1237 cmꢁ1. H NMR
(300 MHz, CDCl3): d ¼ 3:96 (s, 3H, H3COOC), 4.27
(dd, J ¼ 6:9, 3.8 Hz, 1H, HCOBn), 4.57 (dd, J ¼ 14:4,
6.9 Hz, 1H, HaHbCN), 4.61 and 4.67 (AB system,
J ¼ 11:7 Hz, 2H, H2CPh), 4.83 (dd, J ¼ 14:4, 3.8 Hz,
1H, HaHbCN), 7.22–7.26 (m, 2H, C6H5), 7.27–7.37 (m,
4.8. (2S,3S)-3-Benzyloxy-4-(4-methoxycarbonyl-1,2,3-
triazol-1-yl)-1,2-butanediol, (2S,3S)-16
0
3H, C6H5), 8.12 (s, 1H, HC5 ), 9.67 (s, 1H, CHO).
A solution of (2S,3S)-14 (1.477 g, 4.087 mmol) in diox-
ane (30 mL) containing 1 M HCl (15.7 mL) was left at
room temperature for 24 h. The reaction mixture was
neutralised by the addition of solid NaHCO3. The vol-
atiles were evaporated in vacuo, the residue dissolved in
chloroform (15 mL) and dried over MgSO4. The crude
product was chromatographed on a silica gel column
with methylene chloride/methanol (100:1, v/v) and the
appropriate fractions recrystallised from ethyl acetate/
To a solution of the crude aldehyde, (2S)-18 (360 mg,
1.24 mmol) and dimethyl phosphite (170 lL, 1.86 mmol)
in methylene chloride (2 mL) triethylamine (35 lL,
0.25 mmol) was injected. The reaction mixture was left
at room temperature for 20 h, diluted with methylene
chloride (20 mL), extracted with water (4 · 30 mL) and
dried over MgSO4. The volatiles were removed in vacuo
to leave a 1:1 mixture of (1S,2S)-7 and (1R,2S)-7
(447 mg, 90%) as a yellowish oil. 31P NMR (121.5 MHz,
CDCl3): d ¼ 24:1 and 24.8 ppm.
4.9.1. A mixture of phosphonates (1R,2S)- and (1S,2S)-19
from the diol (2S,3S)-16. In a similar manner, from the
crude aldehyde (2S)-18 (138 mg, 0.477 mmol) and di-
ethyl phosphite (55 lL, 0.043 mmol) a yellow oil was
obtained, which was identified as a 1:1 mixture of
(1S,2S)-19 and (1R,2S)-19. 31P NMR (121.5 MHz,
CDCl3): d ¼ 21:98 and 22.98 ppm.
diethyl ether to give (2S,3S)-16 (911 mg, 69%) as a white
20
D
powder. Mp 114–116 ꢁC. ½aꢀ ¼ ꢁ39:8 (c 1.17,
CH3OH). IR (KBr): m ¼ 3369, 1724, 1218 cmꢁ1
.
1H
NMR (300 MHz, CDCl3): d ¼ 2:08 (br t, J ¼ 5:4 Hz,
1H, HOCH2), 2.60 (d, J ¼ 6:3 Hz, 1H, HOCH), 3.58–
3.66 (m, 1H, HCOH), 3.68–3.78 (m, 2H, H2COH), 3.98
(s, 3H, CH3OOC), 4.06 (ddd, J ¼ 7:1, 4.8, 3.8 Hz, 1H,
HCOBn), 4.38 and 4.44 (AB system, J ¼ 11:3 Hz, 2H,
HaHbCPh), 4.58 (dd, J ¼ 14:1, 7.1 Hz, 1H, HaCHbN),
4.69 (dd, J ¼ 14:1, 4.8 Hz, 1H, HaCHbN), 7.18–7.23 (m,
0
2H, C6H5), 7.28–7.38 (m, 3H, C6H5), 8.13 (s, 1H, HC5 ).
13C NMR (75.5 MHz, CD3OD): d ¼ 50:0, 52.6, 63.5,
72.8, 74.8, 79.7, 128.8, 129.3, 130.8, 138.9, 140.2, 162.2.
Anal. Calcd for C15H19N3O5: C, 56.07; H, 5.96; N,
13.08. Found: C, 56.06; H, 5.74; N, 13.33.
Acknowledgements
ꢀ ꢀ
Financial support from the Medical University of Łodz
(502-13-853) is gratefully acknowledged. The authors
_
wish to express their gratitude to Alfred Ozarek, M.Sc.
for his involvement in this project.
4.8.1. (2S,3S)-3-Benzyloxy-4-(5-methoxycarbonyl-1,2,3-
triazol-1-yl)-1,2-butanediol, (2S,3S)-17. In a similar
way, from (2S,3S)-15 (356 mg, 0.985 mmol) diol (2S,3S)-

1464
A. E. Wrꢀoblewski, I. E. Głowacka / Tetrahedron: Asymmetry 15 (2004) 1457–1464
ꢀ
16. Perez-Balderas, F.; Ortega-Munoz, M.; Morales-Sanfru-
tos, J.; Hernandez-Mateo, F.; Calvo-Flores, F. G.; Calvo-
References and notes
ꢀ
ꢀ
Asin, J. A.; Isac-Garcia, J.; Santoyo-Gonzalez, F. Org.
Lett. 2003, 5, 1951–1954.
1. Acylic, Carbocyclic and
Challand, S. R., Eds.; Kluwer Academic: Dodrecht, 1998.
L
-Nucleosides; Agrofolio, L.,
17. Al-Masoudi, N. A.; Al-Soud, Y. A. Nucleosides, Nucleo-
tides, Nucleic Acids 2002, 21, 361–375.
2. Witkowski, J. T.; Robins, R. K.; Sidwell, R. M.; Simon, L.
N. J. Med. Chem. 1972, 15, 1150–1154.
18. Olgen, S.; Chu, C. K. Z. Naturforsch. 2001, 56B, 804–811.
19. Hammerschmidt, F.; Polsterer, J.-P.; Zbiral, E. Synthesis
1995, 415–418.
ꢀ
20. Marco-Contelles, J.; Jimenez, C. A. Tetrahedron 1999, 55,
10511–10526.
21. Norris, P.; Horton, D.; Levine, B. R. Hetrocycles 1996, 43,
2643–2655.
22. Talekar, R. R.; Wightman, R. H. Tetrahedron 1997, 53,
3831–3842.
3. Crotty, S.; Cameron, C.; Andino, R. J. Mol. Med. 2002,
80, 86–95.
4. Lagoja, I. M.; Pannecouque, C.; Musumeci, L.; Froeyen,
M.; Aerschot, A. V.; Balzarini, J.; Herdewijn, P.; De
Clercq, E. Helv. Chim. Acta 2002, 85, 1883–1892.
5. Synthetic Applications of 1,3-Dipolar Cycloaddition Chem-
istry Toward Heterocycles and Natural Products; Padwa,
A., Pearson, W. H., Eds.; Wiley: New York, 2002.
6. Ren, Z.-X.; Chen, X.-M.; Li, Z.-J.; Huang, Z.-T. Hetero-
atom Chem. 2003, 14, 487–490.
23. Engel, R. Synthesis of Carbon–Phosphorus Bond; CRC:
Boca Raton, 1983.
7. Peng, W.; Zhu, S. Synlett 2003, 2, 187–190.
8. Peng, W.; Zhu, S. Tetrahedron 2003, 59, 4395–4404.
ꢀ
24. Wroblewski, A. E.; Głowacka, I. E. Tetrahedron: Asym-
metry 2002, 13, 989–994.
25. Palacios, F.; Ochoa de Retana, A. M.; Pagalday, J.;
€
9. Roper, S.; Franz, M. H.; Wartchow, R.; Hoffmann, H. M.
R. Org. Lett. 2003, 5, 2773–2776.
ꢀ
Sanchez, J. M. Org. Prep. Proced. Int. 1995, 27, 603–612.
26. Louerat, F.; Bougrin, K.; Loupy, A.; Ochoa de Retana, A.
10. Blass, B. E.; Coburn, K. R.; Faulkner, A. L.; Seibel, W.
L.; Srivastava, A. Tetrahedron Lett. 2003, 44, 2153–2155.
11. Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, B. K.
J. Am. Chem. Soc. 2003, 125, 9983–9987.
12. Wang, Z.-X.; Qin, H.-L. Chem. Commun. 2003, 2450–
2451.
€
M.; Pagalday, J.; Palacios, F. Heterocycles 1998, 48, 161–
170.
ꢀ
27. Alonso, G.; Garcia-Lopez, M. T.; Garcia-Munoz, G.;
Madronero, R.; Rico, M. J. Heterocycl. Chem. 1970, 7,
~
~
1269–1272.
28. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057–3064.
29. Howell, S. J.; Spencer, N.; Philp, D. Tetrahedron 2001, 57,
4945–4954.
13. Wu, W.; Bergstrom, D. E.; Davisson, V. J. J. Org. Chem.
2003, 68, 3860–3865.
14. Radi, S.; Lazrek, H. B. Bull. Korean Chem. Soc. 2002, 23,
437–440.
15. Saito, Y.; Escuret, V.; Durantel, D.; Zoulim, F.; Schinazi,
R. F.; Agrofoglio, L. A. Bioorg. Med. Chem. 2003, 11,
3633–3639.
30. van Mersbergen, D.; Wijnen, J. W.; Engberts, J. B. F. N.
J. Org. Chem. 1998, 63, 8801–8805.