New analogues of fosfomycin-synthesis of diethyl (1R,2R)- and (1S,2R)-1,2-epoxy-3-hydroxypropylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2007.02.006

The trans-configured fosfomycin analogue, diethyl (1R,2R)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised via the intramolecular Williamson reaction from 3-O-protected (trityl or TBDMS) or even unprotected diethyl (1S,2R)-2,3-dihydroxy-1-mesyloxypro

Full text of DOI:10.1016/j.tetasy.2007.02.006

Tetrahedron: Asymmetry 18 (2007) 520–526
New analogues of fosfomycin—synthesis of diethyl (1R,2R)-
and (1S,2R)-1,2-epoxy-3-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 15 January 2007; accepted 6 February 2007
Available online 13 March 2007
Abstract—The trans-configured fosfomycin analogue, diethyl (1R,2R)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised via the
intramolecular Williamson reaction from 3-O-protected (trityl or TBDMS) or even unprotected diethyl (1S,2R)-2,3-dihydroxy-1-mes-
yloxypropylphosphonate, which was obtained from the known diethyl (1S,2R)-2,3-O-cyclohexylidene-1,2,3-trihydroxypropylphospho-
nate. On the other hand, the cis-analogue, diethyl (1S,2R)-1,2-epoxy-3-hydroxypropylphosphonate, could only be prepared from
diethyl (1R,2R)-2-hydroxy-1-mesyloxy-3-trityloxypropylphoshonate.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
sugars (cyclic7,8 or acyclic9,10) and nucleosides11 or their
mimetics9,12 have also been obtained.
The discovery of the antibiotic properties of fosfomycin
[(1R,2S)-1,2-epoxypropylphosphonic acid] has accelerated
the search for new synthetic methods for 1,2-epoxyphosph-
onates, which have recently been reviewed.1 The synthetic
approaches to fosfomycin fall into two categories: a direct
epoxidation of (Z)-1-propenylphosphonates and the forma-
tion of the oxirane ring by an intramolecular Williamson
reaction. These two methods have recently been exemplified
by an asymmetric epoxidation2 and a chemo enzymatic syn-
thesis from 1-chloro-2-hydroxypropylphosphonate.3
Several years ago diethyl (1R,2R)- and (1S,2R)-2,3-
O-cyclohexylidene-1,2,3-trihydroxypropylphosphonates
2
became available13 and they were later employed in the
synthesis of diethyl (1R,2R)- and (1S,2R)-2,3-epoxy-1-benz-
yloxypropylphosphonates.14 We envisioned the usefulness
of phosphonates 2 in the synthesis of enantiomerically pure
diethyl (1R,2R)- and (1S,2R)-1,2-epoxy-3-hydroxyprop-
ylphosphonates 1 (Scheme 1). Herein our efforts to this
end are presented.
O
H
H
(O)P(OEt)2
(O)P(OEt)2
(O)P(OEt)2
O
Me
P(O)(OH)2
R'
R
O
O
OMs
O
fosfomycin
O
OH
A vast number of fosfomycin analogues has been synthes-
ised over the years with the anticipation of novel biological
activity. The most prominent examples include compounds
in which the methyl group in fosfomycin was replaced by
substituted methyl residues (e.g., hydroxymethyl, amino-
methyl and their derivatives)4 or acyl chains.5 Further-
more, complex fosfomycin analogues, having a 1,2-
epoxyphosphonate moiety incorporated into steroids,6
2
1
R'=OH, R=H (1
R'=H, R=OH (1
R
,2
R
)
S
,2
R)
Scheme 1. Retrosynthesis of epoxyphosphonates 1.
2. Results and discussion
A standard mesylation of the HO–C-1 groups in the enan-
tiomerically pure phosphonates (1R,2R)- and (1S,2R)-2
and removal of the cyclohexylidene protecting groups14
*
Corresponding author. Tel.: +48 42 677 92 33; 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.2007.02.006

A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 520–526
521
from the respective mesylates (1R,2R)- and (1S,2R)-3 led to
diols (1R,2R)- and (1S,2R)-4 in good yields without the
formation of any side products (Schemes 2 and 3).
The 3-O-protected phosphonates (1R,2R)- and (1S,2R)-5
as well as (1R,2R)- and (1S,2R)-6 were treated with
potassium carbonate suspended in anhydrous ethanol–
methylene chloride mixtures to produce the respective
epoxides in good to excellent yields (Schemes 2 and 3).
Diethyl (1S,2R)-1,2-epoxy-3-trilyloxypropylphosphonate
8 was also formed as a single product upon treatment
of phosphonate (1R,2R)-5 with potassium carbonate
suspended in methanol at room temperature for 24 h.
However, under similar conditions from the trityl
phosphonate (1S,2R)-5, a mixture of the expected epox-
yphosphonate (1R,2R)-8 (57%) containing P-epimeric O-
ethyl-O-methyl epoxyphosphonates (1R,2R,RP)-10a and
(1R,2R,SP)-10b (a 1:1 ratio, total 29%), O,O-dimethyl
epoxyphosphonate (1R,2R)-13 (11%) and some unreacted
starting material (3%) was formed (Fig. 1). Similar
transesterification processes were observed for the silyl
derivative (1R,2R)-6 leading to a mixture of (1S,2R)-9
(45%), (1S,2R,RP)-11a and (1S,2R,SP)-11b (a 1:1 ratio,
total 30%), (1S,2R)-14 (22%) and the unreacted
(1R,2R)-6 (2%), as judged from the 1H and 31P NMR
spectra. Structural assignments in the partially (10 and
11) and fully (13 and 14) transesterified phosphonates
are based on analysis of the 1H NMR spectra of the
crude product formed after treating the silylated phos-
phonate (1R,2R)-6 with potassium carbonate in methanol
and two chromatographic fractions obtained from this
To transform 1-mesyloxy-2-hydroxyalkyl fragments of
diols (1R,2R)-and (1S,2R)-4 into the oxirane rings, we first
decided to protect the primary HO–C-3 groups as trityl or
tert-butyldimethylsilyl derivatives.15 The 3-O-protected
phosphonates 5 and 6 were selectively obtained in good
yields. However, under the basic conditions employed dur-
ing the tritylation or silylation of diol (1R,2R)-4, the forma-
tion of P-epimeric 3,4-epoxy-1,2-oxaphospholanes 7 (d 31
P
30.8 and 30.3 ppm) was noticed. In particular, the crude
products obtained after tritylations could contain up to
25%, while after silylations up to 5% of the bicyclic com-
pounds 7 were observed, depending on the reaction
temperature.
H
O
H
P(O)(OEt)
O
(2R/S,3S,4R)-7
When diol (1S,2R)-4 was subjected to a base-catalysed
tritylation or silylation, the crude trityl (1S,2R)-5 or tert-
butyldimethylsilyl (1S,2R)-6 derivatives were contaminated
with the protected 1,2-epoxyphosphonates (1R,2R)-8 (2%)
or (1R,2R)-9 (8%), respectively. The amounts of the pro-
tected 1,2-epoxyphosphonates gradually increased, when
the reaction times were extended.
crude product, which contained
a 1:1 mixture of
(1S,2R,RP)-11a and (1S,2R,SP)-11b (ca. 80%) and
(1S,2R)-14 (ca. 76%) as the major components. When
the epoxide ring closure was performed on the silyl
derivative (1S,2R)-6 at ꢀ30 ꢁC for 3 days, the rate of
transesterification was significantly slower and the
(O)P(OEt)2
(O)P(OEt)2
RO
P(O)(OEt)2
e
O
b
RO
MsO
c
OH
OR
O
O
H
H
(1R,2R)-2 R=H
(1R,2R)-3 R=Ms
(1R,2R)-4 R=H
(1R,2R)-5 R=Tr
(1S,2R)-8 R=Tr
a
f
d
(1S,2R)-9 R=TBDMS
(1S,2R)-1 R=H
(1R,2R)-6 R=TBDMS
Scheme 2. Reagents and conditions: (a) MsCl, Et3N, DMAP, 0 ꢁC to rt, 5 h, 90%; (b) 1 M HCl, dioxane, rt, 24 h, 91%; (c) TrCl, Et3N, DMAP, 0 ꢁC to rt,
20 h, 87%; (d) TBDMSiCl, Et3N, DMAP, 0 ꢁC to rt, 5 h, 72%; (e) K2CO3, EtOH/CH2Cl2, rt, 20 h, 76% 8 and 95% 9; (f) H2, Pd–C, EtOH, rt, 24 h, 97% or
p-TsOH, ethanol, rt, 24 h.
(O)P(OEt)2
(O)P(OEt)2
e
O
b
RO
H
OMs
OH
OR
OR
O
O
H
P(O)(OEt)2
(1S,2R)-2 R=H
(1S,2R)-3 R=Ms
(1S,2R)-4 R=H
(1S,2R)-5 R=Tr
(1R,2R)-8 R=Tr
a
c
d
f
(1R,2R)-9 R=TBDMS
(1R,2R)-1 R=H
g
(1S,2R)-6 R=TBDMS
Scheme 3. Reagents and conditions: (a) MsCl, Et3N, DMAP, 0 ꢁC to rt, 5 h, 93%; (b) 1 M HCl, dioxane, rt, 24 h, 85%; (c) TrCl, Et3N, DMAP, 0 ꢁC to rt,
20 h, 87%; (d) TBDMSiCl, Et3N, DMAP, 0 ꢁC to rt, 5 h, 88%; (e) K2CO3, EtOH/CH2Cl2, rt, 20 h, 70% 8 and 93% 9; (f) H2, Pd–C, EtOH, rt, 24 h, 90%;
(g) Bu4NF, THF, rt, 24 h, 90%.

522
A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 520–526
O
P
O
P
O
O
O
RO
RO
RO
RO
P(O)(OMe)2
H
OMe
OEt
OEt
OMe
H
H
H
H
H
(1S,2R)-14 R=TBDMS
(1S,2R,SP)-11b R=TBDMS
(1S,2R,RP)-11a R=TBDMS
O
O
H
O
RO
H
RO
H
OMe
OEt
OEt
OMe
P
P
O
H
H
P(O)(OMe)2
H
O
(1R,2R,RP)-10a R=Tr
(1R,2R,SP)-10b R=Tr
(1R,2R)-13 R=Tr
(1R,2R,RP)-12a R=TBDMS
(1R,2R,SP)-12b R=TBDMS
(1R,2R)-14 R=TBDMS
Figure 1. Products of the transesterification of phosphonates 5 and 6 from the epoxide ring formation in methanol.
epoxyphosphonate (1R,2R)-9 was the major (88%) com-
ponent of the crude product, which also contained
(1R,2R,RP)-12a and (1R,2R,SP)-12b (total 8%), traces of
(1R,2R)-14 and the unreacted (1S,2R)-6 (4%). The clean
formation of the cis-epoxide (1S,2R)-8 in the presence of
methanol and significant transesterifications observed in
this solvent for other (cis and trans) phosphonates could
be rationalised by shielding the phosphorus atom in this
molecule by the trityl group and thus protecting it from
nucleophilic attack by methanol.
propylphoshonate 5. As expected, the formation of the
cis-analogue of fosfomycin (1S,2R)-1 was more difficult
than the synthesis of the trans-counterpart (1R,2R)-1.
Extensive transesterification of the O,O-diethyl phospho-
nate group was noticed, when the cyclisation was carried
out in methanol.
4. Experimental
1H NMR spectra were recorded with a Varian Mercury-300
spectrometer; chemical shifts d in ppm with respect to TMS;
coupling constants J in Hz. 13C and 31P NMR spectra were
recorded on a Varian Mercury-300 machine at 75.5 and
121.5 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 uncor-
rected. Elemental analyses were performed by the Micro-
analytical Laboratory of this Faculty on a Perkin–Elmer
PE 2400 CHNS analyzer. Polarimetric measurements were
conducted on a Perkin–Elmer 241 MC apparatus. The
following absorbents were used: column chromatography,
Merck silica gel 60 (70–230 mesh); analytical TLC, Merck
The hydrogenolysis (10% Pd–C) of the trityl derivatives
(1R,2R)- and (1S,2R)-8 gave cleanly the epoxides
(1R,2R)- and (1S,2R)-1 in 90% and 97% isolated yields,
respectively. On the other hand, cleavage (p-TsOH, etha-
nol) of the trityl group in (1S,2R)-8 always led to the con-
tamination of the crude epoxyphosphonate (1S,2R)-1 with
up to 20% of the P-epimeric 3,4-epoxy-1,2-oxaphosphol-
anes 7, which could be removed chromatographically.
Deprotection of the silyl epoxyphosphonates (1R,2R)-
and (1S,2R)-9 was conducted in the presence of tetrabutyl-
ammonium fluoride in THF.16 Pure epoxyphosphonate
(1R,2R)-1 was obtained in 90% isolated yield from the silyl-
derivative (1R,2R)-9. Under the same conditions from the
3-O-silylated epoxyphosphonate (1S,2R)-9, a low yield of
impure (1S,2R)-1 could be isolated. Finally, it appeared
that mesylate (1S,2R)-4 can be directly transformed into
epoxide (1R,2R)-1, when treated with potassium carbonate
in ethanol at room temperature for 20 h. However, under
similar conditions from the mesylate (1R,2R)-4 complex
reaction mixtures were formed.
TLC plastic sheets silica gel 60 F254
.
4.1. Diethyl (1R,2R)-2,3-O-cyclohexylidene-2,3-dihydroxy-
1-mesyloxypropylphosphonate (1R,2R)-3
To a solution of the phosphonate (1R,2R)-2 (1.92 g,
6.23 mmol) in CH2Cl2 (45 mL) containing NEt3
(2.60 mL, 18.7 mmol) cooled to 0 ꢁC, mesyl chloride
(0.98 mL, 12.5 mmol) was added dropwise. After 5 h at
room temperature, the reaction mixture was washed with
water (3 · 30 mL), the organic phase was dried over
MgSO4, concentrated and the crude product was chro-
matographed on a silica gel column with chloroform–
methanol (100:1, v/v) to give the mesylate (1R,2R)-3
3. Conclusions
The intramolecular Williamson reaction was studied on
diethyl (1R,2R)- and (1S,2R)-2,3-dihydroxy-1-mesyloxy-
propylphosphonates 4, which were obtained from the
known diethyl (1R,2R)- and (1S,2R)-2,3-O-cyclohexylid-
ene-1,2,3-trihydroxypropylphosphonates 2 by mesylation
and acetal cleavage. Diethyl (1R,2R)-1,2-epoxy-3-hydr-
(2.14 g, 90%) as a colourless oil. IR (film): m = 2984,
20
2937, 2863, 1364, 1261, 1176, 1024 cmꢀ1. ½aꢁD ¼ ꢀ12:5
(c 0.9, CHCl3). 1H NMR (300 MHz, CDCl3): d = 4.84
(dd, J = 10.8, 8.2 Hz, 1H, HCP), 4.45 (dddd, J = 8.2, 6.6,
6.3, 2.5 Hz, 1H, HCCP), 4.31–4.20 (m, 4H, CH2OP), 4.15
(dd, J = 9.3, 6.3 Hz, 1H, HaCHbCCP), 4.02 (dd, J = 9.3,
6.6 Hz, 1H, HaCHbCCP), 3.22 (s, 3H, CH3SO2), 1.70–
1.60 (m, 2H, CH2), 1.58–1.40 (m, 8H, 4 · CH2), 1.38 and
1.37 (2td, J = 7.1, 0.6 Hz, 6H, CH3CH2OP). 13C NMR
(75.5 MHz, CDCl3): d = 111.0, 77.6 (d, J = 161.5 Hz,
oxypropylphosphonate
1
was formed cleanly from
the 3-O-trityl, 3-O-tert-butyldimethylsilyl derivatives of
(1S,2R)-4 and even from the unprotected phosphonate.
However, the synthesis of diethyl (1S,2R)-1,2-epoxy-3-
hydroxypropylphosphonate 1 could only be accomplished
from diethyl (1R,2R)-2-hydroxy-1-mesyloxy-3-trityloxy-

A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 520–526
523
1
20
CP), 74.0 (d, J = 9.1 Hz, CCP), 65.6 (d, J = 2.0 Hz,
CCCP), 64.4 and 63.7 (2d, J = 6.7 Hz, CH3CH2OP),
39.5, 36.1, 35.1, 25.2, 24.1, 24.1, 16.7 and 16.5 (2d,
J = 5.9 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 15.27. Anal. Calcd for C14H27O8PS: C, 43.36; H,
7.06. Found: C, 43.64; H, 6.90.
1243, 1177, 1026 cmꢀ1. ½aꢁD ¼ þ20:15 (c 1.0, CHCl3). H
NMR (300 MHz, CDCl3): d = 4.98 (dd, J = 9.5, 6.7 Hz,
1H, HCP), 4.33–4.20 (m, 4H, CH2OP), 4.13 (dddd,
J = 6.7, 4.8, 4.6, 4.5 Hz, 1H, HCCP), 3.91 (ddd, J = 12.1,
4.8, 1.2 Hz, 1H, HaCHbCCP), 3.77 (dd, J = 12.1, 4.5 Hz,
1H, HaCHbCCP), 3.19 (s, 3H, CH3SO2), 1.39 (t,
J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz,
CDCl3): d = 75.7 (d, J = 164.3 Hz, CP), 70.8 (d,
J = 5.2 Hz, CCP), 64.5 and 63.9 (2d, J = 6.6 Hz,
CH3CH2OP), 62.1 (d, J = 5.7 Hz, CCCP), 39.1, 16.6 and
16.5 (2d, J = 6.0 Hz, CH3CH2OP). 31P NMR (121.5 MHz,
CDCl3): d = 17.97. Anal. Calcd for C8H19O8PS: C, 31.39;
H, 6.27. Found: C, 31.71; H, 6.58.
4.1.1. Diethyl (1S,2R)-2,3-O-cyclohexylidene-2,3-dihydroxy-
1-mesyloxypropylphosphonate (1S,2R)-3. As described in
the previous section, from the phosphonate (1S,2R)-2
(3.67 g, 11.9 mmol) and mesyl chloride (1.86 mL,
23.8 mmol) in the presence of NEt3 (4.97 mL, 35.6 mmol),
the mesylate (1S,2R)-3 (4.30 g, 93%) was obtained as a
colourless oil. IR (film): m = 2983, 2937, 2863, 1366, 1262,
20
1
1178, 1028 cmꢀ1. ½aꢁD ¼ þ13:8 (c 0.9, CHCl3). H NMR
(300 MHz, CDCl3): d = 5.14 (dd, J = 11.9, 3.0 Hz, 1H,
HCP), 4.50 (dddd, J = 7.8, 6.6, 3.0, 1.4 Hz, 1H, HCCP),
4.28–4.18 (m, 4H, CH2OP), 4.11 (dd, J = 8.5, 6.6 Hz, 1H,
HaCHbCCP), 3.98 (dd, J = 8.5, 7.8 Hz, 1H, HaCHbCCP),
3.19 (s, 3H, CH3SO2), 1.64–1.62 (m, 2H, CH2), 1.60–1.54
(m, 8H, 4 · CH2), 1.38 and 1.37 (2td, J = 7.1, 0.6 Hz,
6H, CH3CH2OP). 13C NMR (75.5 MHz, CDCl3):
d = 110.3, 74.5 (d, J = 165.8 Hz, CP), 73.4 (d,
J = 12.0 Hz, CCP), 64.3 (d, J = 1.4 Hz, CCCP), 64.0 and
63.9 (2d, J = 6.7 Hz, CH3CH2OP), 39.5, 35.9, 34.9, 25.3,
24.1, 24.0, 16.7 and 16.6 (2d, J = 6.0 Hz, CH3CH2OP).
31P NMR (121.5 MHz, CDCl3): d = 15.45. Anal. Calcd
for C14H27O8PSÆ1=4H2O: C, 43.02; H, 7.09. Found: C,
42.81; H, 6.98.
4.3. Diethyl (1R,2R)-2-hydroxy-1-mesyloxy-3-trityloxy-
propylphosphonate (1R,2R)-5
To a solution of diol (1R,2R)-4 (1.30 g, 4.75 mmol) in
CH2Cl2 (22 mL) cooled to 0 ꢁC, trityl chloride (1.59 g,
5.70 mmol) was added, followed by NEt3 (1.06 mL,
7.60 mmol) and DMAP (0.06 g, 0.5 mmol). The solution
was then stirred at room temperature for 20 h and later
treated with cooled saturated NH4Cl (30 mL). The aqueous
layer was extracted with CH2Cl2 (3 · 15 mL), organic
phases were combined and dried over MgSO4. After con-
centration the crude product was chromatographed on a
silica gel column with chloroform–methanol–triethylamine
(100:1:0.05, v/v) to give the trityl derivative (1R,2R)-5
(2.27 g, 87%), which was crystallised from ethyl acetate to
yield a white powder (2.12 g, 81%); mp 125.7–126.5 ꢁC.
4.2. Diethyl (1R,2R)-2,3-dihydroxy-1-mesyloxypropyl-
phosphonate (1R,2R)-4
IR (KBr): m = 3305, 2941, 2927, 2853, 1354, 1249, 1179,
20
1043 cmꢀ1
.
½aꢁD ¼ ꢀ14:4 (c 1.9, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 7.43–7.25 (m, 15H), 5.09 (dd,
J = 10.6, 3.7 Hz, 1H, HCP), 4.27–4.11 (m, 5H, CH2OP
and HCCP), 3.45 (ddd, J = 9.8, 6.6, 1.2 Hz, 1H,
HaCHbCCP), 3.32 (dd, J = 9.8, 6.6 Hz, 1H, HaCHbCCP),
3.05 (d, J = 4.5 Hz, 1H, HO), 2.96 (s, 3H, CH3SO2), 1.35
and 1.33 (2t, J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR
(75.5 MHz, CDCl3): d = 143.4, 128.2, 128.1, 127.4, 87.6,
75.6 (d, J = 166.3 Hz, CP), 69.6 (d, J = 2.3 Hz, CCP),
64.5 (d, J = 6.9 Hz, CCCP), 63.5 and 63.4 (2d,
J = 6.8 Hz, CH3CH2OP), 39.1, 16.8 and 16.7 (2d,
J = 5.9 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 17.97. Anal. Calcd for C27H33O8PS: C, 59.11; H,
6.06. Found: C, 59.33; H, 5.96.
A solution of phosphonate (1R,2R)-3 (1.88 g, 4.86 mmol)
in dioxane (30 mL) containing 1 M HCl (48.6 mL) was
kept at room temperature for 24 h. After neutralisation
with solid NaHCO3 all volatiles were removed in vacuo
and the crude product was evaporated with dry dioxane
(3 · 20 mL). The residue was suspended in CH2Cl2
(30 mL), dried over MgSO4, concentrated and chromato-
graphed on a silica gel column with chloroform–methanol
(50:1, v/v) to give the diol (1R,2R)-4 (1.21 g, 91%) as a
colourless oil. IR (film): m = 3373, 2986, 2938, 1360, 1245,
20
1175, 1025 cmꢀ1. ½aꢁD ¼ ꢀ15:5 (c 1.25, CHCl3). H NMR
(300 MHz, CDCl3): d = 5.00 (dd, J = 11.5, 4.8 Hz, 1H,
HCP), 4.32–4.20 (m, 4H, CH2OP), 4.13 (dddd, J = 5.6,
5.5, 4.8, 4.8 Hz, 1H, HCCP), 3.86 (ddd, J = 11.9, 4.8,
1.1 Hz, 1H, HaCHbCCP), 3.72 (dd, J = 11.9, 5.5 Hz, 1H,
HaCHbCCP), 3.22 (s, 3H, CH3SO2), 1.39 and 1.38 (2td,
J = 7.1, 0.6 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz,
CDCl3): d = 76.2 (d, J = 164.9 Hz, CP), 70.8 (d,
J = 4.3 Hz, CCP), 64.4 and 63.9 (2d, J = 6.7 Hz,
CH3CH2OP), 62.5 (d, J = 7.1 Hz, CCCP), 39.2, 16.6 and
16.5 (2d, J = 6.3 Hz, CH3CH2OP). 31P NMR
(121.5 MHz, CDCl3): d = 17.86. Anal. Calcd for
C8H19O8PS: C, 31.39; H, 6.27. Found: C, 31.65; H, 6.59.
1
4.3.1. Diethyl (1S,2R)-2-hydroxy-1-mesyloxy-3-trityloxy-
propylphosphonate (1S,2R)-5. As described in the previ-
ous section, from the phosphonate (1S,2R)-4 (1.13 g,
4.12 mmol) and trityl chloride (1.38 g, 4.94 mmol) in the
presence of NEt3 (0.92 mL, 6.6 mmol) and DMAP
(0.05 g, 0.4 mmol), the trityl derivative (1S,2R)-5 (1.96 g,
87%) was obtained as a white powder after chromatogra-
phy on a silica gel column with chloroform–methanol–tri-
ethylamine (100:1:0.05, v/v) and crystallisation from ethyl
acetate; mp 127.7–129 ꢁC. IR (KBr): m = 3414, 2994,
20
2929, 1367, 1220, 1180, 1021 cmꢀ1. ½aꢁD ¼ þ2:1 (c 1.8,
1
4.2.1. Diethyl (1S,2R)-2,3-dihydroxy-1-mesyloxypropyl-
phosphonate (1S,2R)-4. As described in the previous
section, from the phosphonate (1S,2R)-3 (1.88 g,
4.86 mmol), diol (1S,2R)-4 (1.13 g, 85%) was obtained as
a colourless oil. IR (film): m = 3376, 2986, 2938, 1360,
CHCl3). H NMR (300 MHz, CDCl3): d = 7.46–7.21 (m,
15H), 5.08 (dd, J = 12.0, 4.2, Hz, 1H, HCP), 4.25 (dddd,
J = 7.8, 4.2, 4.2, 3.9 Hz, 1H, HCCP), 4.18–4.07 (m, 4H,
CH2OP), 3.58 (dd, J = 9.9, 3.9 Hz, 1H, HaCHbCCP),
3.38 (dd, J = 9.9, 7.8 Hz, 1H, HaCHbCCP), 3.18 (dd,

524
A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 520–526
J = 3.9, 2.7 Hz, 1H, HO), 2.96 (s, 3H, CH3SO2), 1.28 and
1.26 (2t, J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR
(75.5 MHz, CDCl3): d = 143.7, 128.7, 128.0, 127.3, 87.4,
76.4 (d, J = 164.4 Hz, CP), 70.2 (d, J = 6.8 Hz, CCP),
64.1 and 63.7 (2d, J = 6.8 Hz, CH3CH2OP), 63.4 (d,
J = 3.8 Hz, CCCP), 39.1, 16.6 and 16.5 (2d, J = 5.9 Hz,
CH3CH2OP). 31P NMR (121.5 MHz, CDCl3): d = 16.70.
Anal. Calcd for C27H33O8PS: C, 59.11; H, 6.06. Found:
C, 59.48; H, 5.82.
4.5. Diethyl (1S,2R)-1,2-epoxy-3-trityloxypropyl-
phosphonate (1S,2R)-8
To a solution of the trityl derivative (1R,2R)-5 (2.27 g,
4.14 mmol) in CH2Cl2 (13 mL) and anhydrous ethanol
(13 mL), anhydrous K2CO3 (0.86 g, 6.2 mmol) was added
at room temperature and the suspension was vigorously
stirred for 20 h. After the addition of CH2Cl2 (13 mL)
and a saturated solution of NH4Cl (20 mL), the aqueous
phase was extracted with CH2Cl2 (3 · 20 mL), and the
organic phases were combined and dried over MgSO4. After
concentration the crude product was chromatographed on
a silica gel column with chloroform–methanol–triethyl-
amine (100:1:0.05, v/v) to give the epoxyphosphonate
(1S,2R)-8 (1.42 g, 76%) as a colourless oil. IR (film):
4.4. Diethyl (1R,2R)-3-(tert-butyldimethylsilyloxy)-2-hydroxy-
1-mesyloxypropylphosphonate (1R,2R)-6
To a solution of diol (1R,2R)-4 (0.54 g, 1.28 mmol) in
CH2Cl2 (5 mL) cooled to 0 ꢁC, tert-butyldimethylsilyl chlo-
ride (0.44 g, 2.95 mmol) was added, followed by NEt3
(0.38 mL, 2.76 mmol) and DMAP (0.01 g, 0.06 mmol).
The solution was then stirred at room temperature for 5 h
and later treated with water (20 mL). The organic phase
was washed with water (2 · 10 mL), 10% aqueous NH4Cl
(10 mL), dried over MgSO4 and concentrated. The crude
product was chromatographed on a silica gel column with
chloroform–methanol (100:1, v/v) to give the silyl derivative
(1R,2R)-6 (0.59 g, 72%) as a slightly yellow oil. IR (film):
m = 3058, 2984, 2932, 2910, 1448, 1264, 1161, 1051,
20
1025 cmꢀ1. ½aꢁD ¼ ꢀ10:0 (c 1.15, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 7.48–7.20 (m, 15H), 4.11–3.96
(m, 4H, CH2OP), 3.58–3.50 (m, 2H, HaCHbCCP), 3.40
(dddd, J = 5.6, 5.4, 4.8, 4.8 Hz, 1H, HCCP), 3.00 (dd,
J = 27.0, 4.8 Hz, 1H, HCP), 1.22 and 1.19 (2td, J = 7.0,
0.6 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz, CDCl3):
d = 143.8, 128.7, 128.2, 127.2, 87.2, 77.4 (s, CCCP), 62.9
and 62.8 (2d, J = 5.6 Hz, CH3CH2OP), 56.6 (d,
J = 2.3 Hz, CCP), 49.0 (d, J = 203.0 Hz, CP), 16.6 and
16.6 (2d, J = 5.9 Hz, CH3CH2OP). 31P NMR
(121.5 MHz, CDCl3): d = 18.97. Anal. Calcd for
C26H29O5PÆ1=4H2O: C, 68.33; H, 6.51. Found: C, 68.55;
H, 6.68.
m = 3368, 2954, 2931, 2858, 1363, 1254, 1177, 1025 cmꢀ1
.
20
½aꢁD ¼ ꢀ19:4 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 5.02 (dd, J = 10.6, 4.6 Hz, 1H, HCP), 4.33–4.19 (m, 4H,
CH2OP), 4.10 (dddd, J = 6.0, 6.0, 4.6, 1.8 Hz, 1H, HCCP),
3.79 (ddd, J = 10.2, 6.0, 0.9 Hz, 1H, HaCHbCCP), 3.75 (dd,
J = 10.2, 6.0 Hz, 1H, HaCHbCCP), 3.21 (s, 3H, CH3SO2),
1.39 (t, J = 7.2 Hz, 6H, CH3CH2OP), 0.91 (s, 9H), 0.10 (s,
6H). 13C NMR (75.5 MHz, CDCl3): d = 75.5 (d,
J = 166.1 Hz, CP), 70.4 (d, J = 3.8 Hz, CCP), 64.3 and
63.5 (2d, J = 6.8 Hz, CH3CH2OP), 62.5 (d, J = 8.3 Hz,
CCCP), 39.2, 26.0, 18.4, 16.7 and 16.6 (2d, J = 5.3 Hz,
CH3CH2OP), ꢀ5.3. 31P NMR (121.5 MHz, CDCl3):
d = 17.25. Anal. Calcd for C14H33O8PSSi: C, 39.97; H,
7.91. Found: C, 40.01; H, 8.12.
4.5.1. Diethyl (1R,2R)-1,2-epoxy-3-trityloxypropylphospho-
nate (1R,2R)-8. As described in the previous section,
from trityl derivative (1S,2R)-5 (1.65 g, 3.02 mmol), the
epoxyphosphonate (1R,2R)-8 (0.096 g, 70%) was obtained
as a colourless oil after chromatography on a silica gel col-
umn with chloroform–methanol–triethylamine (100:1:0.05,
v/v). IR (film): m = 3059, 2984, 2930, 2911, 1448, 1258,
20
1161, 1054, 1026 cmꢀ1. ½aꢁD ¼ þ17:8 (c 1.14, CHCl3). H
NMR (300 MHz, CDCl3): d = 7.44–7.21 (m, 15H), 4.24–
4.13 (m, 4H, CH2OP), 3.49–3.40 (m, 2H, HaCHbCCP
and HCCP), 3.19–3.12 (m, 1H, HaCHbCCP), 3.07 (dd,
J = 30.6, 2.7 Hz, 1H, HCP), 1.36 and 1.36 (2td, J = 7.0,
0.6 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz, CDCl3):
d = 143.5, 128.6, 128.0, 127.7, 87.0, 63.4 and 63.3 (2d,
J = 6.0 Hz, CH3CH2OP), 63.1 (d, J = 0.8 Hz, CCCP),
55.7 (d, J = 1.5 Hz, CCP), 47.8 (d, J = 201.0 Hz, CP),
16.8 and 16.7 (2d, J = 6.0 Hz, CH3CH2OP). 31P NMR
(121.5 MHz, CDCl3): d = 19.28. Anal. Calcd for
C26H29O5PÆ1=4H2O: C, 68.33; H, 6.51. Found: C, 68.19;
H, 6.42.
1
4.4.1. Diethyl (1S,2R)-3-(tert-butyldimethylsilyloxy)-2-
hydroxy-1-mesyloxypropylphosphonate
(1S,2R)-6. As
described in the previous section, from phosphonate
(1S,2R)-4 (0.11 g, 0.39 mmol) and tert-butyldimethylsilyl
chloride (0.09 g, 0.58 mmol) in the presence of NEt3
(0.08 mL, 0.55 mmol) and DMAP (0.002 g, 0.02 mmol),
the silyl derivative (1S,2R)-6 (0.142 g, 88%) was obtained
as a yellowish oil after chromatography on a silica gel col-
umn with chloroform–methanol (100:1, v/v). IR (film):
m = 3370, 2954, 2932, 2867, 1364, 1253, 1178, 1027 cmꢀ1
.
20
1
½aꢁD ¼ þ9:0 (c 2.0, CHCl3). H NMR (300 MHz, CDCl3):
d = 5.05 (dd, J = 10.8, 5.1, Hz, 1H, HCP), 4.31–4.16 (m,
4H, CH2OP), 4.10 (dddd, J = 6.7, 5.1, 4.0, 2.1 Hz, 1H,
HCCP), 3.94 (ddd, J = 10.8, 3.9, 0.6 Hz, 1H, HaCHbCCP),
3.77 (dd, J = 10.8, 6.6 Hz, 1H, HaCHbCCP), 3.20 (s, 3H,
CH3SO2), 1.40 (t, J = 7.0 Hz, 6H, CH3CH2OP), 0.91 (s,
9H), 0.11 (s, 6H). 13C NMR (75.5 MHz, CDCl3):
d = 75.5 (d, J = 165.2 Hz, CP), 70.9 (d, J = 6.0 Hz,
CCP), 64.3 and 63.7 (2d, J = 7.0 Hz, CH3CH2OP), 62.7
(d, J = 4.9 Hz, CCCP), 39.3, 26.1, 18.6, 16.7 and 16.6
(2d, J = 6.5 Hz, CH3CH2OP), ꢀ5.0, ꢀ5.1. 31P NMR
(121.5 MHz, CDCl3): d = 16.82. Anal. Calcd for
C14H33O8PSSi: C, 39.97; H, 7.91. Found: C, 40.01; H, 8.13.
4.6. Diethyl (1S,2R)-3-(tert-butyldimethylsilyloxy)-1,2-
epoxypropylphosphonate (1S,2R)-9
To a solution of the silyl derivative (1R,2R)-6 (0.19 g,
0.45 mmol) in CH2Cl2 (5 mL) and anhydrous ethanol
(2.5 mL), anhydrous K2CO3 (0.09 g, 0.67 mmol) was added
at room temperature and the suspension vigorously stirred
for 20 h. After the addition of CH2Cl2 (5 mL) and a satu-
rated solution of NH4Cl (10 mL), the aqueous phase was
extracted with CH2Cl2 (3 · 5 mL), and the organic phases
were combined and dried over MgSO4. After concentration

A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 520–526
525
the crude product was chromatographed on a silica gel col-
umn with chloroform–methanol (100:1, v/v) to give the
epoxyphosphonate (1S,2R)-9 (0.14 g, 95%) as a colourless
J = 10.9 Hz, CH3OP), 3.36 (dddd, 1H, J = 6.7, 4.6, 3.7,
2.2 Hz, PCCH), 3.03 (dd, 1H, J = 26.8, 4.6 Hz, PCH),
1.37 (2 · t, 3H, J = 6.9 Hz, POCH2CH3), 0.91 (s, 9H),
0.11 (s, 3H), 0.10 (s, 3H). 31P NMR (121.5 MHz, CDCl3):
d = 20.76 and 20.57.
oil. IR (film): m = 2957, 2930, 2857, 1669, 1396, 1259,
20
1094, 1052, 1024 cmꢀ1. ½aꢁ ¼ þ2:6 (c 1.3, CHCl3). 1H
NMR (300 MHz, CDCl3): dD= 4.23–4.13 (m, 4H, CH2OP),
4.12 (dd, J = 12.3, 3.6 Hz, 1H, HaCHbCCP), 3.98 (ddd,
J = 12.3, 6.6, 0.9 Hz, 1H, HaCHbCCP), 3.36 (dddd,
J = 6.6, 6.0, 4.8, 3.6 Hz, 1H, HCCP), 3.02 (dd, J = 26.4,
4.8 Hz, 1H, HCP), 1.38 and 1.37 (2t, J = 7.0 Hz, 6H,
CH3CH2OP), 0.92 (s, 9H), 0.11 (s, 6H). 13C NMR
(75.5 MHz, CDCl3): d = 63.2 and 62.8 (2d, J = 6.2 Hz,
CH3CH2OP), 62.0 (s, CCCP), 58.3 (d, J = 1.4 Hz, CCP),
49.2 (d, J = 203.5 Hz, CP), 26.1, 18.6, 16.8 and 16.7
(2d, J = 6.0 Hz, CH3CH2OP), ꢀ4.8, ꢀ5.0. 31P NMR
(121.5 MHz, CDCl3): d = 19.40. Anal. Calcd for
C13H29O5PSiÆ1=4H2O: C, 47.47; H, 9.04. Found: C,
47.16; H, 9.14.
4.6.2.2. Dimethyl (1S,2R)-3-(tert-butyldimethylsilyloxy)-
1,2-epoxypropylphosphonate
(1S,2R)-14. 1H
NMR
(300 MHz, CDCl3): d = 4.10 (dd, 1H, J = 12.1, 3.6 Hz
HaCHbCCP), 3.96 (ddd 1H, J = 12.1, 6.7, 0.8 Hz
HaCHbCCP), 3.84 and 3.80 (2d, 6H, J = 10.7 Hz, CH3O-
POCH3), 3.36 (dddd, J = 6.7, 4.8, 3.6, 2.4 Hz, 1H, HCCP),
3.03 (dd, J = 26.8, 4.8 Hz, 1H, HCP), 0.91 (s, 9H), 0.11 (s,
3H), 0.10 (s, 3H). 31P NMR (121.5 MHz, CDCl3):
d = 21.89.
4.7. Diethyl (1S,2R)-1,2-epoxy-3-hydroxypropylphos-
phonate (1S,2R)-1
4.6.1. Diethyl (1R,2R)-3-(tert-butyldimethylsilyloxy)-1,2-
epoxypropylphosphonate (1R,2R)-9. As described in the
previous section, from the silyl derivative (1S,2R)-6
(0.12 g, 0.29 mmol), the epoxyphosphonate (1R,2R)-9
(0.09 g, 93%) was obtained as a colourless oil after chroma-
tography on a silica gel column with chloroform–methanol
(100:1, v/v). IR (film): m = 2956, 2930, 2858, 1472, 1258,
4.7.1. By hydrogenolysis of the trityl derivative (1S,2R)-
8. A solution of the trityl derivative (1S,2R)-8 (0.13 g,
0,29 mmol) in ethanol (7 mL) was hydrogenated over
10%-Pd/C (3 mg) for 24 h. After removal of the catalyst
on a layer of Celite, the residue was chromatographed on
silica gel with chloroform–methanol (100:1, v/v) to give
the epoxyphosphonate (1S,2R)-1 (0.060 g, 97%) as a
20
1100, 1056, 1027 cmꢀ1. ½aꢁD ¼ þ16:0 (c 1.5, CHCl3). H
NMR (300 MHz, CDCl3): d = 4.17–4.07 (m, 4H, CH2OP),
3.94 (ddd, J = 12.6, 2.4, 0.6 Hz, 1H, HaCHbCCP), 3.75
(ddd, J = 12.6, 3.9, 0.6 Hz, 1H, HaCHbCCP), 3.39 (dddd,
J = 5.4, 3.9, 2.4, 2.4 Hz, 1H, HCCP), 3.03 (dd, J = 31.2,
2.4 Hz, 1H, HCP), 1.36 and 1.35 (2td, J = 7.0, 0.6 Hz,
6H, CH3CH2OP), 0.9 (s, 9H), 0.07 and 0.06 (2 s, 6H).
13C NMR (75.5 MHz, CDCl3): d = 63.4 and 63.3 (2d,
J = 6.4 Hz, CH3CH2OP), 61.8 (d, J = 0.8 Hz, CCCP),
56.9 (d, J = 0.8 Hz, CCP), 47.3 (d, J = 202.3 Hz, CP),
26.1, 18.6, 16.7 (d, J = 5.6 Hz, CH3CH2OP), ꢀ5.1. 31P
NMR (121.5 MHz, CDCl3): d = 19.63. Anal. Calcd for
C13H29O5PSiÆ1=4H2O: C, 47.47; H, 9.04. Found: C,
47.71; H, 9.39.
1
colourless oil. IR (film): m = 3398, 2956, 2925, 2870, 1247,
20
1024 cmꢀ1
.
½aꢁD ¼ ꢀ10:2 (c 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 4.27–4.10 (m, 4H, CH2OP), 4.12
(dd 1H, J = 12.9, 5.4 Hz HaCHbCCP), 3.93 (dd 1H,
J = 12.9, 5.4 HzHaCHbCCP), 3.43 (dddd, J = 5.4, 5.4,
4.5, 0.3 Hz, 1H, HCCP), 3.05 (dd, J = 26.4, 4.5 Hz, 1H,
HCP), 1.38 and 1.37 (2t, J = 7.2, Hz, 6H, CH3CH2OP).
13C NMR (75.5 MHz, CDCl3): d = 63.8 and 63.0 (2d,
J = 6.3 Hz, CH3CH2OP), 60.7 (s, CCCP), 57.4 (d, J =
0.9 Hz, CCP), 49.4 (d, J = 203.3 Hz, CP), 16.7 (d,
J = 5.9 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 19.59. Anal. Calcd for C7H15O5P · 0.1H2O: C, 39.66;
H, 7.23. Found: C, 39.60; H, 7.04.
4.7.2. By hydrolysis of the trityl derivative (1S,2R)-8.
A
4.6.2. O-Ethyl-O-methyl (1S,2R,RP)- and (1S,2R,SP)-3-
(tert-butyldimethylsilyloxy)-1,2-epoxypropylphosphonates
(1S,2R,RP)-11a and (1S,2R,SP)-11b and dimethyl (1S,2R)-
3-(tert-butyldimethylsilyloxy)-1,2-epoxypropylphosphonate
(1S,2R)-14. As described in Section 4.6, from the silyl
derivative (1R,2R)-6 (0.700 g, 1.66 mmol) in the presence
of anhydrous K2CO3 (0.345 g) in methanol (5.4 mL), a
crude product (0.400 g) was obtained as a colourless oil.
After chromatography on a silica gel column with chloro-
form–methanol (100:1, v/v), two fractions were collected.
The less polar fraction (0.091 g, a colourless oil) contained
a 1:1 mixture of (1S,2R,RP)-11a and (1S,2R,SP)-11b (ca.
80%) as major components. In the more polar fraction
solution of the trityl derivative (1S,2R)-8 (0.073 g,
0.16 mmol) in ethanol (1 mL) containing a few crystals of
p-TsOH monohydrate was left at room temperature for
24 h. The acid was neutralised by the addition of the solid
sodium bicarbonate, the ethanol was evaporated and the
residue was chromatographed on silica gel with chloro-
form–methanol (100:1, v/v) to give two fractions. A less
polar fraction (0.013 g) contained an impure mixture of
(2R/S,3S,4R)-7. In a more polar fraction the epoxyphosph-
onate (1S,2R)-1 (0.029 g, 86%) was collected as a colourless
oil in all respects identical with the substance described in
the previous Section.
(0.062 g,
a
colourless oil) (1S,2R)-14 (ca. 76%)
predominated.
4.7.2.1. (2R/S,3S,4R)-3,4-Epoxy-2-ethoxy-2-oxo-1,2-oxa-
phospholanes 7. 1H NMR (300 MHz, CDCl3): d = 4.39–
4.22 (m, 4H, CH2OP-exo, CH2OP-endo), 4.00 and 3.93
(2 · ddd, J = 5.4, 4.5, 3.6 Hz, 1H, HCCP), 3.53 and 3.44
(2 · dd, J = 40.0, 3.6 Hz, 1H, HCP), 1.40 and 1.38 (td,
J = 7.2, 0.6 Hz, 3H, CH3). 31P NMR (121.5 MHz, CDCl3):
d = 30.79 and 30.57.
4.6.2.1. O-Ethyl-O-methyl (1S,2R,RP)- and (1S,2R,SP)-
3-(tert-butyldimethylsilyloxy)-1,2-epoxypropylphosphonates
(1S,2R,RP)-11a and (1S,2R,SP)-11b. 1H NMR (300 MHz,
CDCl3): d = 4.24–4.09 (m, 3H, POCH2, HaCHbCCP), 3.97
(dd, 1H, J = 12.1, 6.7 Hz, HaCHbCCP), 3.81 (2 · d, 3H,

526
A. E. Wro´blewski, I. I. Ba˛k-Sypien´ / Tetrahedron: Asymmetry 18 (2007) 520–526
4.8. Diethyl (1R,2R)-1,2-epoxy-3-hydroxypropylphospho-
nate (1R,2R)-1
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.
4.8.1. From trityl derivative (1R,2R)-8. As described in
Section 4.7.1, from the trityl derivative (1R,2R)-8 (0.43 g,
0.95 mmol), the epoxyphosphonate (1R,2R)-1 (0.18 g,
90%) was obtained as a colourless oil after chromato-
graphy on a silica gel column with chloroform–methanol
(100:1, v/v). IR (film): m = 3394, 2988, 2916, 2872, 1244,
References
20
1025 cmꢀ1. ½aꢁD ¼ þ24:8 (c 1.5, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 4.24–4.14 (m, 4H, CH2OP), 4.01
(ddd, J = 13.0, 1.8, 0.3 Hz, 1H, HaCHbCCP), 3.75 (ddd,
J = 13.0, 3.3, 0.3 Hz, 1H, HaCHbCCP), 3.46 (dddd,
J = 5.0, 3.3, 2.5, 1.8 Hz, 1H, HCCP), 3.14 (dd, J = 30.1,
2.5 Hz, 1H, HCP), 1.36 and 1.34 (2t, J = 7.0 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 63.3
and 63.1 (2d, J = 6.0 Hz, CH3CH2OP), 60.4 (d,
J = 0.7 Hz, CCCP), 56.8 (d, J = 1.5 Hz, CCP), 47.1 (d,
J = 202.9 Hz, CP), 16.5 (d, J = 5.6 Hz, CH3CH2OP). 31P
NMR (121.5 MHz, CDCl3): d = 18.51. Anal. Calcd for
C7H15O5PÆ0.2H2O: C, 39.33; H, 7.26. Found: C, 39.47;
H, 7.46.
1. Savignac, P.; Iorga, B. Modern Phosphonate Chemistry; CRC
Press: Boca Raton, 2003; Chapter 4, pp 139–181.
2. Wang, X.-Y.; Shi, H.-C.; Sun, C.; Zhang, Z.-G. Tetrahedron
2004, 60, 10993–10998.
3. Wang, K.; Zhang, Y.; Yuan, C. Org. Biomol. Chem. 2003, 1,
3564–3569.
4. 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.
5. Penz, G.; Zbiral, E. Monatsh. Chem. 1982, 113, 1169–1190.
6. Benezra, C.; Ourisson, G. Bull. Soc. Chim. Fr. 1967, 624–
632.
7. Inokawa, S.; Kawata, Y.; Yamamota, K.; Kawamoto, H.;
Yamamoto, H.; Takagi, K.; Yamashita, M. Carbohydr. Res.
1981, 88, 341–344.
8. Inokawa, S.; Yamamoto, H. Phosphorus, Sulfur 1983, 16, 79–
81.
9. Otmar, M.; Rosenberg, I.; Madojidkova, M.; Holy, A. Coll.
Czech. Chem. Commun. 1993, 58, 2180–2196.
10. Glebova, M. A.; Eryuzheva, O. V.; Zhdanov, Y. A. Zh.
Obshch. Khim. 1993, 63, 1677–1678.
11. McEldoon, W. L.; Wiemer, D. F. Tetrahedron 1996, 52,
11695–11704.
4.8.2. From silyl derivative (1R,2R)-9. The silyl derivative
(1R,2R)-9 (0.15 g, 0.46 mmol) was dissolved in THF
(10 mL) and TBAF (1 M THF solution, 0.5 mL) was
added. After 24 h at room temperature, the mixture was
concentrated and the residue was chromatographed on a
silica gel column with chloroform–methanol (100:1, v/v)
to give the epoxyphosphonate (1R,2R)-1 (0.087 g, 90%)
as a colourless oil, in all respects identical to the material
described in Section 4.7.1.
12. Hwang, J.-M.; Jung, K.-Y. Bull. Korean Chem. Soc. 2002, 23,
1848–1850.
4.8.3. From diol (1S,2R)-4. As described in Section 4.5,
from diol (1S,2R)-4 (0.070 g, 0.17 mmol) dissolved in a
mixture of CH2Cl2 (0.5 mL) and anhydrous ethanol
(0.5 mL) in the presence of K2CO3 (0.05 g), the epoxy-
phosphonate (1R,2R)-1 (0.052 g, 92%) was obtained as a
colourless oil after chromatography on a silica gel column
with chloroform–methanol (100:1, v/v), in all respects iden-
tical to the material described in Section 4.8.1.
´
13. Wroblewski, A. E.; Balcerzak, K. B. Tetrahedron 1998, 54,
6833–6840.
´
14. Wroblewski, A. E.; Balcerzak, K. B. Tetrahedron: Asymmetry
2002, 13, 845–850.
15. Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 99–
102.
16. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190–6191.