Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-hydroxypropylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2007.09.003

The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained as O-ethy

Full text of DOI:10.1016/j.tetasy.2007.09.003

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2218–2226
Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-
hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-
hydroxypropylphosphonates
*
´
´
Andrzej E. Wroblewski and Irena I. Ba˛k-Sypien
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ło´dz´, 90-151 Ło´dz´, Muszyn´skiego 1, Poland
Received 23 July 2007; accepted 5 September 2007
Abstract—The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the
intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained
as O-ethyl or O,O-diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonates, when (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphospho-
nate or its 3-O-trityl derivative were used as starting materials, respectively. The intramolecular Williamson cyclisations of diethyl
(1S,2R)- and (1R,2S)-1-benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates led to diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benz-
yloxypropylphosphonates, respectively, with the concomitant formation of diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phosphonate.
From diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, enantiomerically pure diethyl (1S,2S)- and (1R,2S)-1,2-
dihydroxypropylphosphonates were obtained by catalytic hydrogenation, while diethyl (1S,2S)- and (1R,2S)-3-acetamido-1,2-
dihydroxypropylphosphonates were produced after epoxide ring opening with dibenzylamine, acetylation and hydrogenolysis.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
(1R,2S)-2, as well as the trans-configured epoxide
(1S,2S)-2 to complete the syntheses of all four stereoiso-
mers of 2. In our approach to (1R,2R)- and (1S,2R)-2,
diethyl (1R,2R)- and (1S,2R)-2,3-O-cyclohexylidene-1,2,3-
trihydroxypropylphosphonates 312 were employed as start-
ing materials, and the HO–C-1 were transformed into good
leaving groups by mesylation (Scheme 1). To take advan-
tage of the same phosphonates in the synthesis of
(1R,2S)- and (1S,2S)-2, as inversion of configuration at
C-2 was necessary, this could, in principle, be accomplished
via 2-O-mesylates 4 (Scheme 1).
Since the discovery of the antibiotic properties of fosfomy-
cin 1 [(1R,2S)-1,2-epoxypropylphosphonic acid],1 several
syntheses of its analogues have appeared. Among them
compounds of diverse complexity, from those containing
a steroid,2 nucleoside3–5 or sugar4,6–8 frameworks to those
having a methyl group merely replaced by aminomethyl,9
hydroxymethyl9 or acyl10 fragments, have been obtained.
O
H
H
Herein, several new results to this end are presented
together with other important and unexpected transforma-
tions of the intermediate mesylates 4 and 9.
Me
P(O)(OH)2
fosfomycin 1
In continuation of these efforts, we have recently described
the synthesis of enantiomerically pure diethyl (1R,2R)- and
(1S,2R)-1,2-epoxy-3-hydroxypropylphosphonates 2.11 Since
the absolute configuration of the natural fosfomycin
is (1R,2S), we were looking for a method to prepare
2. Results and discussion
The 2,3-dihydroxyphosphonate (1S,2R)-6 was synthesised
according to the described procedure in 80% overall
yield.13 After standard tritylation followed by mesylation
the fully protected phosphonate (1S,2R)-8 was obtained
(Scheme 2). Hydrogenolysis of this compound led to the
formation of the 1,3-dihydroxyphosphonate (1S,2R)-4 in
*
Corresponding author. Tel.: +48 42 6779233; fax: +48 42 678 83 98;
e-mail: aewplld@ich.pharm.am.lodz.pl
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.09.003

A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 2218–2226
2219
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
OMs
O
O
R
R'
O
O
R
R'
OMs
OH
O
O
OH
OH
(1S,2R)-3
(1R,2R)-3
(1S,2R)-4
(1R,2R)-4
(1S,2S)-2
(1R,2S)-2
(1R,2R)-2
(1S,2R)-2
R=H, R'=OH
R=OH, R'=H
Scheme 1. Synthetic strategy to phosphonates (1R,2R)- and (1S,2R)-2 and retrosynthesis of the phosphonates (1R,2S)- and (1S,2S)-2.
P(O)(OEt)2
P(O)(OEt)2
OBn
P(O)(OEt)2
OBn
P(O)(OEt)2
OH
OR
O
O
O
H
P(O)(OEt)2
H
e
f
b
d
OH
OR
OMs
OTr
OMs
OH
HOH2C
(1S,2R)-6
(1S,2R)-7
(1S,2R)-8
(1S,2R)-4
(1S,2S)-2
(1S,2R)-3
(1S,2R)-5
R=H
R=Tr
R=H
R=Bn
c
a
˚
Scheme 2. Reagents and conditions: (a) BnBr, Ag2O, 4 A MS, CH2Cl2, rt, 24 h, 95%; (b) 70% AcOH, rt, 20 h, 84%; (c) TrCl, Et3N, DMAP, CH2Cl2, 0 ꢁC
to rt, 20 h, 92%; (d) MsCl, Et3N, DMAP, CH2Cl2, 0 ꢁC to rt, 20 h, 80%; (e) H2, Pd–C, EtOH, rt, 24 h, 88%; (f) K2CO3, EtOH, rt, 20 h, 74%.
88% yield. Treatment of (1S,2R)-4 with anhydrous potas-
sium carbonate in ethanol for 20 h led almost regioselec-
tively to the formation of diethyl (1S,2S)-1,2-epoxy-
3-hydroxypropylphosphonate (1S,2S)-2, which was sepa-
rated chromatographically in 74% yield. Although the
oxirane ring closure in 1,3-dihydroxy-2-mesyloxypropyl-
phosphonate could lead to the formation of 1,2- or 2,3-
epoxyphosphonates, only the more substituted epoxide
(1S,2S)-2 was obtained. As expected, the intramolecular
cyclisation in (1S,2R)-4 occurred with complete inversion
of configuration at C-2 to produce epoxide (1S,2S)-2. Since
its enantiomer has recently been synthesised,11 this conclu-
sion could be proven by comparison of the signs of the
specific rotation.
with anhydrous potassium carbonate in ethanol for 20 h
to afford the 2,3-epoxide (1S,2S)-10 in 89% yield after
chromatographic separation of diethyl (E)-1-benzyloxy-3-
hydroxyprop-1-en-1-phosphonate (E)-11, which was
formed as an impurity (less than 10%). Since the enantio-
mer of the 2,3-epoxyphosphonate (1S,2S)-10 formed in this
reaction is known,13 it can be concluded that the intra-
molecular cyclisation in (1S,2R)-9 took place with
complete inversion of configuration at C-2.
When the hydrogenolytic removal of the benzyl group in
phosphonate (1S,2S)-10 was attempted (Scheme 4), the
known14 diol (1S,2S)-13 was obtained instead of the
expected diethyl (1S,2S)-2,3-epoxy-1-hydroxypropylphos-
phonate (1S,2S)-12. Several catalysts have been tried, but
in all instances diol (1S,2S)-13 was formed as a single prod-
uct. When the hydrogenolysis was interrupted after 2 h,
the reaction mixture consisted of the unreacted 2,3-epoxy-
phosphonate (1S,2S)-10 and diethyl (1S,2S)-1-benzyloxy-
2-hydroxypropylphosphonate (1S,2S)-13a, as judged
We reasoned that the isomeric (1S,2S)-2,3-epoxy-1-hydr-
oxypropylphosphonate (1S,2S)-12 could be synthesised
from (1S,2R)-8, as shown in Schemes 3 and 4. Hydrolytic
removal of the trityl group from (1S,2R)-8 gave phospho-
nate (1S,2R)-9 in 97% yield. This compound was treated
P(O)(OEt)2
OBn
P(O)(OEt)2
OBn
P(O)(OEt)2
OBn
(EtO)2(O)P
BnO
H
a
b
OMs
OTr
OMs
OH
+
C C
O
CH2OH
(1S,2R)-8
(1S,2R)-9
(1S,2S)-10
(E)-11
Scheme 3. Reagents and conditions: (a) p-TsOH, EtOH, rt, 20 h, 97%; (b) K2CO3, EtOH/CH2Cl2, rt, 20 h, 89%.
P(O)(OEt)2
OBn
P(O)(OEt)2
OBn
P(O)(OEt)2
P(O)(OEt)2
OH
OH
+
a
HO
HO
O
O
CH3
CH3
(1S,2S)-10
Scheme 4. Reagents and conditions: (a) H2, Pd–C, EtOH, rt, 20 h, 70%.
(1S,2S)-13a
(1S,2S)-12
(1S,2S)-13

2220
A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 2218–2226
1
from the H and 31P NMR spectra. Thus, the oxirane ring
opening in (1S,2S)-10 is faster than cleavage of the O–Bn
bond.
basic conditions, the intramolecular cyclisation of
(1R,2S)-2 to the respective 3,4-epoxy-2-ethoxy-2-oxo-1,2-
oxaphospholane occurs rapidly,11 while its hydrolysis leads
to the formation of the monoester (1R,2S)-2a. Since in
phosphonate (1S,2S)-2, the oxirane ring has a trans-config-
uration, the intramolecular cyclisation of this compound to
the respective 1,2-oxaphospholane is not feasible.
To synthesise diethyl (1R,2S)-1,2-epoxy-3-hydroxypropyl-
phosphonate (1R,2S)-2, the 2,3-dihydroxyphosphonate
(1R,2R)-6 was used as a starting material (Schemes 5 and
6).13 The protected phosphonate (1R,2R)-8 was obtained
by tritylation followed by mesylation, in 54% overall yield.
It is worth noting that the complete mesylation of phos-
phonate (1R,2R)-7 required the application of 1.1 equiv
of DMAP instead of triethylamine in the presence of cata-
lytic amounts of DMAP, as was sufficient for phosphonate
(1S,2R)-7. Simultaneous removal of the trityl and benzyl
groups gave 1,3-dihydroxyphosphonate (1R,2R)-4 in 67%
yield, which was further transformed into either the mono-
ester (1R,2S)-2a or the diester (1R,2S)-2 (Scheme 6).
For this reason to prepare the diester (1R,2S)-2, the mesy-
late (1R,2R)-4 had to be subjected to tritylation, since the
removal of the tert-butyldimethylsilyl protecting group
from the structurally similar 1,2-epoxyphosphonates led
to severe decomposition.11 When the trityl derivative
(1R,2R)-14 was treated with potassium carbonate in etha-
nol, the expected epoxyphosphonate (1R,2S)-15 was pro-
duced. Hydrogenolytic deprotection afforded the diester
(1R,2S)-2 in 68% yield. Since the enantiomers of phos-
phonates (1R,2S)-15 and (1R,2S)-2 have already been
described,11 the oxirane ring closure in (1R,2R)-14
proceeded with the complete inversion of configuration at
C-2. Since the removal of the trityl group from the epoxide
(1R,2S)-15 was carried out under neutral conditions, the
cis-configured epoxide could be obtained without traces
of the respective 1,2-oxaphospholane.
Under basic conditions, mesylate (1R,2R)-4 was trans-
formed with the inversion of configuration at C-2 into
the monoester (1R,2S)-2a, which was the major component
(ca. 85%) of the crude product. After purification on a sil-
ica gel column, phosphonate (1R,2S)-2a was obtained in
69% yield. The formation of monoester (1R,2S)-2a instead
of the expected diester (1R,2S)-2 can be rationalised as fol-
lows: initially intramolecular cyclisation leads to the diester
(1R,2S)-2. In this compound, the oxirane ring has a cis-
configuration and this feature brings the hydroxymethyl
and diethoxyphosphoryl groups close together. Under
Hydrolysis of the trityl group in phosphonate (1R,2R)-8
provided 3-hydroxypropylphosphonate (1R,2R)-9 in 87%
yield (Scheme 7). When this compound was treated with
potassium carbonate in ethanol for 6 h, a 35:65 mixture
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
RO
BnO
BnO
HO
e
b
d
O
O
OH
OR
OMs
OTr
OMs
OH
(1R,2R)-6
(1R,2R)-7
(1R,2R)-8
(1R,2R)-4
(1R,2R)-3
(1R,2R)-5
R=H
R=Tr
R=H
R=Bn
c
a
˚
Scheme 5. Reagents and conditions: (a) BnBr, Ag2O, 4 A MS, CH2Cl2, rt, 24 h, 95%; (b) 70% AcOH, rt, 20 h, 86%; (c) TrCl, Et3N, DMAP, CH2Cl2, 0 ꢁC
to rt, 20 h, 85%; (d) MsCl, DMAP, CH2Cl2, 0 ꢁC to rt, 20 h, 77%; (e) H2, Pd(OH)2C, EtOH, rt, 24 h, 67%.
P(O)(OEt)2
HO
b
O
O
H
H
H
H
c
a
OMs
OH
HOH2C
P(O)(OEt)(OH)
ROH2C
P(O)(OEt)2
(1R,2S)-2a
(1R,2R)-4
(1R,2R)-14
(1R,2S)-15
(1R,2S)-2
R=H
R=Tr
R=Tr
R=H
d
Scheme 6. Reagents and conditions: (a) K2CO3, EtOH, rt, 24 h, 69%; (b) TrCl, Et3N, DMAP, CH2Cl2, 0 ꢁC to rt, 20 h, 70%; (c) K2CO3, EtOH, rt, 5 h,
69%; (d) H2, Pd–C, EtOH, rt, 20 h, 68%.
P(O)(OEt)2
+
P(O)(OEt)2
P(O)(OEt)2
BnO
O
BnO
BnO
(EtO)2(O)P
BnO
H
a
b
OMs
OTr
OMs
OH
C C
CH2OH
(E)-11
(1R,2S)-10
(1R,2R)-8
(1R,2R)-9
Scheme 7. Reagents and conditions: (a) p-TsOH, EtOH, rt, 20 h, 87%; (b) K2CO3, EtOH/CH2Cl2, rt, 3 h, 30%.

A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 2218–2226
2221
of the epoxide (1R,2S)-10 and a vinylphosphonate (E)-11
was obtained. After column chromatography, the epoxy-
phosphonate (1R,2S)-10 was separated in 30% yield.
HC@CP and CC@CP couplings, 10.5 and 14.3 Hz, respec-
tively, unequivocally support the cis-orientation of
HC@CP atoms and the trans-configuration of the
hydroxymethyl and diethoxyphosphoryl groups.15 Further-
more, the (E)-isomer of phosphonate 11 is energetically
more stable than (Z)-11, because in the former isomer,
the bulky diethoxyphosphoryl group and a hydrogen atom
are on the same side of the C@C bond, while in the latter
severe repulsions with the hydroxymethyl group are
expected. Since only one isomeric alkene, (E)-11, was
obtained from either 2-mesyloxyphosphonates (1S,2R)-
and (1R,2R)-9 or the respective 2,3-epoxyphosphonates
(1S,2S)- and (1R,2S)-10, we postulate the formation of
carbanion 19 as an intermediate. In separate experiments,
pure epoxyphosphonates (1S,2S)- and (1R,2S)-10 were
cleanly transformed into a vinylphosphonate (E)-11 after
stirring with potassium carbonate in ethanol. The reasons,
why when starting from the mesylate (1S,2R)-9 only min-
ute quantities of (E)-11 were produced, and significant
amounts of this alkene always contaminated the epoxide
obtained from diastereoisomeric mesylate (1R,2R)-9, re-
main obscure so far (Fig. 1).
Attempts at synthesising the epoxyphosphonate (1R,2S)-12
from (1R,2S)-10 by hydrogenolysis led to the formation of
1
complex mixtures. Detailed analyses of H and 31P NMR
spectra of mixtures obtained after 1 and 2 days suggest that
during catalytic hydrogenation of (1R,2S)-10, debenzyl-
ation is faster than the opening of the epoxide ring, on
the contrary to our observations for phosphonate
(1S,2S)-10 (vide supra). When the reaction time was
extended to 3 days, we were able to separate diol
(1R,2S)-13 in 61% yield (Scheme 8).
Since the enantiomers of phosphonates (1S,2S)- and
(1R,2S)-10 have already been described and proved useful
in the preparation of diethyl (1R,2R)- and (1S,2R)-3-
acetamido-1,2-dihydroxypropylphosphonate,13 epoxides
(1S,2S)- and (1R,2S)-10 were transformed into phospho-
nates (1S,2S)- and (1R,2S)-18 in 34% and 42% overall
yields, respectively, by employing the known reaction
sequence (Schemes 9 and 10). Application of catalytic
amounts of calcium triflate accelerated the epoxide ring
opening and reduced the reaction time from 3 days to 24 h.
3. Conclusions
Structural assignments in phosphonate (E)-11 are based on
the 1H and 13C NMR spectral data. Thus, the vicinal
Diethyl (1S,2R)- and (1R,2R)-1,3-dihydroxy-2-mesyl-
oxypropylphosphonates 4 were obtained from the known
diethyl (1S,2R)- and (1R,2R)-2,3-O-cyclohexylidene-1,2,3-
trihydroxypropylphosphonates 3 by benzylation, acetal
cleavage, tritylation, mesylation and hydrogenolysis. When
the mesylate (1S,2R)-4 was subjected to the intramolecular
Williamson reaction, diethyl (1S,2S)-1,2-epoxy-3-hydroxy-
propylphosphonate 2 was produced almost regioselec-
tively, while under the same conditions from the mesylate
(1R,2R)-4, O-ethyl (1R,2S)-1,2-epoxy-3-hydroxypropyl-
phosphonate 2a was formed. Synthesis of diethyl
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
BnO
O
HO
O
HO
HO
a
+
CH3
(1R,2S)-10
(1R,2S)-12
(1R,2S)-13
Scheme 8. Reagents and conditions: (a) H2, Pd–C, EtOH, rt, 3 days, 61%.
(1R,2S)-1,2-epoxy-3-hydroxypropylphosphonate
2
was
accomplished via diethyl (1R,2R)-1-hydroxy-2-mesyloxy-
3-trityloxypropylphosphonate 14.
P(O)(OEt)2
OBn
P(O)(OEt)2
OBn
P(O)(OEt)2
OH
a
c
HO
HO
O
Syntheses of diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benz-
yloxypropylphosphonates 10 were carried out by employ-
ing the intermediate diethyl (1S,2R)- and (1R,2R)-1-
NBn2
NHAc
(1S,2S)-10
(1S,2S)-16
(1S,2S)-17
(1S,2S)-18
R=H
R=Ac
b
benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates
9,
respectively. However, the intramolecular cyclisations were
accompanied by the formation of various amounts of
diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phospho-
nate (E)-11 [less than 10% when starting from (1S,2R)-9
and up to 65% from (1R,2R)-9]. Since under the basic con-
ditions of the Williamson reaction, pure diastereoisomeric
epoxides 10 were also transformed into a vinylphosphonate
Scheme 9. Reagents and conditions: (a) Bn2NH, 5 mol % Ca(OTf)2,
CH2Cl2, 50 ꢁC, 24 h, 60%; (b) Ac2O, Et3N, DMAP, CH2Cl2, 0 ꢁC to rt,
20 h, 93%; (c) H2, Pd–C and Pd(OH)2 (1:1), EtOH, rt, 40 h, 61%.
P(O)(OEt)2
P(O)(OEt)2
NBn2
P(O)(OEt)2
BnO
O
BnO
HO
HO
HO
a
c
NHAc
H2C
BnO
H
P(O)(OEt)2
(1R,2S)-16
(1R,2S)-17
(1R,2S)-18
(1R,2S)-10
R=H
R=Ac
b
O
Scheme 10. Reagents and conditions: (a) Bn2NH, 5 mol % Ca(OTf)2,
CH2Cl2, 50 ꢁC, 24 h, 74%; (b) Ac2O, Et3N, DMAP, CH2Cl2, 0 ꢁC to rt,
20 h, 79%; (c) H2, 20% Pd(OH)2C, EtOH, rt, 3 days, 71%.
19
Figure 1. Intermediate carbanion 19.

2222
A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 2218–2226
11, the P@O stabilised carbanion 19 serves as a common
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 143.9,
137.2, 128.8, 128.3, 128.2, 128.1, 127.9, 127.1, 86.8, 75.5
(d, J = 160.7 Hz, CP), 74.8 (d, J = 3.8 Hz, OCPh), 71.0
(d, J = 4.5 Hz, CCP), 64.0 (d, J = 9.2 Hz, CCCP), 63.3
and 62.7 (2d, J = 6.7 Hz, CH3CH2OP), 16.8 and 16.8 (2d,
J = 5.6 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 24.45. Anal. Calcd for C33H37O6PÆH2O: C, 68.50; H,
6.74. Found: C, 68.42; H, 6.71.
intermediate of the epoxide isomerisation.
The catalytic hydrogenation of diethyl (1S,2S)- and
(1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates 10 did
not yield the requested diethyl (1S,2S)- and (1R,2S)-2,3-
epoxy-1-hydroxypropylphosphonates 12, which could have
served as starting materials in studies of Payne rearrange-
ment16 in the phosphonate series. Instead, diethyl
(1S,2S)- and (1R,2S)-1,2-dihydroxypropylphosphonates
13 were obtained as pure enantiomers for the first time.
In the case of (1S,2S)-10 the epoxide ring opening is faster
than the removal of the benzyl group, while for (1R,2S)-10,
the opposite is true. From diethyl (1S,2S)- and (1R,2S)-2,3-
epoxy-1-benzyloxypropylphosphonates 10, diethyl (1S,2S)-
4.2.1. Diethyl (1R,2R)-1-benzyloxy-2-hydroxy-3-trityloxy-
propylphosphonate (1R,2R)-7. As described in the previ-
ous section, from phosphonate (1R,2R)-6 (0.637 g,
2.00 mmol) and trityl chloride (0.660 g, 2.40 mmol) in the
presence of NEt3 (0.35 mL, 3.2 mmol) and DMAP
(0.024 g, 0.20 mmol), the trityl derivative (1R,2R)-7
and
(1R,2S)-3-acetamido-1,2-dihydroxypropylphospho-
(0.953 g, 85%) was obtained as
a
colourless oil.
20
nates 18 were obtained according to a known procedure.13
½aꢀD ¼ ꢁ21:6 (c 3.65, CHCl3). IR (film): m = 3366, 3059,
3031, 2982, 2930, 2873, 1597, 1491, 1449, 1391, 1225,
1093, 1027, 967, 747, 700 cmꢁ1 1H NMR (300 MHz,
.
4. Experimental
4.1. General
CDCl3): d = 7.47–7.11 (m, 20H), 4.77 (d, J = 10.8 Hz,
1H, HaCHbPh), 4.42 (d, J = 10.8 Hz, 1H, HaCHbPh),
4.23–4.11 (m, 5H, CH2OP and HCCP), 4.06 (dd, J = 7.2,
2.1 Hz, 1H, HCP), 3.39 (ddd, J = 9.3, 5.7, 2.1 Hz, 1H,
HaCHbCCP), 3.14 (dd, J = 9.3, 7.5 Hz, 1H, HaCHbCCP),
2.78 (br s, 1H, HO), 1.34 and 1.32 (2t, J = 7.2 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CD3OD): d = 145.2,
138.7, 129.8, 129.4, 129.3, 128.9, 128.9, 128.2, 88.3, 77.1
(d, J = 164.6 Hz, CP), 76.3 (d, J = 3.1 Hz, OCPh), 70.9
(d, J = 0.9 Hz, CCP), 64.9 (d, J = 11.2 Hz, CCCP), 64.4
and 63.8 (2d, J = 6.9 Hz, CH3CH2OP), 17.1 and 17.0 (2d,
J = 5.6 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 23.85. Anal. Calcd for C33H37O6PÆ2H2O: C, 66.43; H,
6.93. Found: C, 66.66; H, 6.81.
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 31
P
NMR spectra were recorded on a Varian Mercury-300 ma-
chine at 75.5 and 121.5 MHz, respectively. IR spectral data
were measured 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 analyzer. Polarimetric mea-
surements were conducted on a Perkin Elmer 241 MC
apparatus. The following absorbents were used: column
chromatography, Merck silica gel 60 (70–230 mesh); ana-
4.3. Diethyl (1S,2R)-1-benzyloxy-2-mesyloxy-3-trityloxyprop-
ylphosphonate (1S,2R)-8
lytical TLC, Merck TLC plastic sheets silica gel 60 F254
.
To a solution of phosphonate (1S,2R)-7 (1.40 g, 2.50
mmol) in CH2Cl2 (15 mL) containing NEt3 (1.04 mL,
7.50 mmol) and DMAP (a few crystals) cooled to 0 ꢁC,
mesyl chloride (0.39 mL, 5.0 mmol) was added dropwise.
After 20 h at room temperature, the reaction mixture was
washed with water (10 mL) and the aqueous phase ex-
tracted with CH2Cl2 (3 · 15 mL). The organic phases were
collected, washed with cold brine (20 mL), dried over
MgSO4, concentrated and the crude product was chro-
matographed on a silica gel column with chloroform–
4.2. Diethyl (1S,2R)-1-benzyloxy-2-hydroxy-3-trityloxy-
propylphosphonate (1S,2R)-7
To a solution of the diol (1S,2R)-6 (0.919 g, 2.89 mmol) in
CH2Cl2 (30 mL) containing NEt3 (0.65 mL, 4.6 mmol)
cooled to 0 ꢁC, trityl chloride (0.97 g, 3.5 mmol) was added
followed by DMAP (0.004 g, 0.03 mmol). The solution was
then stirred at room temperature for 20 h and treated with
a cold saturated NH4Cl (20 mL). The aqueous layer was
extracted with CH2Cl2 (3 · 15 mL), and the organic phases
were combined and dried over MgSO4. After concentra-
tion, the crude product was chromatographed on a silica
gel column with chloroform–methanol–triethylamine
methanol–triethylamine (100:1:0.05, v/v) to give the mesy-
20
late (1S,2R)-8 (1.28 g, 80%) as a colourless oil; ½aꢀD ¼ þ3:2
(c 2.5, CHCl3). IR (film): m = 3061, 3021, 2936, 2884, 1595,
1490, 1448, 1347, 1245, 1147, 1047, 1018, 751, 700 cmꢁ1
.
(100:1:0.05, v/v) to give trityl derivative (1S,2R)-7 (1.49 g,
1H NMR (300 MHz, CDCl3): d = 7.44–7.18 (m, 20H),
5.10 (dddd, J = 10.0, 7.7, 3.2, 2.8 Hz, 1H, HCCP), 4.70
and 4.61 (AB system, JAB = 11.1 Hz, 2H, HaCHbPh),
4.14 (dd, J = 12.9, J = 3.2 Hz, 1H, HCP), 4.10–3.94 (m,
4H, CH2OP), 3.67 (dd, J = 11.3, 2.8 Hz, 1H, HaCHbCCP),
3.54 (dd, J = 11.3, 7.7 Hz, 1H, HaCHbCCP), 3.07 (s, 3H,
CH3SO2), 1.24 and 1.20 (2t, J = 6.9 Hz, 6H, CH3CH2OP).
13C NMR (75.5 MHz, CDCl3): d = 143.4, 136.7, 128.8,
128.4, 128.4, 128.2, 128.0, 127.3, 87.6, 81.7 (d, J =
10.0 Hz, CCP), 75.6 (d, J = 165.2 Hz, CP), 75.2 (d, J =
6.0 Hz, OCPh), 63.2 and 63.2 (2d, J = 7.1 Hz,
20
92%) as a colourless oil; ½aꢀD ¼ þ13:1 (c 1.8, CHCl3). IR
(film): m = 3341, 3059, 3031, 2982, 2930, 2873, 1597, 1491,
1449, 1391, 1225, 1049, 748, 700 cmꢁ1
.
1H NMR
(300 MHz, CDCl3): d = 7.46–7.08 (m, 20H), 4.70 (d,
J = 11.1 Hz, 1H, HaCHbPh), 4.44 (d, J = 11.1 Hz, 1H,
HaCHbPh), 4.21–4.03 (m, 5H, CH2OP and HCCP), 3.99
(dAB, JAB = 7.3, J = 5.6 Hz, 1H, HCP), 3.50 (ddd,
J = 9.9, 3.3, 0.6 Hz, 1H, HaCHbCCP), 3.38 (d,
J = 3.8 Hz, 1H, HO), 3.26 (dd, J = 9.9, 5.4 Hz, 1H,
HaCHbCCP), 1.29 and 1.29 (2t, J = 6.9 Hz, 6H,

A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 2218–2226
2223
1
CH3CH2OP), 62.6 (d, J = 1.5 Hz, CCCP), 39.0, 16.7 and
16.7 (2d, J = 5.3 Hz, CH3CH2OP). 31P NMR (121.5
MHz, CDCl3): d = 18.90. Anal. Calcd for C34H39O8PSÆ
H2O: C, 62.18; H, 6.29. Found: C, 62.23; H, 6.06.
1047, 1025, 971, 919 cmꢁ1. H NMR (300 MHz, CDCl3):
d = 4.90 (qu, J = 4.8 Hz, 1H, HCCP), 4.31–4.15 (m, 5H,
CH2OP and HCP), 4.00 (dd, J = 6.6, 4.8 Hz 2H,
CH2CCP), 3.70 (dd, J = 9.0, 8.1 Hz, 1H, HOCP), 3.20 (t,
3.16 J = 6.6, 1H, HOCH2), 3.18 (s, 3H, CH3SO2), 1.38
and 1.38 (2t, J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR
(75.5 MHz, CDCl3): d = 82.1 (d, J = 6.6 Hz, CCP), 66.7
(d, J = 165.2 Hz, CP), 63.9 and 63.8 (2d, J = 7.3 Hz,
CH3CH2OP), 61.5 (d, J = 6.9 Hz, CCCP), 38.9, 16.7 (d,
J = 5.4 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 20.20. Anal. Calcd for C8H19O8PS: C, 31.37; H, 6.25.
Found: C, 31.10; H, 6.10.
4.3.1. Diethyl (1R,2R)-1-benzyloxy-2-mesyloxy-3-trityloxy-
propylphosphonate (1R,2R)-8. As described in the previ-
ous section, from phosphonate (1R,2R)-7 (0.715 g,
1.28 mmol) and mesyl chloride (0.20 mL, 2.6 mmol) in
the presence of DMAP (0.250 g, 2.05 mmol) in CH2Cl2
(15 mL), mesylate (1R,2R)-8 (0.631 g, 80%) was obtained
20
as a colourless oil; ½aꢀD ¼ ꢁ6:2 (c 0.87, CHCl3). IR (film):
m = 3060, 3031, 2986, 2936, 2908, 1597, 1492, 1449, 1363,
1255, 1175, 1048, 1025, 751, 707 cmꢁ1
.
1H NMR
4.5. Diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate
(1S,2S)-2
(300 MHz, CDCl3): d = 7.42–7.19 (m, 20H), 4.90
(dddd ꢂ qu, J = 5.7 Hz, 1H, HCCP), 4.82 and 4.57 (AB
system, JAB = 10.8 Hz, 2H, HaCHbPh), 4.24–4.02 (m, 5H,
CH2OP and HCP), 3.59 and 3,54 (AB part of ABX,
JAB = 10.5, JBX = 5.7, Hz, 2H, HaCHbCCP), 3.00 (s, 3H,
CH3SO2), 1.27 and 1.25 (2t, J = 7.1 Hz, 6H, CH3CH2OP).
13C NMR (75.5 MHz, CDCl3): d = 143.4, 136.9, 128.7,
128.4, 128.4, 128.2, 128.1, 127.4, 87.8, 79.9 (d,
J = 5.3 Hz, CCP), 75.7 (d, J = 3.0 Hz, OCPh), 74.2 (d,
J = 166.8 Hz, CP), 63.3 (d, J = 6.8 Hz, CH3CH2OP), 62.4
(d, J = 6.0 Hz, CCCP), 38.9, 16.7 and 16.7 (2d,
J = 5.3 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 19.42. Anal. Calcd for C34H39O8PSÆ2H2O: C, 60.52;
H, 6.42. Found: C, 60.33; H, 6.16.
A suspension of anhydrous potassium carbonate (0.127 g,
0.92 mmol) in
a solution of phosphonate (0.070 g,
0.23 mmol) in ethanol (1 mL) was stirred at room temper-
ature for 20 h. After filtration through a pad of Celite, a
solution was concentrated and chromatographed on silica
gel with chloroform–methanol (100:1, v/v) to give epox-
yphosphonate (1S,2S)-2 (0.035 g, 74%) as a colourless oil;
20
20
½aꢀD ¼ ꢁ24:7 (c 0.8, CHCl3); lit.11 ½aꢀD ¼ þ24:4 (c 1.5,
CHCl3) for (1R,2R)-2. Anal. Calcd for C7H15O5P: C,
40.00; H, 7.19. Found: C, 40.30; H, 6.90.
4.6. Diethyl (1S,2R)-1-benzyloxy-3-hydroxy-2-mesyloxy-
propylphosphonate (1S,2R)-9
4.4. Diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropyl-
phosphonate (1S,2R)-4
A solution of the trityloxyphosphonate (1S,2R)-8 (1.16 g,
1.81 mmol) in ethanol (20 mL) containing enough TsOH
to achieve pH 3 was left at room temperature for 20 h. Eth-
anol was evaporated, the residue dissolved in CH2Cl2
(20 mL) and the solution was washed with cold saturated
aqueous NaHCO3. After drying over MgSO4 and evapora-
tion of the solvent, the residue was chromatographed on a
silica gel column with chloroform–methanol (100:1, v/v) to
give phosphonate (1S,2R)-9 (0.695 g, 97%) as a colourless
oil; IR (film): m = 3381, 3031, 2985, 2938, 2911, 2878,
A suspension of 10% Pd–C (10 mg) in a solution of phos-
phonate (1S,2R)-8 (0.169 g, 0.26 mmol) in ethanol (8 mL)
was stirred under a hydrogen atmosphere (balloon) for
24 h. The catalyst was removed by filtration through a
layer of Celite, a solution was concentrated and the residue
was chromatographed on a silica gel column with chloro-
form–methanol (50:1, v/v) to give the diol (1S,2R)-4
20
(0.070 g, 88%) as a colourless oil; ½aꢀD ¼ þ10:9 (c 1.0,
CHCl3). IR (film): m = 3376, 2986, 2938, 1360, 1243,
1455, 1355, 1233, 1175, 1024, 973, 751, 701 cmꢁ1
.
20
1
1177, 1026, 977, 821 cmꢁ1. H NMR (300 MHz, CDCl3):
½aꢀD ¼ þ23:4 (c 1.3, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 7.38–7.32 (m, 5H), 4.98 (dddd, J = 8.4, 6.0, 4.2, 3.0 Hz,
1H, HCCP), 4.81 and 4.77 (AB system, JAB = 11.3 Hz, 2H,
HaCHbPh), 4.24–4.12 (m, 5H, CH2OP and HCP), 4.12 (dd,
J = 12.8, 4.2 Hz, 1H, HaCHbCCP), 3.93 (dd, J = 12.8,
6.0 Hz, 1H, HaCHbCCP), 3.06 (s, 3H, CH3SO2), 2.6–2.4
(br s, 1H, HO), 1.35 and 1.32 (2t, J = 6.9 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 136.6,
128.6, 128.5, 128.4, 128.0, 82.6 (d, J = 13.2 Hz, CCP),
75.7 (d, J = 164.6 Hz, CP), 75.5 (d, J = 6.3 Hz, OCPh),
63.9 and 63.3 (2d, J = 7.0 Hz, CH3CH2OP), 61.1 (s,
CCCP), 38.7, 16.7 and 16.6 (2d, J = 5.7 Hz, CH3CH2OP).
31P NMR (121.5 MHz, CDCl3): d = 19.60. Anal. Calcd for
C15H25O8PS: C, 45.41; H, 6.31. Found: C, 45.17; H, 6.05.
d = 4.93 (dddd, J = 9.0, 4.8, 4.2, 4.0 Hz, 1H, HCCP),
4.35 (ddd, J = 11.7, 5.7, 4.2 Hz, 1H, HCP), 4.29–4.15 (m,
5H, CH2OP and HO), 4.13–4.05 (m, 2H, HaCHbCCP),
3.46–3.35 (br s, 1H, HO), 3.16 (s, 3H, CH3SO2), 1.37 (t,
J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz,
CDCl3): d = 82.0 (d, J = 10.0 Hz, CCP), 68.5 (d, J =
162.3 Hz, CP), 64.1 and 63.7 (2d, J = 7.0 Hz, CH3CH2OP),
61.6 (d, J = 2.9 Hz, CCCP), 38.9, 16.7 and 16.7 (2d,
J = 5.7 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 20.34. Anal. Calcd for C8H19O8PS: C, 31.37; H, 6.25.
Found: C, 31.66; H, 6.50.
4.4.1. Diethyl (1R,2R)-1,3-dihydroxy-2-mesyloxypropyl-
phosphonate (1R,2R)-4. As described in the previous sec-
tion, from phosphonate (1R,2R)-8 (0.800 g, 1.25 mmol)
dissolved in ethanol (10 mL) in the presence of 10% Pd–
C (13 mg) the 1,3-dihydroxypropylphosphonate (1R,2R)-4
4.6.1. Diethyl (1R,2R)-1-benzyloxy-3-hydroxy-2-mesyloxy-
propylphosphonate (1R,2R)-9. As described in the previ-
ous section, from phosphonate (1R,2R)-8 (0.631 g,
0.99 mmol) dissolved in ethanol (30 mL) in the presence
(0.257 g, 67%) was obtained as
a
colourless oil;
20
20
½aꢀD ¼ þ0:8 (c 2.5, CHCl3); ½aꢀD ¼ þ4:7 (c 0.97, MeOH).
of TsOH, phosphonate (1R,2R)-9 (0.340 g, 87%) was ob-
20
IR (film): m = 3343, 2985, 2925, 2853, 1342, 1224, 1173,
tained as a colourless oil. ½aꢀD ¼ ꢁ14:2 (c 1.5, CHCl3).

2224
A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 2218–2226
IR (film): m = 3368, 2984, 2938, 2911, 1357, 1232, 1174,
1025, 971, 915, 750, 701 cmꢁ1 1H NMR (300 MHz,
d = 11.00. Anal. Calcd for C14H21O5PÆH2O: C, 52.83; H,
7.28. Found: C, 52.55; H, 6.98.
.
CDCl3): d = 7.38–7.32 (m, 5H), 4.88 (d, J = 11.1 Hz, 1H,
HaCHbPh), 4.81 (dddd, J = 7.2, 6.6, 4.2, 4.2 Hz, 1H,
HCCP), 4.65 (d, J = 11.1 Hz, 1H, HaCHbPh), 4.28–4.17
(m, 4H, CH2OP), 4.06 (dd, J = 9.6, 6.6 Hz, 1H, HCP),
4.01 (ddd, J = 12.9, 4.2, 0.3 Hz, 1H, HaCHbCCP), 3.91
(ddd, J = 12.9, 4.2, 0.6 Hz, 1H, HaCHbCCP), 2.98 (s, 3H,
CH3SO2), 1.9–1.6 (br s, 1H, HO), 1.38 and 1.37 (2t,
J = 7.2 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz,
CDCl3): d = 136.7, 128.6, 128.5, 128.4, 82.2 (d,
J = 10.6 Hz, CCP), 75.6 (d, J = 3.0 Hz, OCPh), 74.3 (d,
J = 163.7 Hz, CP), 63.8 and 63.5 (2d, J = 6.8 Hz,
CH3CH2OP), 61.8 (d, J = 3.8 Hz, CCCP), 38.7, 16.7 (d,
J = 3.8 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 20.28. Anal. Calcd for C15H25O8PS: C, 45.40; H,
6.31. Found: C, 45.63; H, 6.52.
4.9. Diethyl (1S,2S)-1,2-dihydroxypropylphosphonate
(1S,2S)-13
A suspension of 10% Pd–C (20 mg) in a solution of phos-
phonate (1S,2S)-10 (0.200 g, 0.670 mmol) in ethanol
(10 mL) was stirred under a hydrogen atmosphere (bal-
loon) for 24 h. The catalyst was removed by filtration
through a layer of Celite, the solution concentrated and
the residue was chromatographed on a silica gel column
with chloroform–methanol (100:1, v/v) to give the diol
(1S,2S)-13 (0.100 g, 70%) as
a
colourless oil;
20
20
½aꢀD ¼ þ10:3 (c 1.4, CHCl3) {lit.14 ½aꢀD ¼ þ3:7 (c 1.0,
MeOH) for a material of ee = 33%}. IR (film): m = 3368,
2983, 2913, 1445, 1394, 1218, 1028, 971 cmꢁ1. H NMR
1
(300 MHz, CDCl3): d = 4.27–4.12 (m, 5H, CH2OP and
HCCP), 4.0–3.9 (br s, 1H, HO), 3.69 (ddd, J = 9.0, 8.2,
3.1 Hz, 1H, HCP), 3.65–3.55 (br s, 1H, HO), 1.36 and
1.35 (2t, J = 7.2 Hz, 6H, CH3CH2OP), 1.31 (dd, J = 6.6,
1.5 Hz, 3H, H3CCCP). 13C NMR (75.5 MHz, CDCl3):
d = 72.1 (d, J = 158.9 Hz, CP), 66.8 (d, J = 2.9 Hz,
CCP), 63.5 and 62.9 (2d, J = 7.2 Hz, CH3CH2OP), 19.5
(d, J = 10.3 Hz, CCCP), 16.7 and 16.7 (2d, J = 5.6 Hz,
CH3CH2OP). 31P NMR (121.5 MHz, CDCl3): d = 24.66.
Anal. Calcd for C7H17O5PÆ1/2H2O: C, 38.01; H, 8.20.
Found: C, 37.76; H, 8.49.
4.7. Diethyl (1S,2S)-2,3-epoxy-1-benzyloxypropylphospho-
nate (1S,2S)-10
A suspension of anhydrous potassium carbonate (0.274 g,
1.98 mmol) in a solution of phosphonate (1S,2R)-9
(0.525 g, 1.32 mmol) in ethanol (20 mL) was stirred at
room temperature for 20 h. After filtration through a pad
of Celite, a solution was concentrated and chromato-
graphed on silica gel with chloroform–methanol (100:1,
v/v) to give the epoxyphosphonate (1S,2S)-10 (0.353 g,
20
89%) as a colourless oil; ½aꢀD ¼ ꢁ20:6 (c 4.0, CHCl3)
20
{lit.13 ½aꢀD ¼ þ20:7 (c 1.23, CHCl3)}. 1H, 13C and 31P
4.9.1. Diethyl (1R,2S)-1,2-dihydroxypropylphosphonate
(1R,2S)-13. As described in the previous section, from
phosphonate (1R,2S)-10 (0.050 g, 0.17 mmol) dissolved in
ethanol (2 mL) in the presence 5% Pd–C (0.005 g), after
NMR spectral data of this compound were identical with
those described earlier for its enantiomer.13 Anal. Calcd
for C14H21O5P: C, 55.98; H, 7.06. Found: C, 56.22; H, 7.32.
3 days the diol (1R,2S)-13 (0.022 g, 61%) was obtained as
20
4.7.1. Diethyl (1R,2S)-2,3-epoxy-1-benzyloxypropylphospho-
nate (1R,2S)-10. As described in the previous section,
from phosphonate (1R,2R)-9 (0.150 g, 0.380 mmol) dis-
solved in ethanol (10 mL) in the presence of K2CO3
(0.105 g, 0.76 mmol) after 6 h of stirring, the epoxyphospho-
nate (1R,2S)-10 (0.035 g, 30%) was obtained as a colourless
a colourless oil; ½aꢀD ¼ ꢁ4:4 (c 4.05, CHCl3). IR (film):
m = 3368, 2984, 2917, 2874, 1445, 1394, 1208, 1025,
970 cmꢁ1. 1H NMR (300 MHz, CDCl3): d = 4.29–4.13 (m,
4H, CH2OP), 4.06 (ddqd, J = 15.9, 6.6, 6.3, 5.4 Hz, 1H,
HCCP), 3.78 (ddd, J = 7.8, 6.6, 5.4 Hz, 1H, HCP), 3.15
(br d, J = 6.3 Hz, 1H, HOCCP), 3.01 (dd, J = 7.8, 6.6 Hz,
1H, HOCP), 1.38 and 1.37 (2t, J = 6.9 Hz, 6H,
CH3CH2OP), 1.37 (d, J = 6.6 Hz, 3H, H3CCCP). 13C
NMR (75.5 MHz, CDCl3): d = 72.0 (d, J = 154.0 Hz, CP),
68.5 (d, J = 2.3 Hz, CCP), 63.3 and 62.6 (2d, J = 7.1 Hz,
CH3CH2OP), 19.2 (d, J = 6.0 Hz, CCCP), 16.5 and 16.5
(2d, J = 5.5 Hz, CH3CH2OP). 31P NMR (121.5 MHz,
CDCl3): d = 24.48. Anal. Calcd for C7H17O5PÆ1/2H2O: C,
38.01; H, 8.20. Found: C, 37.86; H, 8.16.
20
20
oil. ½aꢀD ¼ ꢁ19:7 (c 1.0, CHCl3) {lit.13 ½aꢀD ¼ þ22:7 (c
0.997, CHCl3)}. 1H, 13C and 31P NMR spectral data of this
compound were identical with those described earlier for its
enantiomer.13 Anal. Calcd for C14H21O5PÆ1/2H2O: C,
54.36; H, 7.17. Found: C, 54.31; H, 7.47.
4.8. Diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phos-
phonate (E)-11
Further elution of the silica gel column (Section 4.7.1) gave
a vinylphosphonate (E)-11 (0.073 g, 60%) as a colourless
oil. IR (film): m = 3396, 2984, 2931, 287311, 1638, 1455,
4.10. O-Ethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphospho-
nate (1R,2S)-2a
1233, 1130, 1023, 973, 740, 699 cmꢁ1
.
1H NMR
A suspension of anhydrous potassium carbonate (0.048 g,
0.35 mmol) in a solution of phosphonate (1R,2R)-4
(0.050 g, 0.16 mmol) in ethanol (1 mL) was stirred at room
temperature for 24 h. After filtration through a pad of Cel-
ite, a solution was concentrated and chromatographed on
silica gel with chloroform–methanol (5:1, v/v) to give the
epoxyphosphonate (1R,2S)-2a (0.020 g, 69%) as a white
(300 MHz, CDCl3): d = 7.42–7.26 (m, 5H), 6.12 (dt,
J = 10.5, 6.0 Hz, 1H, HC@), 5.00 (s, 2H, CH2Ph), 4.23–
4.10 (m, 6H, CH2OP and CH2OH), 1.7–1.6 (br s, 3H,
HO and H2O), 1.37 (t, J = 7.2 Hz, 6H, CH3CH2OP). 13C
NMR (75.5 MHz, CDCl3): d = 145.8 (d, J = 211.3 Hz,
CP), 136.8, 131.2 (d, J = 22.6 Hz, CCP), 128.6, 128.4,
128.3, 74.4 (d, J = 2.3 Hz, OCPh), 62.8 (2d, J = 5.3 Hz,
CH3CH2OP), 57.4 (d, J = 14.3 Hz, CCCP), 16.7 (d,
J = 6.0 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
amorphous solid; the compound did not melt or change
20
its appearance up to 260 ꢁC; ½aꢀD ¼ þ12:2 (c 0.8, water);
IR (KBr): m = 3600–3100, 2982, 2932, 1649, 1445, 1370,

A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 2218–2226
2225
1204, 1044, 950 cmꢁ1
.
1H NMR (300 MHz, CD3OD):
The catalyst was removed by filtration, the solution was
concentrated and the residue chromatographed on a silica
gel column with chloroform–methanol (100:1, v/v) to give
phosphonate (1R,2S)-2 (0.010 g, 68%) as a colourless oil;
d = 4.05–3.94 (m, 2H, CH2OP), 3.95 (d, J = 5.4 Hz, 1H,
HCCCP), 3.24 (dddd, J = 5.4, 5.4, 5.1, 4.8 Hz, 1H, HCCP),
2.93 (dd, J = 22.2, 5.1 Hz, 1H, HCP), 1.27 (t, J = 7.2 Hz,
3H, CH3CH2OP). 13C NMR (75.5 MHz, CD3OD):
d = 61.9 (d, J = 5.1 Hz, CH3CH2OP), 58.4 (CCCP), 52.2
(d, J = 188.1 Hz, CP), 39.5 (CCP), 17.3 (d, J = 6.3 Hz,
CH3CH2OP). 31P NMR (121.5 MHz, CDCl3): d = 12.89.
Anal. Calcd for C5H11O5P: C, 32.98; H, 6.09. Found: C,
33.04; H, 6.05.
20
20
½aꢀD ¼ þ11:7 (c 0.8, CHCl3) {lit.11 ½aꢀD ¼ ꢁ10:2 (c
1
1.0, CHCl3) for its enantiomer}. H, 13C and 31P NMR
spectral data of this compound were identical with those
described earlier for its enantiomer.11 Anal. Calcd for
C7H15O5PÆH2O: C, 36.85; H, 7.50. Found: C, 37.12; H, 7.74.
4.12. Diethyl (1S,2S)-3-dibenzyloamino-1-benzyloxy-2-
hydroxypropylphosphonate (1S,2S)-16
4.11. Diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphospho-
nate (1R,2S)-2
A suspension of calcium triflate (0.062 g, 0.18 mmol) in a
solution of the epoxyphosphonate (1S,2S)-10 (0.110 g,
0.370 mmol) and dibenzylamine (0.078 mL, 0.41 mmol) in
acetonitrile (10 mL) was stirred at 50 ꢁC for 20 h. The sol-
vent was evaporated, the residue dissolved in CH2Cl2
(15 mL) and the solution washed with water (3 · 5 mL).
After drying with MgSO4 and concentration the crude
product was chromatographed on a silica gel column with
chloroform–methanol (100:1, v/v). The appropriate frac-
tions were collected and crystallised from ethyl acetate to
give phosphonate (1S,2S)-14 (0.110 g, 60%) as white nee-
4.11.1. Diethyl (1R,2R)-1-hydroxy-2-mesyloxy-3-trityloxy-
propylphosphonate (1R,2R)-14. To a solution of diol
(1R,2R)-4 (0.090 g, 0.29 mmol) in CH2Cl2 (5 mL) contain-
ing NEt3 (0.12 mL, 0.87 mmol) cooled to 0 ꢁC, trityl chlo-
ride (0.13 g, 0.46 mmol) was added followed by DMAP (a
few crystals). The solution was then stirred at room tem-
perature for 20 h and treated with cooled, saturated NH4Cl
(5 mL). The aqueous layer was extracted with CH2Cl2
(3 · 2 mL), and the organic phases combined and dried
over MgSO4. After concentration, the crude product was
chromatographed on a silica gel column with chloro-
form–methanol–triethylamine (100:1:0.05, v/v) to give the
20
20
dles; ½aꢀD ¼ þ4:7 (c 1.2, CHCl3) {lit.13 ½aꢀD ¼ ꢁ4:0 (c
1
0.73, CHCl3)}. H, 13C and 31P NMR spectral data of this
trityl derivative (1R,2R)-14 (0.110 g, 70%) as a colourless
compound were identical with those described earlier for its
enantiomer.13 Anal. Calcd for C28H36NO5P: C, 67.58; H,
7.31; N, 2.81. Found: C, 67.48; H, 7.24; N, 3.08.
20
oil; ½aꢀD ¼ þ1:5 (c 1.1, CHCl3). IR (film): m = 3305, 3061,
3037, 2986, 2941, 2927, 2853, 1597, 1493, 1450, 1354,
1
1250, 1055, 747, 708 cmꢁ1. H NMR (300 MHz, CDCl3):
d = 7.45–7.22 (m, 15H), 4.92 (m, 1H, HCCP), 4.19 (dd,
J = 7.5, 4.2 Hz, 1H, HCP), 4.17–4.07 (m, 4H, CH2OP),
3.64 (dd, J = 10.3, 5.3 Hz, 1H, HaCHbCCP), 3.49 (ddd,
J = 10.3, 6.0, 1.4 Hz, 1H, HaCHbCCP), 3.10 (s, 3H), 1.68
(s, 1H, OH), 1.30 and 1.28 (2t, J = 7.0 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 143.1,
128.5, 127.8, 127.1, 87.5, 79.8 (d, J = 4.3 Hz, CCP), 67.2
(d, J = 163.5 Hz, CP), 63.4 and 63.2 (2d, J = 7.2 Hz,
CH3CH2OP), 62.6 (d, J = 7.2 Hz, CCCP), 38.8, 16.5 (d,
J = 5.1 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 20.81. Anal. Calcd for C27H33O8PS: C, 59.11; H,
6.06. Found: C, 59.40; H, 6.13.
4.12.1. Diethyl (1R,2S)-3-dibenzyloamino-1-benzyloxy-2-
hydroxypropylphosphonate (1R,2S)-16. As described in
the previous section, from phosphonate (1R,2S)-10
(0.070 g, 0.23 mmol) and dibenzylamine (0.049 mL,
0.25 mmol) dissolved in acetonitrile (3 mL) in the presence
of calcium triflate (0.039 g, 0.12 mmol), phosphonate
(1R,2S)-16 (0.086 g, 74%) was obtained as a white powder
after crystallisation from diethyl ether–heptane; mp
20
63–64 ꢁC (lit.13 mp 56–57 ꢁC). ½aꢀD ¼ ꢁ42:1 (c 1.2, CHCl3)
20
{lit.13 ½aꢀD ¼ þ45:4 (c 0.82, CHCl3)}. 1H, 13C and 31P
NMR spectral data of this compound were identical with
those described earlier for its enantiomer.13 Anal. Calcd
for C28H36NO5P: C, 67.58; H, 7.31; N, 2.81. Found: C,
67.64; H, 7.18; N, 3.05.
4.11.2. Diethyl (1R,2S)-1,2-epoxy-3-trityloxypropylphospho-
nate (1R,2S)-15. A suspension of anhydrous potassium
carbonate (0.055 g, 0.40 mmol) in a solution of phospho-
nate (1R,2R)-14 (0.11 g, 0.20 mmol) in ethanol (1 mL)
was stirred at room temperature for 5 h. After filtration
through a pad of Celite, the solution was concentrated
and chromatographed on silica gel with chloroform–meth-
4.13. Diethyl (1S,2S)-2-acetyloxy-3-dibenzyloamino-1-benz-
yloxy-propylphosphonate (1S,2S)-17
Standard acetylation of (1S,2S)-16 (0.080 g, 0.16 mmol)
with acetic anhydride (18.0 lL, 0.19 mmol) in the presence
of NEt3 (33.0 lL, 0.24 mmol) and DMAP (two crystals) in
CH2Cl2 (2.0 mL) gave, after column chromatography on a
silica gel column, acetate (1S,2S)-17 (0.080 g, 93%) as a col-
anol (50:1, v/v) to give the epoxyphosphonate (1R,2S)-15
20
(0.069 g, 62%) as a colourless oil; ½aꢀD ¼ þ9:4 (c 1.6,
20
CHCl3); {lit.11 ½aꢀD ¼ ꢁ10:0 (c 1.15, CHCl3) for its enan-
20
20
1
tiomer}. H, 13C and 31P NMR spectral data of this com-
ourless oil. ½aꢀD ¼ þ11:7 (c 1.0, CHCl3) {lit.13 ½aꢀD ¼ ꢁ11:3
1
pound were identical with those described earlier for its
enantiomer.11 Anal. Calcd for C26H29O5PÆ1/4H2O: C,
68.33; H, 6.51. Found: C, 68.50; H, 6.38.
(c 1.42, CHCl3)}. H, 13C and 31P NMR spectral data of
this compound were identical with those described earlier
for its enantiomer.13 Anal. Calcd for C30H38NO6P: C,
66.78; H, 7.10; N, 2.60. Found: C, 66.70; H, 6.89; N, 2.88.
4.11.3. Diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphospho-
nate (1R,2S)-2. A solution of phosphonate (1R,2S)-15
(0.062 g, 0.14 mmol) in ethanol (1 mL) was hydrogenated
over Pd–C (10%, 5 mg) at room temperature for 24 h.
4.13.1. Diethyl (1R,2S)-2-acetyloxy-3-dibenzyloamino-1-
benzyloxy-propylphosphonate (1R,2S)-17. As described
in the previous section, from phosphonate (1R,2S)-16

2226
A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 2218–2226
(0.047 g, 0.09 mmol) and acetic anhydride (10.0 lL,
0.11 mmol) in the presence of NEt3 (12.0 lL, 0.14 mmol)
and DMAP (two crystals) in CH2Cl2 (1.0 mL), acetate
(1R,2S)-17 (0.038 g, 79%) was obtained as a colourless
Acknowledgements
´ ´
Financial support from the Medical University of Łodz
(502-13-331) is gratefully acknowledged. The authors wish
to express their gratitude to Mrs. Edyta Grzelewska for her
involvement in this project.
20
20
oil. ½aꢀD ¼ ꢁ38:2 (c 0.9, CHCl3) {lit.13 ½aꢀD ¼ þ37:5
1
(c 0.84, CHCl3)}. H, 13C and 31P NMR spectral data of
this compound were identical with those described earlier
for its enantiomer.13 Anal. Calcd for C30H38NO6P: C,
66.78; H, 7.10; N, 2.60. Found: C, 66.90; H, 7.21; N, 2.65.
References
1. Savignac, P.; Iorga, B. Modern Phosphonate Chemistry; CRC
Press: Boca Raton, 2003; Chapter 4, pp 139–181.
2. Benezra, C.; Ourisson, G. Bull. Soc. Chim. Fr. 1967, 624–632.
3. McEldoon, W. L.; Wiemer, D. F. Tetrahedron 1996, 52,
11695–11704.
4. Otmar, M.; Rosenberg, I.; Madojidkova, M.; Holy, A.
Collect. Czech. Chem. Commun. 1993, 58, 2180–2196.
5. Hwang, J.-M.; Jung, K.-Y. Bull. Korean Chem. Soc. 2002, 23,
1848–1850.
6. Glebova, M. A.; Eryuzheva, O. V.; Zhdanov, Y. A. Zh.
Obshch. Khim. 1993, 63, 1677–1678.
7. Inokawa, S.; Kawata, Y.; Yamamota, K.; Kawamoto, H.;
Yamamoto, H.; Takagi, K.; Yamashita, M. Carbohydrate
Research 1981, 88, 341–344.
4.14. Diethyl (1S,2S)-3-acetamido-1,2-dihydroxypropyl-
phosphonate (1S,2S)-18
A solution of phosphonate (1S,2S)-17 (0.100 g, 0.18 mmol)
in ethanol (5 mL) was hydrogenated over Pd(OH)2–C
(20%, 30 mg) and Pd–C (10%, 30 mg) at room temperature
for 2 days. The catalyst was removed by filtration, the solu-
tion concentrated and the residue chromatographed on a
silica gel column with chloroform–methanol (50:1, v/v) to
give phosphonate (1S,2S)-18 (0.030 g, 61%) as a colourless
20
20
oil; ½aꢀD ¼ ꢁ16:4 (c 1.45, CHCl3) {lit.13 ½aꢀD ¼ þ19:0 (c
0.98, CHCl3) for its enantiomer}. H, 13C and 31P NMR
1
spectral data of this compound were identical with those
described earlier for its enantiomer.13 Anal. Calcd for
C9H20NO6P: C, 40.14; H, 7.50; N, 5.20. Found: C, 40.40;
H, 7.26; N, 5.36.
8. Inokawa, S.; Yamamoto, H. Phosphorus, Sulfur 1983, 16, 79–
81.
9. Christensen, B. G.; Plains, S.; Beattie, T. R.; Plainfield, N.;
Graham, D. W. US Patent 3,657,282; Christensen, B. G.;
Beattie, T. R.; Graham, D. W. FR 2034480; Chem. Abstr.,
1971, 75, 88759.
10. Penz, G.; Zbiral, E. Monatsh. Chem. 1982, 113, 1169–1190.
4.14.1. Diethyl (1R,2S)-3-acetamido-1,2-dihydroxypropyl-
(1R,2S)-17
´
´
11. Wroblewski, A. E.; Ba˛k-Sypien, I. I. Tetrahedron: Asymmetry
phosphonate
(1R,2S)-18. Phosphonate
2007, 18, 520–526.
(0.030 g, 0.060 mmol) was hydrogenated over Pd(OH)2-C
(20%, 6 mg) at room temperature for 3 days and worked
up as described in the previous section to provide phospho-
nate (1R,2S)-18 (0.011 g, 71%) as a colourless oil;
´
12. Wroblewski, A. E.; Balcerzak, K. B. Tetrahedron 1998, 54,
6833–6840.
´
13. Wroblewski, A. E.; Balcerzak, K. B. Tetrahedron: Asymmetry
2002, 13, 845–850.
20
20
½aꢀD ¼ þ72:2 (c 1.1, CHCl3) {lit.13 ½aꢀD ¼ ꢁ77:2 (c 1.01,
CHCl3) for its enantiomer}. 1H, 13C and 31P NMR spectral
data of this compound were identical with those described
earlier for its enantiomer.13 Anal. Calcd for C9H20NO6P:
C, 40.14; H, 7.50; N, 5.20. Found: C, 40.38; H, 7.59; N,
5.26.
14. Yokomatsu, T.; Yamagishi, T.; Suemune, K.; Yoshida, Y.;
Shibuya, S. Tetrahedron 1998, 54, 767–780.
15. Phosphorus-31 NMR Spectroscopy in Stereochemical Analy-
sis; Verkade, J. G., Quin, L. D., Eds.; VCH, 1987; Chapters
11 and 12.
16. Payne, G. B. J. Org. Chem. 1962, 27, 3819–3822.