Chiral, non-racemic α-hydroxyphosphonates and phosphonic acids via stereoselective hydroxylation of diallyl benzylphosphonates

Article abstract of DOI:10.1016/S0957-4166(02)00786-3

Chiral, non-racemic α-hydroxyphosphonates have been prepared in high enantiomeric excess (96-98% ee), via stereoselective oxaziridine-mediated hydroxylation of diallyl benzylphosphonates. The enantiomeric purity and absolute configuration of the α-hydroxy

Full text of DOI:10.1016/S0957-4166(02)00786-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 265–273
Chiral, non-racemic a-hydroxyphosphonates and phosphonic acids
via stereoselective hydroxylation of diallyl benzylphosphonates
Danielle Skropeta*,† and Richard R. Schmidt
Fachbereich Chemie, Universitaet Konstanz, Fach M 725, D-78457 Konstanz, Germany
Received 28 October 2002; accepted 20 November 2002
Abstract—Chiral, non-racemic a-hydroxyphosphonates have been prepared in high enantiomeric excess (96–98% ee), via
stereoselective oxaziridine-mediated hydroxylation of diallyl benzylphosphonates. The enantiomeric purity and absolute configura-
1
tion of the a-hydroxyphosphonates was established from H and 31P NMR spectroscopy of the (S)-O-methylmandelate esters.
Deprotection of the diallyl a-hydroxyphosphonates under neutral conditions furnished the corresponding free phosphonic acids,
retaining a high degree of stereochemical purity (90 to >98% ee). © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
gation into the role of a-hydroxyphosphoryl com-
pounds in biological processes.
a-Hydroxyphosphoryl compounds are important bioac-
tive molecules known to inhibit a range of enzymes.
They are also attractive precursors to a-aminophospho-
ryl isosteres of a-amino acids. a-Hydroxyphosphonic
acids are found to inhibit farnesyl protein transferase,1
enolpyruvylshikimate-3-phosphate synthase,2 tyrosine-
specific protein kinase3 and HIV protease,4 whereas
a-hydroxyphosphonate esters are found to inhibit renin
angiotensin synthase.5 Most bioactivity studies have
been performed using either free phosphonic acids1–3 or
phosphonate diesters, however, those studies which
have compared the activities of both, have often
revealed a drastic difference in potency attributed to
additional hydrogen bond formation of the free acid, or
conversely, interaction of the ester groups with catalytic
moieties in the active site of the enzyme.4,5 Further-
more, although the absolute configuration at the a-cen-
tre has been shown to influence the biological
properties of a-substituted phosphoryl compounds,5
most bioactivity studies are performed employing
racemic compounds.1–4 We were interested in a simple
and efficient stereoselective route that gives rise to both
enantiomerically pure a-hydroxyphosphonates and
their corresponding phosphonic acids, as key precursors
in the asymmetric synthesis of potent sialyltransferase
inhibitors,6 and as an essential tool for further investi-
Chiral, non-racemic dialkyl a-hydroxyphosphonates
have been prepared via several methods, as has been
recently reviewed,7,8 including chiral variations of either
the Pudovik reaction9 or the Abramov reaction,10
chemical11 or enzymatic resolution,12 or employing cat-
alytic asymmetric methods.8 On the other hand, enan-
tioenriched dialkyl a-hydroxyphosphonic acids have
been prepared by enantioselective addition of aldehydes
to chiral phosphorous acid diamides13 followed by
hydrolysis of the phosphonamides,14 or more often by
hydrolysis of the corresponding non-racemic a-hydroxy-
phosphonates prepared by one of the methods
described above.
The majority of these stereoselective routes are aimed
at the preparation of dialkyl a-hydroxyphosphonates,7,8
and yet, unlike their related carboxylate esters, simple
phosphonate dialkyl esters are not generally converted
in vivo to their corresponding free acids.15 For the
majority of bioactivity studies, which require phospho-
nic acids, the harsh conditions necessary to liberate the
free acid from the dialkyl ester form, may lead to
substantial racemisation of the crucial, newly-formed,
non-racemic a-centre.11
Since their introduction as easily removable phospho-
nate protecting groups,16 diallyl phosphonate esters
have been employed successfully in the synthesis of
sialyltransferase inhibitors,6,17 in the field of solid-phase
peptide synthesis of phosphonic acid isosteres of a-
amino acids18 and also in the synthesis of a,a-
* Corresponding author. Tel.: +49-(0)7531-88-2018; fax: +49-(0)7531-
88-3135; e-mail: danielle.skropeta@uni-konstanz.de
† As of 12/02: University of Sydney, School of Chemistry, NSW,
2006, Australia. Tel.: +61-(0)2-9351-2297; fax: +61-(0)2-9351-3329;
e-mail: d.skropeta@chem.usyd.edu.au
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00786-3

266
D. Skropeta, R. R. Schmidt / Tetrahedron: Asymmetry 14 (2003) 265–273
Scheme 1. Stereoselective synthesis of a-hydroxyphosphonates and phosphonic acids via oxaziridine hydroxylation of diallyl
benzylphosphonates. Reagents and conditions: (i) 3 equiv. TMSBr/0°C/3 h, then 3 equiv. (COCl)2/cat. DMF/CH2Cl2/rt/1 h, then
2.1 equiv. 2-propenol/2.1 equiv. pyridine/cat. DMAP/CH2Cl2/−20°C to rt/18 h; (ii) 1.5 equiv. NaHMDS/THF/−78°C/20 min, then
2 equiv. (+)-(3)/THF/−78°C/3 h; (iii) cat. Pd(PPh3)4/10 equiv. dimedone/THF/rt/30 min; (iv) 2.1 equiv. NMe4OH/1:1 H2O–acet-
one/−5°C/30 min, dried in vacuo, then 2.1 equiv. EtBr/DME/reflux/5 h.
difluoroalkylphosphonates.19 Herein, we report on the
synthesis of chiral, non-racemic a-hydroxyphospho-
nates utilising the enantioselective oxaziridine-mediated
hydroxylation of phosphoryl stabilised anions intro-
duced by Wiemer et al.,11,20 and employing key diallyl
benzylphosphonates, which are readily deprotected
under neutral conditions21 to afford the corresponding
phosphonic acids in high enantiomeric excess (ee).
phosphoryl-stabilised anions, which were then treated
with (+)-8,8-(dichlorocamphor)sulfonyloxaziridine (+)-3
as has been described,20 to give the chiral, non-racemic
a-hydroxyphosphonates (S)-4a–c and (S)-5a–c, respec-
tively (Scheme 1), in good yields and in high ee (Table
1). The (R)-enantiomers were prepared in an analogous
manner employing oxaziridine (−)-3.
The enantiomeric purity and absolute configuration of
the products was established by the chemical shift
differences of the 31P and H NMR spectral resonances
1
2. Results and discussion
of the (S)-O-methyl mandelate (MMA) derivatised
alcohols as described by Spilling et al.24 Employing the
accepted model for the conformation of the (S)-O-
MMA esters of a-hydroxyphosphonates (Scheme 2),24
the esters derived from (R)-a-hydroxyphosphonates
have the phosphorus atom shielded by the mandelate
phenyl ring and are thus shifted upfield relative to the
(S)-esters (e.g. entries 4 and 7, Table 1). The chemical
shift differences we obtained for the phosphorus atom
of the (S)-O-MMA esters of (S)-4a–c and (S)-5a–c (as
well as their (R)-enantiomers), are in the range 0.4–0.5
ppm (Table 1), in agreement with reported values for
applications of this method,11,24 and confirmed that
oxidations employing the (+)-oxaziridine reagent, (+)-3,
afford the (S)-a-hydroxyphosphonates.20
As part of a study into the asymmetric synthesis of
sialyltransferase inhibitors, we required a series of chi-
ral, non-racemic meta-substituted a-hydroxyben-
zylphosphonates and initially prepared the diethyl
phosphonates (S)-4a–c (Scheme 1) and (R)-4a–c in high
ee, employing the procedure of Pogatchnik and
Wiemer.20 It was apparent, however, that liberation of
the free phosphonic acid may be accompanied by
racemisation11 and thus another phosphonate protect-
ing group was sought. The allyl group, as a protecting
group for phosphonate esters,16 has been used exten-
sively in our group6,17,22 as it can be cleaved under
neutral conditions and thus, the analogous diallyl phos-
phonates (S)-5a–c (Scheme 1) and (R)-5a–c were syn-
thesised, expecting that deprotection of the diallyl
phosphonates could be effected without racemisation.
Deprotection of the diallyl phosphonates (S)-5a–c and
(R)-5a–c using Pd(Ph3)4 in the presence of dimedone as
an allyl scavenger21 gave the desired chiral, non-racemic
phosphonic acids (S)-6a–c and (R)-6a–c, respectively,
in high yields and showing essentially equal but oppo-
site rotations. However, as there are no reported spe-
cific rotation values for either enantiomer of the
phosphonic acids 6b and 6c, the ee values could not be
established from the specific rotation alone. Thus, each
of the (S)-enantiomers of phosphonic acids (S)-6a–c
were converted to their tetramethylammonium salts,
followed by SN2 reaction with ethyl bromide in reflux-
The requisite diethyl benzylphosphonates 1a–c were
readily available from the corresponding benzyl halides
via Arbuzov reaction23 with triethyl phosphite. How-
ever, due to reports of low yielding Arbuzov reactions
using triallyl phosphite, we prepared the desired diallyl
benzylphosphonates 2a–c from the diethyl benzyl phos-
phonates 1a–c via a high-yielding, one-pot, three-step
transesterification procedure (Scheme 1).17 Low-temper-
ature reaction of the benzyl phosphonates 1a–c and
2a–c with NaHMDS in THF generated the requisite

D. Skropeta, R. R. Schmidt / Tetrahedron: Asymmetry 14 (2003) 265–273
267
Table 1. 31P NMR shifts of the (S)-O-MMA esters of a-hydroxyphosphonates (S)-4b,c, (S)-5a–c and (R)-5a
Entry
[h]2D0
R1
R2
(S)-O-MMA esters
31P NMR: l (minor)
Dl
% ee
31P NMR: l (major)
1
2
3
4
5
6
7
(S)-4a
(S)-4b
(S)-4c
(S)-5a
(S)-5b
(S)-5c
(R)-5a
−38
−19
−27
−29
−16
−27
+28
H
Et
Et
Et
All
All
All
All
–
–
–
\99a
86b
98
96
98
OPh
CF3
H
OPh
CF3
H
17.60 (93%)
17.06 (99%)
18.80 (98%)
18.08 (99%)
20.47 (98%)
18.38 (98%)
17.15 (7%)
16.68 (1%)
18.38 (2%)
17.62 (1%)
20.06 (2%)
18.80 (2%)
0.45
0.38
0.42
0.46
0.41
0.42
96
96
a By comparison to reported chiroptical data.
b Analysis of the 1H NMR spectrum gives a value of 90% de.
ing DME,25 to regenerate the diethyl phosphonates
(S)-4a–c, in order to compare their specific rotation
values to those obtained previously (Scheme 1).
corresponding free phosphonic acids ((S)- or (R)-6a–c)
in high ee (90 to >99% ee), via the enantioselective
oxaziridine-mediated hydroxylation11,20 of diallyl ben-
zylphosphonates 2a–c. We expect that this will be a
synthetically valuable method, contributing to further
investigation into the role of a-hydroxyphosphoryl
compounds in biological processes.
The specific rotations obtained for the regenerated
diethyl phosphonates (S)-4a–c were all somewhat lower
than the previous values (cf. entries 1–3 in Table 1 with
entries 1–3 in Table 2). Furthermore, conversion into
1
their corresponding (S)-O-MMA esters and H NMR
spectroscopic analysis gave values for regenerated (S)-
4a–c of 76, 88, and 55% ee, respectively (entries 1–3,
Table 2), based on integration of the methine resonance
of the mandelate component, observed upfield (0.04 to
0.07 ppm24) for esters derived from (R)-a-hydroxyphos-
phonates, relative to the (S)-esters, due to shielding by
the benzyl ring. Similar ee values were obtained by 31P
NMR spectroscopy, as described before (entries 1–3,
Table 2).
4. Experimental
4.1. General
Unless specified otherwise, all reactions were performed
under an inert atmosphere of nitrogen with dry, freshly
distilled solvents under anhydrous conditions and mon-
itored by TLC using plastic plates coated with Merck
Silica Gel 60 F254 and visualised using either UV light
(254 or 366 nm) or a molybdenum staining reagent.28
All compounds were purified by flash chromatography
(FC) as described by Still et al.29 using Merck Silica Gel
60 (particle size 40–63 mm) and the yields given refer to
The high, essentially equal but opposite, specific rota-
tion values of the phosphonic acid enantiomers (S)-
and (R)-6a–c suggested that the loss of enantiomeric
purity occurred during the esterification step26 rather
than the deprotection step. This was confirmed by
conversion of the phosphonic acids (S)-6a–c into their
corresponding methyl phosphonate esters (S)-7a–c via
an alternative procedure employing trimethylsilyldia-
zomethane. In this manner, the specific rotation value
obtained for (S)-7a ([h]2D0=−45 (c 0.8, CHCl3), lit.27
[h]2D0=−46 (c 1.0, acetone)) matched the reported value,
showing a high degree of enantiomeric purity. There
are no reported specific rotations for either enantiomer
of the methyl phosphonates 7b and 7c, and thus the
esters were further derivatised with (S)-O-MMA
(Scheme 2), whereupon analysis of their 1H NMR
spectra revealed for (S)-7a–c values of 90, 94 and >98%
ee, respectively (entries 4–6, Table 2), establishing that
the deprotection of the allyl moiety does indeed proceed
with retention of a very high degree of stereochemical
integrity.
3. Conclusion
We have presented a simple and efficient stereoselective
route that gives rise to both pure a-hydroxyphospho-
nates ((S)- or (R)-4a–c, and (S)- or (R)-5a–c) and their
Scheme 2. (S)-O-Methylmandelate esters of a-hydroxyphos-
phonates.

268
D. Skropeta, R. R. Schmidt / Tetrahedron: Asymmetry 14 (2003) 265–273
Table 2. NMR Shifts of the (S)-O-MMA esters of ‘regenerated’ diethyl a-hydroxyphosphonates (S)-4a–c and dimethyl
a-hydroxyphosphonates (S)-7a–c
Entry
[h]2D0
R1
R2
(S)-O-MMA esters
1H NMR: l (minor)
Dl
% ee
1H NMR: l (major)
1
2
3
4
5
6
(S)-4a
(S)-4b
(S)-4c
(S)-7a
(S)-7b
(S)-7c
−36
−18
−21
−45
−39
−37
H
Et
Et
Et
Me
Me
Me
4.90 (88%)
4.90 (94%)
4.94 (78%)
4.91 (95%)
4.89 (97%)
4.93 (\98%)
4.85 (12%)
4.83 (6%)
4.90 (22%)
4.86 (5%)
4.86 (3%)
4.88 (B2%)
0.05
0.07
0.04
0.05
0.03
0.05
76a
88a
OPh
CF3
H
OPh
CF3
55a
90b
94b
\98b
a By 31P NMR spectroscopy, (S)-4a: 80% ee, (S)-4b: 90% ee, (S)-4c: 55% ee.
b By 31P NMR spectroscopy, (S)-7a: 86% ee, (S)-7b: 94% ee, (S)-7c: >99% ee.
1
chromatographically and spectroscopically (1H NMR)
homogenous material. NMR spectra were recorded on
a Bruker AC 250 Cryospec, a Bruker DRX 600, or a
a colourless oil. H NMR (CDCl3, 250 MHz): l 1.20 (t,
3J=7.2 Hz, 6H, CH2CH3
2H, CH2P), 3.98 (quin., 3J=7.2 Hz, 4H, CH2
6.88–7.32 (m, 9H, ArH); 13C NMR (CDCl3, 63 MHz):
16.3 (d, 3J(C,P)=6.0 Hz, CH2C
H3), 33.7 (d,
1J(C,P)=138.2 Hz), 62.1 (d, 2J(C,P)=6.9 Hz,
H2CH3), 117.3 (d, J(C,P)=3.8 Hz), 119.0, 120.1,
120.2, 123.3, 124.6, 124.7, 129.7, 129.8 (ArCH), 133.5
(ArC), 157.1 (ArCO), 157.4 (ArCO); 31P NMR (CDCl3,
162 MHz): l 26.7 (s, P(O)O2); MALDI-MS (negative
mode, matrix: ATT) m/z=321 ([MH]+, 100%), 343
([MNa]+, 24%), 320.3 for C17H21O4P. Calcd: C, 63.74;
H, 6.61. Found: C, 63.33; H, 6.56%.
6
), 3.07 (d, J(H,P)=21.7 Hz,
CH3),
2
6
1
JEOL JNM-GX 400 instrument, where the solvent H
and 13C signals, lH??7.24 for residual CHCl3 and lC
77.0 for CDCl3, lH 3.31 and lC 49.0 for MeOH-d4, and
lH 4.63 for D2O (a drop of MeOH-d4 was added to
D2O for referencing 13C spectra), were used as internal
references. For 31P NMR spectra, phosphoric acid was
used as an external reference. Matrix-assisted laser des-
orption ionisation mass spectra (MALDI-MS) were
recorded on a Kratos Kompact Maldi 2, using 2,5-
dihydroxybenzoic acid (DHB), hydroxycinnamic acid
(CHCA) or 6-azathiothymine (ATT) as matrices. Opti-
cal rotations were measured on a Buchi polar monitor
in a 1 dm cell at 22°C. Microanalyses were measured on
a Heraeus CHN-O-Rapid apparatus. Reagents, includ-
ing diethylbenzylphosphonate (1a) and both (−)- and
(+)-8,8-(dichlorocamphor)sulfonyloxaziridine, (−)- or
(+)-3, were purchased from either Fluka, Aldrich or
Acros and used as supplied. m-Phenoxybenzylbromide
was prepared and characterised as described in the
literature.30 Ee is assumed equal to the percent de
l
6
C6
4.2.2. Diethyl m-trifluorobenzylphosphonate, 1c. From
m-trifluorobenzylbromide (1.50 g, 6.30 mmol): purifica-
tion by FC (silica gel, 1:1 EtOAc–hexane, Rf=0.2) gave
the known phosphonate 1c (1.81 g, 97% yield) as a
colourless oil.31 1H NMR (CDCl3, 250 MHz): l 1.25 (t,
3J=7.2 Hz, 6H, CH2CH3
6
), 3.18 (d, J(H,P)=21.8 Hz,
2
2H, CH2P), 4.03 (quin., 3J=7.2 Hz, 4H, CH2
6 CH3),
7.41–7.57 (m, 4H, ArH).
1
calculated from integration of the H and 31P NMR
4.3. Preparation of diallyl benzylphosphonates18
spectral signals of the diastereomeric esters formed
from the a-hydroxyphosphonates with (S)-methylman-
delic acid.
TMSBr (3 equiv.) was added to the neat diethyl phos-
phonate (1 equiv.) at 0°C and the reaction stirred for 3
h, after which the excess TMSBr and the nascent ethyl
bromide were removed by evaporation. The crude
4.2. Preparation of diethyl benzylphosphonates via the
Michealis–Arbuzov rearrangement23
bis(trimethylsilyl)phosphonate
was
diluted
with
dichloromethane (10 mL), and 4 drops of DMF were
added followed by the dropwise addition of oxalyl
chloride (3 equiv.), resulting in the vigorous evolution
of gas (CO, CO2). The reaction mixture was stirred at rt
for 1 h, after which the volatile by-products (TMSCl,
CO, CO2 and excess oxalyl chloride) were removed by
rotary evaporation. The crude dichlorophosphonate
was diluted with dichloromethane (5 mL), and added to
a flask containing 2-propenol (2.1 equiv.), pyridine (2.1
equiv.), and 2 drops of DMAP in dichloromethane (10
mL), previously stirred together for 30 min at −10°C
(salt/ice bath). The reaction mixture was stirred at
−20°C for 1 h and then allowed to warm to rt and
stirred overnight. The excess reactants were then
removed by rotary evaporation followed by concentra-
tion under high vacuum and the residue purified by FC
to give the desired diallyl phosphonates.
Triethylphosphite (1–3 equiv.) was added slowly via a
dropping funnel to a two-necked round-bottomed flask
fitted with a condenser and containing 1 equiv. of the
neat benzylbromide. The mixture was heated to reflux
and maintained at this temperature until the reaction
was complete as judged by TLC, typically 1–3 h. The
reflux condenser was replaced with a fractionating
column and distillation head and the nascent ethyl
bromide removed by distillation. The residue was
purified by FC to give the desired diethyl benzylphos-
phonates in quantitative yield.
4.2.1. Diethyl m-phenoxybenzylphosphonate, 1b. From
m-phenoxybenzylbromide30 (15.3 g, 58.0 mmol): purifi-
cation by FC (silica gel, 1:1 EtOAc–hexane, Rf=0.3)
gave the desired phosphonate 1b (18.2 g, 98% yield) as

D. Skropeta, R. R. Schmidt / Tetrahedron: Asymmetry 14 (2003) 265–273
269
4.3.1. Diallyl benzylphosphonate, 2a. From 1a (1.73 g,
7.58 mmol): purification by FC (silica gel, 8:2 CH2Cl2–
acetone, Rf=0.5) gave the known phosphonate 2a (1.37
g, 72% yield) as a colourless oil.32 1H NMR (CDCl3,
benzylphosphonate (1 equiv.) in THF (10 mL) at −78°C
and the yellow coloured solution stirred for 30 min. A
solution of the oxaziridine reagent (+)- or (−)-3 (2
equiv.) in THF (10 mL) was added dropwise via syringe
and the reaction stirred for a further 3 h, while the
temperature was maintained at −78°C (dry ice–acetone
bath). The reaction was quenched at −78°C by the
addition of saturated NH4Cl, brought to rt, extracted
several times with ethyl acetate, the combined organic
fractions washed with saturated NH4Cl, followed by
saturated NaHCO3 and brine, dried (MgSO4), filtered
and the residue purified by FC to give the desired
a-hydroxyphosphonates.
2
250 MHz): l 3.18 (d, J(H,P)=21.7 Hz, 2H, CH2P),
3
4.38–4.46 (m, 4H, H1%), 5.18 (dq, J3b%,2%)=10.4 Hz,
2J(3b%,3a%):3J(3b%,1%)=1.5 Hz, 2H, H3b%), 5.25 (dq,
2
3J(3a%,2%)=17.2 Hz, J(3a%,3b%):3J(3a%,1%)=1.5 Hz, 2H,
H3a%), 5.83 (ddt, 3J(2%,3a%)=17.2 Hz, 3J(2%,3b%)=10.4
Hz, 3J(2%,1%)=5.5 Hz, 2H, H2%), 7.20–7.34 (m, 5H,
ArH).
4.3.2. Diallyl m-phenoxybenzylphosphonate, 2b. From
1b (3.48 g, 10.9 mmol): purification by FC (silica gel,
3:1 EtOAc–hexane, Rf=0.6) gave the desired phospho-
4.4.1. Diethyl (S)-a-hydroxybenzylphosphonate, (S)-4a.
From 1a (100 mg, 0.44 mmol) and employing
oxaziridine (+)-(3): purification by FC (silica gel, 8:2
CH2Cl2–acetone, Rf=0.3) gave the known phosphonate
(S)-4a (47.9 mg, 45% yield, [h]2D0=−38 (c 1.3 CHCl3),
lit.33 [h]D20=−38 (c 2.7, CHCl3), >99% ee) as a colourless
oil with spectroscopic data identical to those reported.33
1
nate 2b (1.87 g, 50% yield) as a colourless oil. H NMR
2
(CDCl3, 250 MHz): l 3.15 (d, J(H,P)=21.8 Hz, 2H,
3
CH2P), 4.41–4.48 (m, 4H, H1%), 5.18 (dq, J(3b%,2%)=
10.4 Hz, 2J(3b%,3a%):3J(3b%,1%)=1.5 Hz, 2H, H3b%),
5.27 (dq, 3J(3a%,2%)=17.1 Hz, 2J(3a%,3b%):3J(3a%,1%)=
1.5 Hz, 2H, H3a%), 5.87 (ddt, 3J(2%,3a%)=17.1 Hz,
3
1
3J(2%,3b%)=10.4 Hz, J(2%,1%)=5.6 Hz, 2H, H2%), 6.87–
For the (S)-O-MMA ester of (S)-4a: H NMR (CDCl3,
7.35 (m, 9H, ArH); 13C NMR (CDCl3, 63 MHz): l 33.8
250 MHz): l 1.14 (t, J=7.1 Hz, 3H, CH2CH3
6
), 1.19 (t,
2
(1J(C,P)=137.8 Hz, CHP), 66.6 (d, J(C,P)=6.0 Hz,
J=7.1 Hz, 3H, CH2CH6 3), 3.41 (s, 3H, OMe), 3.81–4.13
C1%), 117.4 (d, J(C,P)=2.0 Hz), 117.9, 119.0,‡ 120.2 (d,
J(C,P)=6.8 Hz), 123.4,‡ 124.5 (d, J(C,P)=6.6 Hz),
129.7, 129.8 (d, J(C,P)=3.0 Hz), 132.9 (d, J(C,P)=6.8
Hz), 133.2 (ArCH, ArC, C3% and C2%), 157.0 (2×ArCO);
31P NMR (CDCl3, 162 MHz): l 30.5 (s, P(O)O2);
MALDI-MS (positive mode, matrix: DHB) m/z=345
([MH]+, 100%), 367 ([MNa]+, 42), 344.3 for C19H21O4P.
Calcd: C, 66.27; H, 6.15. Found: C, 65.73; H, 6.13%.
(m, 4H, CH6 2CH3), 4.90 (s, 1H, CH[OMe]), 6.13 (d,
2J(H,P)=13.3 Hz, 1H, CHP), 7.12–7.42 (m, 5H, ArH).
4.4.2. Diethyl (S)-a-hydroxy(m-phenoxy)benzylphos-
phonate, (S)-4b. From 1b (70.0 mg, 0.22 mmol) and
employing oxaziridine (+)-(3): purification by FC (silica
gel, 3:2 EtOAc–hexane, Rf=0.3) gave the desired phos-
phonate (S)-4b (18.6 mg, 25% yield, [h]2D0=−19 (c 1.0,
CHCl3)) as a colourless oil with spectroscopic data
identical to those reported for its racemate.34 For the
(S)-O-MMA ester of (S)-4b: 1H NMR (CDCl3, 600
4.3.3. Diallyl m-trifluorobenzylphosphonate, 2c. From 1c
(6.33 g, 21.4 mmol): purification by FC (silica gel, 3:1
EtOAc–hexane, Rf=0.6) gave the desired phosphonate
2c (3.29 g, 48% yield) as a colourless oil. 1H NMR
MHz): l 1.18 (t, J=7.1 Hz, 3H, CH2CH3
J=7.1 Hz, 3H, CH2CH3), 3.41 (s, 3H, OMe), 3.95–4.05
(m, 4H, CH
6 ), 1.21 (t,
6
2
(CDCl3, 250 MHz): l 3.23 (d, J(H,P)=21.9 Hz, 2H,
6 2CH3), 4.90 (s, 1H, CH[OMe]), 6.12 (d,
3
CH2P), 4.42–4.48 (m, 4H, H1%), 5.19 (dq, J(3b%,2%)=
2J(H,P)=13.5 Hz, 1H, CHP), 6.83 (s, 1H, ArH), 6.91–
6.92 (m, 4H, ArH), 7.10 (m, 1H, ArH), 7.16 (m, 1H,
ArH), 7.26–7.32 (m, 5H, ArH), 7.38 (m, 2H, ArH), 90%
ee; 31P NMR (CDCl3, 245 MHz): l 17.60 (s, P(O)O2,
86% ee).
10.4 Hz, 2J(3b%,3a%):3J(3b%,1%)=1.5 Hz, 2H, H3b%),
5.26 (dq, 3J(3a%,2%)=17.2 Hz, 2J(3a%,3b%):3J(3a%,1%)=
1.5 Hz, 2H, H3a%), 5.84 (ddt, 3J(2%,3a%)=17.2 Hz,
3
3J(2%,3b%)=10.4 Hz, J(2%,1%)=5.3 Hz, 2H, H2%), 7.42–
7.52 (m, 4H, ArH); 13C NMR (CDCl3, 63 MHz): l 33.7
2
(1J(C,P)=138.7 Hz, CH2P), 66.5 (d, J(C,P)=6.4 Hz,
4.4.3. Diethyl (R)-a-hydroxy(m-phenoxy)benzylphos-
phonate, (R)-4b. From 1b (114 mg, 0.35 mmol) and
employing oxaziridine (−)-3: purification by FC (silica
gel, 3:2 EtOAc–hexane, Rf=0.3) gave the desired phos-
phonate (R)-4b (54.2 mg, 46% yield, [h]2D0=+17 (c 1.2,
CHCl3)) as a colourless oil with spectroscopic data
identical to those of its enantiomer, (S)-4b. For the
(S)-O-MMA ester of (R)-4b: 1H NMR (CDCl3, 250
MHz): l 1.02, 1.06 (overlapping t, J=7.1 Hz, 6H,
C1%), 118.0 (s, C3%), 123.7 (bs, ArCH), 123.9 (q,
1J(C,F)=272.4.0 Hz, CF3), 126.5 (bs, ArCH), 128.9 (s,
2
C2%), 130.9 (q, J(C,F)=32.0 Hz, ArC
6
-CF3), 132.5 (s,
ArC), 132.6 (d, J(C,F)=5.8 Hz, ArCH), 133.1 (d,
J(C,F)=6.1 Hz, ArCH); 31P NMR (CDCl3, 162 MHz):
l 29.5 (s, P(O)O2); MALDI-MS (positive mode, matrix:
DHB) m/z=321 ([MH]+, 100%), 343 ([MNa]+, 14),
320.1 for C14H16F3O3P. Calcd: C, 52.51; H, 5.04.
Found: C, 52.65; H, 5.32%.
CH2CH3
6 ), 3.37 (s, 3H, OMe), 3.53–3.92 (m, 4H,
2
CH2CH3), 4.83 (s, 1H, CH[OMe]), 6.09 (d, J(H,P)=
6
4.4. Preparation of chiral, non-racemic a-hydroxy-
benzylphosphonates
13.2 Hz, 1H, CHP), 6.90–7.48 (m, 14H, ArH).
4.4.4. Diethyl (S)-a-hydroxy(m-trifluoro)benzylphos-
phonate, (S)-4c. From 1c (116 mg, 0.39 mmol) and
employing oxaziridine (+)-(3): purification by FC (silica
gel, 3:1 EtOAc–hexane, Rf=0.2) gave the desired phos-
phonate (S)-4c (59.3 mg, 45% yield, [h]2D0=−27 (c 2.4,
CHCl3)) as a colourless oil, the racemate of which has
According to the reported procedure,11,20 NaHMDSA
(1.5 equiv.) was added dropwise to a solution of the
‡ Coincident peaks.

270
D. Skropeta, R. R. Schmidt / Tetrahedron: Asymmetry 14 (2003) 265–273
been reported.35 1H NMR (CDCl3, 250 MHz): l 1.22 (t,
J=7.1 Hz, 3H, CH2CH3), 1.25 (t, J=7.1 Hz, 3H,
CH2CH3), 4.05 (quin., J=7.1 Hz, 4H, CH2CH3), 4.33
(brs, 1H, OH), 5.08 (brd, J(H,P)=10.6 Hz, 1H, CHP),
7.40–7.78 (m, 4H, ArH). For the (S)-O-MMA ester of
(S)-4c: 1H NMR (CDCl3, 600 MHz): l 1.19, 1.21
as a colourless oil with spectroscopic data identical to
6
those of its enantiomer, (S)-5a. For the (S)-O-MMA
1
6
6
ester of (R)-5a: H NMR (CDCl3, 250 MHz): l 3.40 (s,
2
3H, OMe), 3.98 (m, 1H, Ha-1%), 4.20 (m, 1H, Hb-1%),
4.25–4.30 (m, 2H, H1%), 4.88 (s, 1H, CH[OMe]), 5.09–
5.16 (m, 4H, H3%), 5.63–5.66 (m, 2H, H2%), 6.18 (d,
2J(H,P)=13.1 Hz, 1H, CHP), 7.34–7.37 (m, 6H, ArH),
7.47–7.50 (m, 4H, ArH); 31P NMR (CDCl3, 162 MHz):
l 18.38 (s, P(O)O2, 96% ee).
(overlapping t, J=7.1 Hz, 6H, CH2CH3
6
), 3.43 (s, 3H,
OMe), 3.97–4.07 (m, 4H, CH2
6 CH3), 4.94 (s, 1H,
CH[OMe]), 6.16 (d, 2J(H,P)=13.8 Hz, 1H, CHP), 7.32–
7.37 (m, 8H, ArH), 7.40 (m, 1H, ArH); 31P NMR
(CDCl3, 245 MHz): l 17.06 (s, P(O)O2, 98% ee).
4.4.8. Diallyl (S)-a-hydroxy(m-phenoxy)benzylphos-
phonate, (S)-5b. From 2b (1.16 mg, 3.37 mmol) and
employing oxaziridine (+)-(3): purification by FC (silica
gel, 3:1 EtOAc–hexane, Rf=0.4) gave the desired phos-
phonate (S)-5b (559 mg, 46% yield, [h]2D0=−16 (c 0.9,
4.4.5. Diethyl (R)-a-hydroxy(m-trifluoro)benzylphos-
phonate, (R)-4c. From 1c (131 mg, 0.44 mmol) and
employing oxaziridine (−)-(3): purification by FC (silica
gel, 3:1 EtOAc–hexane, Rf=0.2) gave the desired phos-
phonate (R)-4c (64.4 mg, 47% yield, [h]2D0=+25 (c 0.4,
CHCl3)) as a colourless oil with spectroscopic data
identical to those of its enantiomer, (S)-4c. For the
(S)-O-MMA ester of (R)-4c: 1H NMR (CDCl3, 600
MHz): l 1.07, 1.10 (overlapping t, J=7.1 Hz, 6H,
1
CHCl3)) as a pale yellow oil. H NMR (CDCl3, 250
MHz): l 4.33–4.58 (m, 5H, H1% and OH), 5.01 (d,
2J(H,P)=10.6 Hz, 1H, CHP), 5.15–5.33 (m, 4H, H3%),
5.73–5.95 (m, 2H, H2%), 6.90–7.36 (m, 9H, ArH); 13C
2
NMR (CDCl3, 63 MHz): l 67.3 (d, J(C,P)=7.2 Hz,
C1%), 67.7 (d, 2J(C,P)=6.9 Hz, C1%), 70.7 (1J(C,P)=
158.9 Hz, CHP), 117.7 (d, J(C,P)=8.9 Hz, ArCH),
CH2CH3
CH2CH3), 3.85 (m, 2H, CH2
CH2CH3), 4.90 (s, 1H, CH[OMe]), 6.17 (d, J(H,P)=
6
), 3.41 (s, 3H, OMe), 3.67 (m, 1H, Ha of
4
6
6
CH3), 3.92 (m, 1H, Hb of
118.1 (d, J(C,P)=4.7 Hz, C3%), 118.5 (d, J(C,P)=3.6
2
6
Hz), 118.9, 122.0 (d, J(C,P)=5.8 Hz), 123.3,‡ 129.5 (d,
J(C,P)=2.3 Hz), 129.7,‡ 132.6 (d, J(C,P)=5.8 Hz,
ArCH and C2%), 138.5 (ArC), 157.1 (ArCO), 157.2
(ArCO); 31P NMR (CDCl3, 162 MHz): l 22.4 (s,
P(O)O2); MALDI-MS (positive mode, matrix: DHB)
m/z=361 ([MH]+, 100%), 383 ([MNa]+, 72), 360.3 for
C19H21O5P. Calcd: C, 63.33; H, 5.87. Found: C, 62.81;
H, 5.83%. For the (S)-O-MMA ester of (S)-5b: 1H
NMR (CDCl3, 250 MHz): l 3.38 (s, 3H, OMe), 4.28–
4.50 (m, 4H, H1%), 4.87 (s, 1H, CH[OMe]), 5.10–5.28
(m, 4H, H3%), 5.67–5.85 (m, 2H, H2%), 6.12 (d,
2J(H,P)=13.5 Hz, 1H, CHP), 6.78–7.39 (m, 14H,
ArH); 31P NMR (CDCl3, 245 MHz): l 18.08 (s,
P(O)O2, 98% ee).
13.6 Hz, 1H, CHP), 7.35–7.39 (m, 3H, ArH), 7.45–7.51
(m, 3H, ArH), 7.51 (m, 1H, ArH), 7.63 (m, 1H, ArH),
7.68 (m, 1H, ArH); 31P NMR (CDCl3, 245 MHz): l
16.68 (s, P(O)O2, 98% ee).
4.4.6. Diallyl (S)-a-hydroxybenzylphosphonate, (S)-5a.
From 2a (613 mg, 2.43 mmol) and employing
oxaziridine (+)-(3): purification by FC (silica gel, 8:2
CH2Cl2–acetone, Rf=0.4) gave the desired phospho-
nate (S)-5a (236 mg, 36% yield, [h]2D0=−29 (c 1.0,
CHCl3)) as a colourless oil. 1H NMR (CDCl3, 250
MHz): l 4.31–4.54 (m, 5H, H1% and OH), 5.04 (dd,
2
J(H,OH)=4.9, J(H,P)=10.9 Hz, 1H, CHP), 5.12–5.30
(m, 4H, H3%), 5.73–5.93 (m, 2H, H2%), 7.27–7.37 (m, 3H,
m- and p-ArH), 7.43–7.50 (m, 2H, o-ArH); 13C NMR
4.4.9. Diallyl (R)-a-hydroxy(m-phenoxy)benzylphos-
phonate, (R)-5b. From 2b (764 mg, 2.22 mmol) and
employing oxaziridine (−)-(3): purification by FC (silica
gel, 3:1 EtOAc–hexane, Rf=0.4) gave the desired phos-
phonate (R)-5b (338 mg, 42% yield, [h]2D0=+17 (c 1.3,
CHCl3)) as a pale yellow oil with spectroscopic data
identical to those of its enantiomer, (S)-5b. For the
(S)-O-MMA ester of (R)-5b: 1H NMR (CDCl3, 250
MHz): l 3.36 (s, 3H, OMe), 3.92–4.35 (m, 4H, H1%),
4.82 (s, 1H, CH[OMe]), 5.05–5.18 (m, 4H, H3%), 5.54–
5.70 (m, 2H, H2%), 6.13 (d, 2J(H,P)=13.8 Hz, 1H,
CHP), 6.88–7.45 (m, 14H, ArH); 31P NMR (CDCl3,
245 MHz): l 17.62 (s, P(O)O2, 98% ee).
2
(CDCl3, 63 MHz): l 67.3 (d, J(C,P)=7.0 Hz, C1%),
67.6 (d, 2J(C,P)=6.9 Hz, C1%), 70.8 (1J(C,P)=159.5
4
Hz, CHP), 117.9 (d, J(C,P)=3.2 Hz, C3%), 127.2‡ (d,
J(C,P)=5.9 Hz, ArCH), 128.0 (d, J(C,P)=3.5 Hz,
ArCH), 128.1‡ (d, J(C,P)=2.1 Hz, ArCH), 132.7 (d,
3J(C,P)=5.9 Hz, C2%), 136.5 (d, 2J(C,P)=2.0 Hz, ArC);
31P NMR (CDCl3, 162 MHz): l 26.2 (s, P(O)O2);
MALDI-MS (positive mode, matrix: DHB) m/z=269
([MH]+, 100%), 273 ([M−H2O+Na]+, 30), 279 (26), 291
([MNa]+, 24), 268.2 for C13H17O4P. Calcd: C, 58.21; H,
6.39. Found: C, 58.06; H, 6.23%. For the (S)-O-MMA
1
ester of (S)-5a: H NMR (CDCl3, 600 MHz): l 3.42 (s,
3H, OMe), 4.36 (m, 2H, H1%), 4.44 (m, 2H, H1%), 4.91
(s, 1H, CH[OMe]), 5.15–5.27 (m, 4H, H3%), 5.78 (m,
2H, H2%), 6.18 (d, J(H,P)=13.3 Hz, 1H, CHP), 7.14–
7.20 (m, 5H, ArH), 7.32–7.33 (m, 3H, m- and p-ArH),
7.39–7.40 (m, 2H, o-ArH); 31P NMR (CDCl3, 245
MHz): l 18.80 (s, P(O)O2, 96% ee).
4.4.10. Diallyl (S)-a-hydroxy(m-trifluoro)benzylphos-
phonate, (S)-5c. From 2c (799 mg, 2.49 mmol) and
employing oxaziridine (+)-(3): purification by FC (silica
gel, 7:3 CH2Cl2–acetone, Rf=0.6) gave the desired
phosphonate (S)-5c (349 mg, 42% yield, [h]2D0=−27 (c
2
1
2.8, CHCl3)) as a colourless oil. H NMR (CDCl3, 250
4.4.7. Diallyl (R)-a-hydroxybenzylphosphonate, (R)-5a.
From 2a (748 mg, 3.00 mmol) and employing
oxaziridine (−)-(3): purification by FC (silica gel, 3:1
EtOAc–hexane, Rf=0.4) gave the desired phosphonate
(R)-5a (380 mg, 48% yield, [h]2D0=+28 (c 0.7, CHCl3))
MHz): l 4.44–4.53 (m, 4H, H1%), 5.10 (dd, J(H,OH)=
5.7, J(H,P)=11.3 Hz, 1H, CHP), 5.16–5.33 (m, 5H,
2
H3% and OH), 5.72–5.92 (m, 2H, H2%), 7.40–7.78 (m,
4H, ArH); 13C NMR (CDCl3, 63 MHz): l 67.4 (d,
2
2J(C,P)=7.2 Hz, C1%), 67.9 (d, J(C,P)=6.9 Hz, C1%),

D. Skropeta, R. R. Schmidt / Tetrahedron: Asymmetry 14 (2003) 265–273
271
70.3 (1J(C,P)=159.6 Hz, CHP), 118.4 (s, C3%), 124.0
(bs, ArCH), 130.7 (q, J(C,F)=258.6 Hz, CF3), 124.8
For further characterisation and storage, the phospho-
nic acid (R)-6a was subjected to ion exchange (IR 120
Na+), followed by precipitation from EtOH and
lyophilisation from water, which gave the known di-
sodium salt of (R)-6a (21.9 mg, 52% yield, [h]2D0=+21 (c
0.4, 3:1 MeOH–H2O)), lit.37 [h]D20=+27 (c 0.2, H2O)).
1
(bs, ArCH), 128.6 (s, C2%), 130.3 (d, J(C,F)=5.2 Hz,
2
ArCH), 130.7 (q, J(C,F)=29.2 Hz, ArC
6
-CF3), 132.5
(d, J(C,F)=5.8 Hz, ArCH), 137.7 (s, ArC); 31P NMR
(CDCl3, 162 MHz): l 24.84 (s, P(O)O2); MALDI-MS
(positive mode, matrix: DHB) m/z=337 ([MH]+,
100%), 359 ([MNa]+, 74), 336.1 for C14H16F3O4P.
Calcd: C, 50.01; H, 4.80. Found: C, 50.32; H, 5.50%.
4.5.3. (S)-a-Hydroxy(m-phenoxy)benzylphosphonic acid,
(S)-6b. From (S)-5b (38.1 mg, 0.11 mmol):§ purification
by RP FC (C18 silica gel, 1:3 EtOH–H2O, Rf=0.3) gave
the known phosphonic acid38 (S)-6a (15.1 mg, 51%
1
For the (S)-O-MMA ester of (S)-5c: H NMR (CDCl3,
250 MHz): l 3.39 (s, 3H, OMe), 4.32–4.52 (m, 4H,
H1%), 4.91 (s, 1H, CH[OMe]), 5.15–5.27 (m, 4H, H3%),
1
yield) as a colourless amorphous solid, H NMR (D2O,
2
5.68–5.83 (m, 2H, H2%), 6.19 (d, J(H,P)=13.9 Hz, 1H,
250 MHz): l 4.53 (d, 2J(H,P)=12.9 Hz, 1H, CHP),
6.52–7.18 (m, 9H, ArH). For further characterisation
and storage, the remaining phosphonic acid (S)-6a not
employed in subsequent reactions was subjected to ion
exchange (IR 120 Na+), followed by precipitation from
EtOH and lyophilisation from water, which gave the
desired sodium salt of (S)-6b ([h]2D0=−22 (c 0.2, H2O)).
CHP), 7.28–7.51 (m, 9H, ArH); 31P NMR (CDCl3, 162
MHz): l 20.47 (s, P(O)O2, 96% ee).
4.4.11. Diallyl (R)-a-hydroxy(m-trifluoro)benzylphos-
phonate, (R)-5c. From 2c (907 mg, 2.83 mmol) and
employing oxaziridine (−)-(3): purification by FC (silica
gel, 7:3 CH2Cl2–acetone, Rf=0.6) gave the desired
phosphonate (R)-5c (453 mg, 45% yield, [h]2D0=+25 (c
2.7, CHCl3)) as a colourless oil with spectroscopic data
identical to those of its enantiomer, (S)-5c. For the
(S)-O-MMA ester of (R)-5c: 1H NMR (CDCl3, 250
MHz): l 3.38 (s, 3H, OMe), 3.95–4.48 (m, 4H, H1%),
4.88 (s, 1H, CH[OMe]), 5.07–5.20 (m, 4H, H3%), 5.56–
5.73 (m, 2H, H2%), 6.18 (d, 2J(H,P)=13.8 Hz, 1H,
CHP), 7.37–7.70 (m, 9H, ArH); 31P NMR (CDCl3, 162
MHz): l 20.06 (s, P(O)O2, 96% ee).
1
Sodium salt of (S)-6b: H NMR (D2O, 250 MHz): l
4.47 (d, 2J(H,P)=12.2 Hz, 1H, CHP), 6.69–7.28 (m,
9H, ArH); 13C NMR (D2O, 63 MHz): l 72.8 (d,
1J(C,P)=152.3 Hz, CHP), 118.4, 118.6, 119.9,‡ 123.4,
124.8, 130.7, 131.0‡ (ArCH), 142.7, 157.5, 157.7 (ArC);
31P NMR (CDCl3, 245 MHz): l 19.8 (s, P(O)O2, 98%
ee). MALDI-MS (positive mode, matrix: DHB) m/z=
347 ([MNa]+, 100%), 324.2 for C13H11Na2O5P.
4.5.4. (R)-a-Hydroxy(m-phenoxy)benzylphosphonic acid,
(R)-6b. From (R)-5b (174 mg, 0.48 mmol): purification
by RP FC (C18 silica gel, 1:3 EtOH–H2O, Rf=0.3) gave
the desired phosphonic acid (R)-6b (135 mg, quantita-
tive yield) as a colourless amorphous solid with spectro-
scopic data identical to those of its enantiomer, (S)-6b.
For further characterisation and storage, the phospho-
nic acid (R)-6b was subjected to ion exchange (IR 120
Na+), followed by precipitation from EtOH and
lyophilisation from water, which gave the desired
sodium salt of (R)-6b (15.1 mg, 32% yield, [h]2D0=+20 (c
0.1, 50% aq. DMSO)), as a colourless lyophilisate with
spectroscopic data identical to those of its enantiomer,
(S)-6b.
4.5. Deprotection of the diallyl a-hydroxybenzyl-
phosphonates
To a solution of the diallyl a-hydroxyphosphonates (1
equiv.) in THF (10 mL) at rt, dimedone (10 equiv.) was
added, the flask covered with foil and Pd(PPh3)4 (0.2
equiv.) added. The reaction was stirred at rt for 30 min,
concentrated and purified by RP FC to give the free
phosphonic acids.
4.5.1. (S)-a-Hydroxybenzylphosphonic acid, (S)-6a.
From (S)-5a (50.0 mg, 0.19 mmol): purification by RP
FC (C18 silica gel, 1:3 EtOH–H2O, Rf=0.9) gave the
known phosphonic acid (S)-6a (35.7 mg, 100% yield) as
a colourless amorphous solid, with spectroscopic data
identical to those reported for its racemate.36 For fur-
ther characterisation and storage, the remaining phos-
phonic acid (S)-6a not employed in subsequent
reactions was subjected to ion exchange (IR 120 Na+),
followed by precipitation from EtOH and lyophilisation
from water, which gave the known disodium salt of
(S)-6a ([h]2D0=−23 (c 0.4, 3:1 MeOH–H2O).37
4.5.5. (S)-a-Hydroxy(m-trifluoro)benzylphosphonic acid,
(S)-6c. From (S)-5c (142 mg, 0.43 mmol): purification
by RP FC (C18 silica gel, 1:3 EtOH–H2O, Rf=0.4) gave
the desired phosphonic acid (S)-6c (70.3 mg, 65% yield)
1
as a colourless amorphous solid, H NMR (D2O, 250
2
MHz): l 4.78 (d, J(H,P)=12.0 Hz, 1H, CHP), 7.47
(m, 2H, ArH), 7.72–7.88 (m, 2H, ArH). For further
characterisation and storage, the remaining phosphonic
acid (S)-6c not employed in subsequent reactions was
subjected to ion exchange (IR 120 Na+), followed by
precipitation from EtOH and lyophilisation from water,
which gave the desired sodium salt of (S)-6c ([h]2D0=−16
4.5.2. (R)-a-Hydroxybenzylphosphonic acid, (R)-6a.
From (R)-5a (47.5 mg, 0.18 mmol): purification by RP
FC (C18 silica gel, 1:3 EtOH–H2O, Rf=0.9) gave the
desired phosphonic acid (R)-6a (33.9 mg, quantitative
yield) as a colourless amorphous solid with spectro-
scopic data identical to those of its enantiomer, (S)-6a.
1
(c 1.1, 1:3 acetone–H2O)). Sodium salt of (S)-6c: H
2
NMR (D2O, 250 MHz): l 4.70 (d, J(H,P)=12.7 Hz,
1H, CHP), 7.30–7.64 (m, 4H, ArH); 13C NMR (D2O,
1
245 MHz): l 73.1 (d, J(C,P)=148.4 Hz, CHP), 124.6
1
(ArCH), 124.8 (ArCH), 125.3 (q, J(C,P)=271.8 Hz,
2
CF3), 129.6 (ArCH), 130.7 (q, J(C,P)=33.2 Hz, ArC
6
-
CF3), 131.6 (ArCH), 142.0 (ArC); 31P NMR (CDCl3,
§ Dimedone was replaced with diisopropylamine to assist purification.
245 MHz): l 16.4 (s, P(O)O2). MALDI-MS (positive

272
D. Skropeta, R. R. Schmidt / Tetrahedron: Asymmetry 14 (2003) 265–273
mode, matrix: DHB) m/z=301 ([MH]+, 64%), 279 ([M−
Na+2H]+, 36%); MALDI-MS (negative mode, matrix:
ATT) m/z=255 ([M−2Na+H]−, 100%), 300.1 for
C8H6F3Na2O4P.
4.7. Determination of the ee of deprotection products
through preparation of dimethyl phosphonates
To a solution of the phosphonic acids (1 equiv.) in
MeOH–benzene (1:3, 4 mL), TMSCHN2 (2.6 equiv.)
was added and the reaction mixture stirred at rt for 30
min, then concentrated under reduced pressure and the
residue purified by FC to give the desired dimethyl
phosphonates in good yield.
4.5.6. (R)-a-Hydroxy(m-trifluoro)benzylphosphonic acid,
(R)-6c. From (R)-5c (89.8 mg, 0.27 mmol): purification
by RP FC (C18 silica gel, 1:3 EtOH–H2O, Rf=0.4) gave
the desired phosphonic acid (R)-6c (37.5 mg, 55% yield)
as a white amorphous solid with spectroscopic data
identical to those of its enantiomer, (S)-6c. For further
characterisation and storage, the phosphonic acid (R)-
6c was subjected to ion exchange (IR 120 Na+), fol-
lowed by precipitation from EtOH and lyophilisation
from water, which gave the desired sodium salt of
(R)-5c ([h]2D0=+15 (c 1.2, 1:3 acetone–H2O)), as a
colourless lyophilisate with spectroscopic data identical
to those of its enantiomer, (S)-6c.
4.7.1. Dimethyl (S)-a-hydroxybenzylphosphonate, (S)-
7a. From (S)-6a (30.2 mg, 0.16 mmol): purification by
FC (silica gel, 3:1 EtOAc–hexane, Rf=0.3) gave the
known phosphonate (S)-7a (20.1 mg, 58% yield, [h]2D0=
−45 (c 0.8, CHCl3), lit.27 [h]2D0=−46 (c 1.0, acetone)), as
colourless crystalline material, with spectroscopic data
identical to those reported. For the (S)-O-MMA ester
1
of (S)-7a: H NMR (CDCl3, 250 MHz): l 3.40 (s, 3H,
3
OMe), 3.58 (d, J(H,P)=10.6 Hz, 3H, OMe), 3.60 (d,
3J(H,P)=10.7 Hz, 3H, OMe), 4.91 (s, 1H, CH[OMe]),
6.16 (d, 2J(H,P)=13.3 Hz, 1H, CHP), 7.10–7.44 (m,
10H, ArH), 90% ee. 31P NMR (CDCl3, 245 MHz): l
18.00 (s, P(O)O2, 86% ee).
4.6. Regeneration of the diethyl phosphonates
To a freshly prepared solution of the free phosphonic
acid in of 1:1 acetone–H2O (2 mL), a 5% aq. solution of
tetramethylammonium hydroxide (2 equiv.) was added
dropwise, while the reaction mixture was maintained at
−5 to −10°C (salt/ice-bath). The reaction mixture was
stirred for 30 min and thereafter, the solvent removed
by rotary evaporation at <40°C and the residue dried in
vacuo overnight. Ethyl bromide (2 equiv.) was then
added to a solution of the tetramethylammonium salts
in DME (5 mL) and the mixture refluxed for 5 h,
cooled, filtered, the filtrate concentrated and the residue
purified by FC to give the desired diethyl
phosphonates.
4.7.2. Dimethyl (S)-a-hydroxy(m-phenoxy)benzylphos-
phonate, (S)-7b. From (S)-6b (46.5 mg, 0.17 mmol):
purification by FC (silica gel, 3:1 EtOAc–hexane, Rf=
0.3) gave the phosphonate (S)-7b (29.2 mg, 57% yield,
[h]2D0=−39 (c 0.9, CHCl3)), as colourless crystalline
material with spectroscopic data identical to those
reported for its racemate.34 For the (S)-O-MMA ester
1
of (S)-7b: H NMR (CDCl3, 250 MHz): l 3.39 (s, 3H,
3
OMe), 3.51 (d, J(H,P)=10.7 Hz, 3H, OMe), 3.62 (d,
3J(H,P)=10.7 Hz, 3H, OMe), 4.89 (s, 1H, CH[OMe]),
6.13 (d, 2J(H,P)=13.3 Hz, 1H, CHP), 6.78–7.40 (m,
14H, ArH), 94% ee. 31P NMR (CDCl3, 245 MHz): l
17.57 (s, P(O)O2, 94% ee).
4.6.1. Diethyl (−)-(S)-a-hydroxybenzylphosphonate, (S)-
4a. From (S)-6a (21.8 mg, 0.12 mmol): purification by
FC (silica gel, 3:1 EtOAc–hexane, Rf=0.3) gave phos-
phonate (S)-4a (13.1 mg, 46% yield, [h]2D0=−36 (c 0.5,
CHCl3)), as a colourless oil. Esterification of (S)-4a
with (S)-O-MMA and analysis as described previously
4.7.3. Dimethyl (S)-a-hydroxy(m-trifluoro)benzylphos-
phonate, (S)-7c. From (S)-6c (20.7 mg, 80.8 mmol):
purification by FC (silica gel, 3:1 EtOAc–hexane, Rf=
0.3) gave phosphonate (S)-7c (11.4 mg, 57% yield,
[h]2D0=−37 (c 0.6, CHCl3)), as colourless crystalline
material. 1H NMR (CDCl3, 250 MHz): l 3.72 (d,
2J(H,P)=10.1 Hz, 6H, OMe), 4.20 (m, 1H, OH), 5.12
(d, 2J(H,P)=11.9 Hz, 1H, CHP), 7.45–7.79 (m, 4H,
ArH); 13C NMR (CDCl3, 63 MHz): l 53.8 (2J(C,P)=
7.4 Hz, OMe), 54.1 (2J(C,P)=6.9 Hz, OMe), 70.2
(1J(C,P)=59.0 Hz, CHP), 123.7, 125.0, 128.9 (d,
1
revealed: 31P NMR (163 MHz): 80% ee, H NMR (250
MHz): 76% ee.
4.6.2. Diethyl (S)-a-hydroxy(m-phenoxy)benzylphos-
phonate, (S)-4b. From (S)-6b (54.1 mg, 0.19 mmol):
purification by FC (silica gel, 3:1 EtOAc–hexane, Rf=
0.3) gave phosphonate (S)-4b (26.4 mg, 45% yield,
[h]2D0=−18 (c 1.1, CHCl3)), as a colourless oil. Esterifi-
cation of (S)-4b with (S)-O-MMA and analysis as
described previously revealed: 31P NMR (245 MHz):
J(C,F)=2.0 Hz), 130.3 (ArCH), 137.4 (ArC), ArC6 -CF3
and C6 F3 not detected; MALDI-MS (positive mode,
matrix: CHCA) m/z=285 ([MH]+, 30%), 307 ([MNa]+,
100), 284.2 for C10H12F3O4P. For the (S)-O-MMA ester
1
of (S)-7c: H NMR (CDCl3, 250 MHz): l 3.41 (s, 3H,
3
1
OMe), 3.63 (d, J(H,P)=10.8 Hz, 3H, OMe), 3.64 (d,
90% ee, H NMR (250 MHz): 88% ee.
3J(H,P)=10.7 Hz, 3H, OMe), 4.93 (s, 1H, CH[OMe]),
6.19 (d, 2J(H,P)=13.8 Hz, 1H, CHP), 7.34 (m, 4H,
ArH), >98% ee. 31P NMR (CDCl3, 245 MHz): l 17.10
(s, P(O)O2, >99% ee).
4.6.3. Diethyl (S)-a-hydroxy(m-trifluoro)benzylphos-
phonate, (S)-4c. From (S)-6c (40.1 mg, 0.16 mmol):
purification by FC (silica gel, 3:2 EtOAc–hexane, Rf=
0.3) gave phosphonate (S)-4c (15.0 mg, 30% yield,
[h]2D0=−21 (c 0.5, CHCl3)), as a colourless oil. Esterifi-
cation of (S)-4c with (S)-O-MMA and analysis as
described previously revealed: 31P NMR (163 MHz):
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie.
1
55% ee, H NMR (250 MHz): 55% ee.

D. Skropeta, R. R. Schmidt / Tetrahedron: Asymmetry 14 (2003) 265–273
273
References
20. Pogatchnik, D. M.; Wiemer, D. F. Tetrahedron Lett.
1997, 38, 3495–3498.
1. Pompliano, D. L.; Rands, E.; Schaber, M. D.; Mosser, S.
D.; Anthony, N. J.; Gibbs, J. B. Biochemistry 1992, 31,
3800–3807.
2. Sikorski, J. A.; Miller, M. J.; Braccolino, D. S.; Cleary,
D. G.; Corey, S. D.; Font, J. L.; Gruys, K. J.; Han, C.
Y.; Lin, K.-C.; Pansegrau, P. D.; Ream, J. E.; Schnur,
D.; Shah, A.; Walker, M. C. Phosphorus Sulfur Silicon
1993, 76, 115–118.
21. Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed. Engl.
1984, 23, 36.
22. Schwoerer, R.; Schmidt, R. R. J. Am. Chem. Soc. 2002,
124, 1632–1637.
23. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981,
81, 415–430.
24. Kozlowski, J. K.; Rath, N. P.; Spilling, C. D. Tetra-
hedron 1995, 51, 6385–6396.
25. Zwierak, A.; Kluba, M. Tetrahedron 1971, 27, 3163–3170.
26. Other phosphonic acid esterification methods such as
heating the free phosphonic acids in triethylorthoformate
(Gilmore, W. F.; McBride, H. A. J. Pharm. Sci. 1974, 63,
1087–1090) or refluxing benzene containing O-diakyl
N,N%-dicyclohexylurea (Elhaddadi, M.; Jacquier, R.;
Gastal, F.; Petrus, C.; Petrus, F. Phosphorus Sulfur Sili-
con 1990, 54, 143–150) gave poor yields of diethyl phos-
phonates with low specific rotation values, indicative of
racemisation.
27. Smaardijk, A. A.; Noorda, S.; van Bolhuis, F.; Wynberg,
H. Tetrahedron Lett. 1985, 26, 493–496.
28. Jork, H.; Funk, W.; Fischer, W.; Wimmer, H. Thin-
Layer Chromatography. Reagents and Detection Methods;
VCH: Weinheim, 1990; Vol. 1a.
3. Burke, T. R.; Li, Z.-H.; Bolen, J. B.; Marquez, V. E. J.
Med. Chem. 1991, 34, 1577–1581.
4. Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.;
Ruppert, D. Tetrahedron Lett. 1992, 33, 6625–6628.
5. Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C.
A.; Rogers, W. L.; Smith, S. A.; Oehl, R. S.; Petrillo, E.
W., Jr. J. Med. Chem. 1995, 38, 4557–4569.
6. Mueller, B.; Schaub, C.; Schmidt, R. R. Angew. Chem.,
Int. Ed. 1998, 37, 2893–2897.
7. Wiemer, D. F. Tetrahedron 1997, 53, 16609–16644.
8. Groeger, H.; Hammer, B. Chem. Eur. J. 2000, 6, 943–948.
9. Rowe, B. J.; Spilling, C. D. Tetrahedron: Asymmetry
2001, 12, 1701–1708.
10. Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron:
Asymmetry 1993, 4, 1401–1404.
29. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923–2925.
11. Cermak, D. M.; Yanming, D.; Wiemer, D. F. J. Org.
Chem. 1999, 64, 388–393.
30. Shapiro, E. A.; Eismont, M. Yu.; Pereverzeva, Yu. O.;
Nefedov, A. O.; Strashnenko, A. V.; Kostyrko, I. N.;
Roslavtseva, S. A. Bull. Acad. Sci. USSR Div. Chem. Sci.
(Engl. Transl.) 1990, 39, 573–577.
31. Detert, H.; Sugiono, E. J. Phys. Org. Chem. 2000, 587–
590. NMR spectral data were not reported.
32. Toy, A. D. F.; Cooper, R. S. J. Am. Chem. Soc. 1954, 76,
2191–2195. NMR spectral data were not reported.
33. Hammerschmidt, F.; Hanninger, A. Chem. Ber. 1995,
128, 823–830.
34. Kormachev, V. V.; Kolyamshin, O. A.; Mitrasov, Yu. N.;
Anisimova, E. A. J. Gen. Chem. USSR 1992, 478–482.
35. Creary, X.; Underiner, T. L. J. Org. Chem. 1985, 50,
2165–2170. NMR spectral data were not reported.
36. Albouy, D.; Brun, A.; Munoz, A.; Etemad-Moghadam,
G. J. Org. Chem. 1998, 63, 7223–7230.
12. Hammerschmidt, F.; Linder, W.; Wuggenig, F.; Zarbl, E.
Tetrahedron: Asymmetry 2000, 11, 2955–2964.
13. Blazis, V. J.; Koeller, K. J.; Spilling, C. D. J. Org. Chem.
1995, 60, 931–940.
14. Employing the procedure from Ref. 12, Wiemer et al.10
write ‘‘...hydrolysis of the phosphonamides by reaction
with
4
M
HCl in dioxane only resulted in
decomposition’’.
15. Dickson, J. K., Jr.; Biller, S. A.; Magnin, D. R.; Petrillo,
E. W., Jr.; Hillyer, J. W.; Hsieh, D. C.; Lan, S.-J.;
Rinehart, J. K.; Gregg, P. E.; Harrity, T. W.; Julibuis, K.
G.; Kalinowski, S. S.; Kinselman, L. K.; Mookhtiar, K.
A.; Ciosek, C. P., Jr. J. Med. Chem. 1996, 39, 661–664.
16. Kamber, M.; Just, G. Can. J. Chem. 1985, 63, 823–827.
17. Schaub, C.; Mueller, B.; Schmidt, R. R. Eur. J. Org.
Chem. 2000, 9, 1745–1758.
37. St. Maurice, M.; Bearne, S. L. Biochemistry 2000, 39,
13324–13335.
38. Gibbs, J. B.; Koblan, K. S.; Macleod, A. M.; Merchant,
K. J. Int. Pat. Appl. US 5,519,163, 1995.
18. Ruiz, M.; Ojea, V.; Shapiro, G.; Weber, H.-P.; Pombo-
Villar, E. Tetrahedron Lett. 1994, 35, 4551–4554.
19. Berkowitz, D. B.; Sloss, D. G. J. Org. Chem. 1995, 60,
7047–7050.