Stereochemical consequences of the use of chiral N-phosphoryl oxazolidinones in the attempted kinetic resolution of bromomagnesium alkoxides

Article abstract of DOI:10.1016/j.tetasy.2005.08.025

A number of chiral N-phosphoryl oxazolidinones have been prepared and evaluated as asymmetric phosphoryl transfer agents with the magnesium alkoxide of 1-phenyl ethanol. The reaction proceeded with little stereoselection, which was shown to be a consequence of the reaction mechanism that occurs with inversion of configuration at phosphorus consistent with in-line attack opposite the leaving group.

Full text of DOI:10.1016/j.tetasy.2005.08.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3128–3138
Stereochemical consequences of the use of chiral N-phosphoryl
oxazolidinones in the attempted kinetic resolution of
bromomagnesium alkoxides
Simon Jonesa,b, and Dimitrios Selitsianos
a
*
aDepartment of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
bSchool of Natural Sciences—Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, UK
Received 11 August 2005; accepted 18 August 2005
Abstract—A number of chiral N-phosphoryl oxazolidinones have been prepared and evaluated as asymmetric phosphoryl transfer
agents with the magnesium alkoxide of 1-phenyl ethanol. The reaction proceeded with little stereoselection, which was shown to be a
consequence of the reaction mechanism that occurs with inversion of configuration at phosphorus consistent with in-line attack
opposite the leaving group.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
phate group or cofactor. For example, glycerol kinase
from Escherichia coli or Saccharomyces cerevisiae read-
ily phosphorylates glycerol, L-glyceraldehyde or dihy-
droxyacetone (Scheme 1).8 As a cofactor, ATP is
most commonly used, although different glycerol
kinases can also utilise GTP, UTP or CTP, in addition
to employing phosphoenol pyruvate (PEP) as a source
of phosphate and pyruvate kinase to recycle the ADP
to ATP.
Phosphate esters play an important role in many bio-
chemical pathways, from regulating immune response,
host–pathogen interactions and tumour metathesis as
part of cell wall polysaccharides,1 to regulating trans-
membrane signalling, in the form of inositol phos-
phates.2 Aside from their biological significance,
phosphate esters are useful synthetic intermediates that
can be used as a source of organolithium compounds,3
be dehydrated to yield alkenes4 or act as substrates for
O
5
stereoselective displacement withGrignard reagents.
As a result phosphate esters are important synthetic
targets.
(i)
P
OH
HO
OH
HO
O
>95% yield
>97% ee
OH
OH
OH
Scheme 1. Reagents: Glycerol kinase, pyruvate kinase, ATP, PEP,
MgCl2.
In spite of the abundant examples of chemical phos-
phorylation,6 enantioselective chemical phosphoryla-
tion is relatively underdeveloped. The only method
that is widely used for the enantioselective phosphoryl-
ation of alcohols utilises enzyme systems, either isolated
or as whole cells, which allow the stereo- and often
enantioselective introduction of phosphate groups in
generally good yields.7 Suchenzyme systems comprise
of the enzyme, which catalyses the transfer of the phos-
phate group to the substrate and a source of the phos-
The only non-enzymatic development in this area has
used a histidine-containing oligopeptide capable of
phosphorylating the D-myo-inositol-1-phosphate pre-
cursor 1 in good yield and excellent enantioselectivity
(Scheme 2).9 The peptide was obtained via combinato-
rial methods that has the advantage of only requiring
the use of an oligopeptide rather than a whole enzyme,
essentially mimicking the enzyme active site. Conse-
quently, in principle it can be optimised for any other
molecule aside from D-myo-inositol by the use of combi-
natorial methods.
*
Corresponding author. Tel.: +44 114 222 9483; fax: +44 114 222
9346; e-mail: simon.jones@sheffield.ac.uk
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.025

S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
3129
OBn
OBn
O
O
O
OPh
OPh
HO
OH
HO
O P
P OPh
OPh
(i)
O
N
(i)
65% yield
>98% ee
O
BnO
OBn
BnO
OBn
Ph
O
72%
84%
5
OH
OH
P OEt
OEt
O
NH
nBu
1
O
O
Ph
(ii)
P OEt
OEt
7
Scheme 2. Reagents: (i) 2 mol % pentapeptide, (PhO)2P(O)Cl, Et3N,
toluene, 0 ꢂC.
4
O
N
Ph
6
Scheme 4. Reagents: (i) n-BuLi, THF then (PhO)2P(O)Cl; (ii) n-BuLi,
THF then (EtO)2P(O)Cl.
Previous work from our group has described the synthe-
sis and application of N-phosphoryl oxazolidinones.10
We have demonstrated that such reagents act as efficient
phosphorylation agents for a wide range of alcohol sub-
strates. Moreover, the structures of these reagents make
them ideal for modification into chiral reagents of the
type 2 that would be suitable for evaluation in phos-
phoryl transfer. Chiral oxazolidinones are amongst the
most widely used auxiliaries and have been successfully
used in acyl chemistry.11 It is not surprising then that a
related application of the proposed reagent 2 has been
previously reported. The N-benzoyl tert-leucinol derived
reagent 3 has been used in the asymmetric acylation of
the magnesium alkoxide of 1-phenyl ethanol (Scheme
3).12 An excess of alkoxide was used in this work, how-
ever the yield and ee of the ester product were excellent.
Herein, we describe the synthesis and preliminary evalu-
ation of chiral N-phosphoryl oxazolidinones 2 as a
chemical reagent to effect the kinetic resolution of race-
mic alcohols via phosphorylation.
which were the phosphates 10 and 11 and ether 12.
The instability of the triester 9 has been previously
noted, and the desired product 9 was finally prepared
in 40% yield by treatment with1.1 equiv DMAP, fol-
lowed by immediate purification via column chromato-
graphy (Scheme 5).13 This was stored in the freezer,
where it was stable for a few days. In contrast, the
diethyl phosphate product 13 was prepared from the
lithium alkoxide of racemic 1-phenyl ethanol 8 and diethyl
chlorophosphate in 92% yield and found to be signifi-
cantly more stable compared to the corresponding diphe-
nyl phosphate over a period of several months. This is not
surprising since the rate of hydrolysis of phosphate esters
depends on the pKa values of the substituents,13 with
lower pKa values resulting in higher hydrolysis rates.
Since the pKa of ethanol is 16 compared to a pKa of
9.95 for phenol, the diethyl phosphate 13 is expected to
be less prone to hydrolysis compared to the diphenyl
phosphate 9.
2. Results and discussion
Initial trials were carried out using the (4R)-benz-
yloxazolidinone 4, which was phosphorylated using
both diphenyl and diethyl chlorophosphate (Scheme
4). While purification of the diphenyloxazolidinone 5
posed no problem, purification of the diethyl analogue
6 proved to be very difficult witha small amount of
impurity present even after a series of silica and Sepha-
dexꢁ columns. Subsequent work (see phosphonamides
19 and 20) suggested the by-product to be the phospho-
nate 7 formed from the reaction between n-butyl lithium
and diethyl chlorophosphate.
O
(i)
P
OPh
OPh
Ph
OH
Ph
O
40%
8
9
>12 hrs, RT
(ii)
92%
O
P
OPh
O
O
P
OH
OH
OH
Ph
O
Ph
O
P
OEt
OEt
Ph
O
11
10
13
The expected products of the kinetic resolution were
also prepared. Treatment of the lithium alkoxide of 1-
phenyl ethanol 8 with diphenyl chlorophosphate gave
product 9, however decomposition with loss of the
phenoxy groups was found to occur within 24 h at room
temperature, giving a number of products amongst
Ph
O
Ph
12
Scheme 5. Reagents: (i) 1.1 equiv DMAP, (PhO)2P(O)Cl, THF; (ii) n-
BuLi, THF, then (EtO)2P(O)Cl.
O
O
O
O
P
O
OR3
OR3
O
N
O
N
Ph
Ph
OMgBr
Ph
O
Ph
>95% yield
95% ee
R1
R2
R1
2
3
Scheme 3.

3130
S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
Table 1. Preparation of N-phosphoryl oxazolidinonesa
With authentic products in hand, the diphenyl phosphon-
amide 5 was reacted with1 equiv of the bromomagne-
sium alkoxide of racemic 1-phenyl ethanol.
Deprotonation of the alcohol with methyl magnesium
bromide was initially carried out in ether and subse-
quently reacted with phosphonamide 5, which gave
unreacted starting material due to the insolubility of
the magnesium alkoxide in ether. This was overcome
by forming the alkoxide in ether and then solubilising
it by adding dichloromethane (dichloromethane/ether
3:2, Scheme 6). However, analysis of the enantiomeric
excess of unreacted alcohol 8 by chiral GC indicated
no selectivity, while the 1H NMR spectrum of the crude
reaction mixture indicated cleavage of the P–N bond
(30% cleavage after 150 min) and presence of the ether
12. However, when the reaction was left stirring for
19 hat room temperature, althoughcomplete consump-
tion of reagent 5 was observed, the main product
observed was the bromide 14, while the ether 12 was also
present.
Oxazolidinone
Phosphonamide
Yield (%)b
O
O
O
P OEt
OEt
O
NH
Ph
O
N
63
15
Ph
EtO
EtO P
O
H
N
O
O
N
44
O
O
16
O
O
O
P OEt
OEt
O
NH
i-Pr
O
N
78
81
17
i-Pr
O
O
O
P OEt
OEt
O
NH
Bn
O
N
Since the diethyl phosphate ester 13 appeared to be con-
siderably more stable, the phosphonamide 6 was treated
under identical conditions to those described above.
Once again a reaction took place, this time generating
only the desired diethyl phosphate ester 13 (75% conver-
sion after 150 min). However, chiral GC analysis of the
residual alcohol 8 indicated that there was no enantio-
meric excess.
Ph
Ph
18
Bn
Ph
Ph
a Reactions performed according to conditions in Scheme 4.
b Refers to the amount of contaminant free material obtained.
amides by stirring for 30 min at various reaction temper-
atures. Samples were removed and analysed, the results
are shown in Table 2. Since the enantiomers of the
diethyl phosphate product 13 could not be separated
by chiral HPLC, the enantioselectivity of these reactions
was directly determined by the use of a chiral solvating
reagent, (R)-(À)-2,2,2-trifluoro-1-(9-anthryl) ethanol,
which facilitated the separation of the methyl groups
Somewhat surprised by this in view of the work previ-
ously described by Evans et al.,12 several chiral diethyl
N-phosphoryl oxazolidinones were prepared as previ-
ously described by deprotonation of the parent oxazolid-
inone followed by quench with diethyl chlorophosphate
(Table 1). Diethyl phosphonamides were chosen to limit
the by-products observed during the reaction. All of the
reactions proceeded withquantitative conversion to the
crude phosphonamide product. However purification
was problematic in some cases, particularly the oxazolid-
inones 15 and 16 where, as in the case of the oxazolidi-
none 6, repeated column chromatography failed to give
analytically pure product. On the other hand, the 5,5-
disubstituted phosphonamides 17 and 18 were easier to
purify, possessing different Rf values to that of the
phosphonate impurity.
1
of the two enantiomers by H NMR spectroscopy. A
sample of enantiomerically enriched phosphate of
known stereochemistry was independently prepared by
treatment of enantiomerically pure (S)-1-phenyl ethanol
with n-BuLi in THF and subsequent reaction with
diethyl chlorophosphate. In all cases, the enantioselec-
tivities were very low, corresponding to selectivity fac-
tors (s) of less than 1. The best selectivities were
observed for the sterically demanding 5,5-disubstituted
oxazolidinones, which may be a consequence of the pro-
pensity of these reagents to locate the 4-substituent close
to the reactive centre.14 Given the success of the Evans
system for acyl transfer it at first appeared strange that
Kinetic resolution of the bromomagnesium alkoxide of
1-phenyl ethanol was attempted with these phosphon-
O
O
O
O
P OPh
OPh
(i)
O
O
NH
NH
O
O
N
N
P OPh
OPh
Ph
Ph
OH
OH
Ph
Br
Ph
O
Ph
Ph
Ph
O
(ii)
Ph
Ph
Ph
8
8
5
O
9
12
14
O
O
O
P OEt
OEt
(i)
P OEt
OEt
(ii)
O
Ph
6
13
Scheme 6. Reagents: (i) alcohol 8, Et2O, then MeMgBr; (ii) CH2Cl2, reagents 5 or 6.

S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
Table 2. Reactivity and selectivity of N-phosphoryl oxazolidinones
3131
O
O
P
OEt
O
O
OEt
(i)
O
N
O
NH
R2
EtO P
EtO
R1
Ph
OH
R1
O
Ph
R2
R1
R1
6, 15-18
8
13
Reagents: (i) Alcohol 8, Et2O, then MeMgBr; (ii) CH2Cl2, reagent 6 or 15-18
Reagent
Temperature (ꢂC)
Conversion (%)
ee (%) of phosphate 13a
Major enantiomer of phosphate 13b
6
À16
25
41
75
20
35
59
15
47
66
6
20
67
21
45
88
<5
<5
<5
<5
<5
<5
7
<5
7
<5
7
R
R
R
S
S
S
S
S
S
S
S
S
S
S
S
6
2
6
20
À16
2
20
À16
2
20
À16
2
20
À16
2
15
15
15
16
16
16
17
17
17
18
18
18
12
<5
6
20
10
a Determined by 1H NMR using (R)-(À)-2,2,2-trifluoro-1-(9-anthryl) ethanol.
b Determined by comparison witha sample of authentic product.
suchpoor results were obtained withteh analogous
phosphate one.
since there was no literature precedence of such phos-
phonamides, the stereochemistry at phosphorus would
be determined directly from the crystal structure of
the phosphonamide. For this reason, the phosphon-
amides 19 and 20 were selected due to the crystallinity
of the corresponding diethyl phosphonamide 17 and
the very similar nature of the O-alkyl groups, which
should not influence the outcome of the reaction
(Fig. 2).
The lack of selectivity could be attributed to the site of
attack of the alkoxide. Nucleophilic attack at a phos-
phorus atom is known to proceed with in-line attack,
opposite to the leaving group, with inversion of config-
uration at phosphorus (Fig. 1).15 As a result, the stereo-
chemical information is probably too far away for the
selectivity of the reaction to be affected.
This in-line attack of the alkoxide with inversion of
configuration at phosphorus could be directly observed
if a P-chiral phosphonamide was used instead. The
product of a reaction of such a phosphonamide with
an alkoxide should yield a P-chiral phosphate, the abso-
lute configuration of which could be determined by
comparing the [a]D values or the retention times from
chiral GC or HPLC with the literature values. However,
O
O
O
P
O
P
OMe
OEt
OEt
OMe
O
N
O
N
20
19
Figure 2. Target P-chiral phosphonamides.
SN2(P)
Mg2
mechanism
proceeds via 'in-
line' attack
O
O
Attack along
Bürgi-Dunitz angle
Ph
Ph
Ph
O
N
Mg2
BrMgO
Ph
Stereogenic
elements can
interact
O
O
OEt
OEt
P
O
N
Stereogenic
centres cannot
interact
BrMgO
Ph
Figure 1. Trajectory of attack at N-acyl and N-phosphoryl oxazolidinones.

3132
S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
The racemic ethyl methyl chlorophosphate 22 required
to access these targets was prepared as colourless oil in
two steps from phosphorus oxychloride by treatment
of 1 equiv of ethanol and triethylamine and purification
of the dichloride 21 by distillation, followed by the same
procedure using methanol (Scheme 7).
O
P
O
P
O
P
(ii)
(i)
OEt
OEt
Cl
Cl
Cl
Cl
Cl
Cl
OMe
48%
72%
21
22
Scheme 7. Reagents: (i) EtOH, Et3N, petrol; MeOH, Et3N, petrol.
The phosphonamides 19 and 20 witha stereogenic phos-
phorus centre were then prepared by treating the lithium
salt of the 5,5-dimethyl oxazolidinone 23 withetyhl
methyl chlorophosphate 22 and separating the two dia-
stereoisomers by column chromatography (Scheme 8).
Figure 3. Crystal structure of phosphonamide 19.
1
The H NMR spectrum of the crude product indicated
complete conversion of starting material and that some
degree of selectivity in this process was evident, giving
the phosphonamide in 8% de in favour of the phosphon-
amide 20. This indicated possible dynamic kinetic reso-
lution since chlorophosphates such as 22 are known to
undergo racemisation, although the rate of this reaction
has not been studied.16
antiperiplanar geometry to the carbonyl group, similar
to that of the carbonyl group in Evansꢀ chemistry.18
Phosphonamide 20, which was available in larger quan-
tities of high purity material than diastereoisomer 19,
was then treated with the magnesium alkoxide of isopro-
panol giving quantitative conversion to ethyl isopropyl
methyl phosphate (S)-25 in >95% ee according to chiral
GC (Scheme 10). Attempts to purify this triester led to
loss of material due to the scale of reaction and
visualisation difficulties on TLC.
1
The H NMR spectrum of the crude product also sug-
gested the presence of a by-product, which was found
to have a very similar Rf value to the two diastereoiso-
mers, thus making their separation and purification very
difficult. This by-product was found to be the phospho-
nate 24, formed from the reaction between n-butyl lith-
ium and the chlorophosphate 22. This was proven by
treating the chlorophosphate with n-butyl lithium in
THF, yielding the pure phosphonate in 73% yield after
distillation of the crude product (Scheme 9).
O
P
O
OEt
OMe
O
P
(i)
N
O
OH
EtO
MeO
OiPr
100%
conversion
i-Pr
20
(S) 25
Scheme 10. Reagents: (i) i-PrOH, Et2O, then MeMgBr; (ii) CH2Cl2,
reagent 20.
O
O
P
(i)
OEt
OMe
P OEt
OMe
Cl
73%
The phosphate (S)-25 had a very small [a]D value, which
could not be accurately compared to the literature
value,19 and there was no literature data to compare
the GC conditions. Furthermore, attempts to determine
22
24
Scheme 9. Reagents: (i) n-BuLi, THF.
1
the ratio of the two enantiomers by H NMR spectro-
Separation and crystallisation of these diastereoisomers
was very difficult, however, a crystal structure of the
(SP)-enantiomer 19 was eventually obtained (Fig. 3)17
that clearly shows the phosphate group adopting an
scopy with the use of Eu[(+)-(hfc)]3, for which there
was literature precedence also proved unsuccessful, since
the peaks corresponding to the two enantiomers could
not be adequately separated from eachother. 19a For this
O
O
O
O
P
O
P
(i)
OMe
OEt
OEt
OMe
O
NH
O
N
O
N
100%
conversion
23
Scheme 8. Reagents: (i) n-BuLi, THF, then 22.
19
20

S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
3133
reason, triester (R)-25 was prepared in >95% ee by an
4.3. Chromatography
established independent route,19a in order for a chiral
GC of the new sample to be obtained and for the stereo-
chemistry of the phosphorylation product to be conclu-
sively established. Additionally, a sample of racemic
triester 25 was also prepared in 75% yield by the
action of the lithium alkoxide of isopropyl alcohol with
chlorophosphate 22.
Flash column chromatography was carried out with
BDH silica gel (product number 153325P; particle size
40–63 lm), or Fluorochem Limited Silica Gel 60A (par-
ticle size 40–63 lm), while particle column chromatogra-
phy was performed with Sephadexꢁ LH-20 and ionic
column chromatography with diethylaminoethyl cellu-
lose DE22 purchased from Whatman. Thin layer chro-
matography was carried out with Merck aluminium
TLC (Silica gel F254). Unless otherwise noted, visualisa-
tion of TLC plates was performed withalkaline potas-
sium permanganate or phosphomolybdic acid and
heating.
Gas chromatography using a chiral stationary phase
was then performed on the triester products from these
different routes. It was shown that the triester derived
from the phosphonamide 20 had the opposite stereo-
chemistry to the sample of (R)-25 that was prepared
by established literature methods. As a consequence,
the reaction of magnesium alkoxides with these phos-
phonamides proceeds via a typical SN2(P) reaction with
apical attack of the nucleophile opposite to the leaving
group and inversion of configuration. This result is in
accordance withWestheimer ꢀs guidelines and all known
literature data, since they all support an apical attack of
the nucleophile opposite to the leaving group.15
4.4. Solvents
Dichloromethane and petroleum ether 40–60 were dis-
tilled under a nitrogen atmosphere from lithium alumin-
ium hydride. THF and diethyl ether were distilled under
nitrogen atmosphere from metallic sodium and
benzophenone.
4.5. Instrumentation
3. Conclusion
1H (200 MHz), and 50 MHz 13C NMR spectroscopy
was performed on a Bruker AC 200 spectrometer,
121 MHz 31P NMR spectroscopy on a Bruker Aspect
3000 spectrometer, 300 MHz 1H, and 75 MHz 13C
We have found that the attempted kinetic resolution of
N-phosphoryl oxazolidinones with racemic alkoxides
proceeds withlittle or no stereoselection unlike the anal-
ogous acylation developed by Evans. This is due to the
change in geometry at the reactive centre, since moving
from a trigonal planar arrangement for acyl transfer to a
tetrahedral one for phosphoryl transfer changes the
trajectory of attack of any incoming nucleophile.
NMR spectroscopy on
a Bruker WM300, while
500 MHz 1H, 125 MHz 13C and 202 MHz 31P NMR
spectroscopy on a JEOL (Japan Electron Optical Ltd)
k 500 MHz system. Residual proton signals from the
deuteriated solvents were used as references (1H
7.25 ppm, 13C 77 ppm for chloroform), while coupling
constants were measured in hertz. Mass spectroscopy
was carried out on a Micromass Autospec M system,
IR spectroscopy on a Nicklet 5 PC FT-IR Spectrometer,
while elemental analysis was performed using a Carlo
Erba 1106. Gas chromatography was carried out on a
Hewlett Packard Model 427 instrument witha fused sil-
ica capillary and b-cyclodextrin as the stationery phase
and a flame ionisation detector as the means of detection.
Hydrogen was used as a carrier gas. Optical rotations
were measured on a Polaar 2001 automatic polarimeter
at 589 nm at 20 ꢂC unless otherwise stated. [a]D values
are given in 10À1 deg cm2 gÀ1. Melting points were deter-
mined using a Gallenkamp melting point apparatus (reg-
istered design 889339) and are uncorrected.
4. Experimental
4.1. General
All experiments that were carried out under a nitrogen
atmosphere were performed using Schlenk line tech-
niques. Glassware was routinely flame-dried and cooled
in vacuo, followed by introduction of nitrogen. Reac-
tions performed at À78 ꢂC were cooled by means of
an acetone/dry ice bath, at À16 ꢂC by an ice/salt bath,
while those at 0 ꢂC by an ice bath.
4.2. Reagents
4.6. ( )-1-Phenylethanol diphenyl phosphate 913
All amines used were previously dried by distilling them
under a nitrogen atmosphere from potassium hydroxide
pellets. n-Butyl lithium was used as a solution in hexanes
and was titrated against 1,3-diphenyl-2-propanone tosyl
hydrazone,20 while methylmagnesium bromide was used
as supplied as a solution in diethyl ether (Aldrich).
Samples of authentic materials for identification pur-
poses were prepared according to the following estab-
lished literature methods; bis-(1-phenylethyl)ether 12,21
1-phenylethyl bromide 14,22 (4S)-isopropyl-5,5-dimeth-
yloxazolidin-2-one 23;14a (4S)-4-benzyl-5,5-diphenylox-
azolidin-2-one.23
A
solution of diphenyl chlorophosphate (0.66 g,
0.51 cm3, 2.46 mmol) in dichloromethane (2 cm3) was
added to a solution of 1-phenyl ethanol 8 (0.30 g,
0.30 cm3, 2.46 mmol) and DMAP (0.33 g; 2.70 mmol)
in dichloromethane (3 cm3) at ꢀ18 ꢂC and the solution
was allowed to stir for 20 h. Aqueous satd ammonium
chloride (5 cm3) was added, the aqueous layer extracted
with dichloromethane (3 · 10 cm3) and the combined
organic extracts washed with aqueous satd sodium
bicarbonate (10 cm3), brine (10 cm3) and dried over
magnesium sulfate. The solution was filtered, the solvent

3134
S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
was removed using rotary evaporation and the residue
was purified by flash column chromatography (diethyl
ether/petroleum ether 40–60, 2:1) to afford a colourless
oil (0.35 g, 40% yield); dH (200 MHz; CDCl3) 1.63
(3H, d, J 6.4 CHCH3), 5.69 (1H, quintet, J 6.4,
CHCH3), 6.99–7.36 (15H, m, ArH); dP (121 MHz;
CDCl3) À11.54.
hydro-1H-inden-1-yl]carbamate27 (0.90 g, 3.60 mmol)
in THF (20 cm3) at ꢀ18 ꢂC. The solution was allowed
to stir for 30 min, water (5 cm3) was added and the solu-
tion extracted withethyl acetate (3 · 10 cm3). The com-
bined organic extracts were washed with sodium
hydroxide (1.0 M, 10 cm3), dried over magnesium sul-
fate, filtered and the solvent was removed using rotary
evaporation. The residue was recrystallised from ethyl
acetate to afford white needles (0.44 g, 70 % yield); mp
195–196 ꢂC (lit.26 203–205 ꢂC); [a]D = +73.0 (c 1,
CHCl3) (lit.26 +76.9; c 1.2, CHCl3); dH (300 MHz;
CDCl3) 3.37–3.41 (2H, m, CH2CH), 5.19 (1H, d, J 7.3,
CHN), 5.41–5.46 (1H, m, CH2CH), 6.84 (1H, s, NH),
7.23–7.35 (4H, m, ArH); dC (75 MHz; CDCl3) 39.2
(CH2CH), 61.6 (CHN), 81.0 (CH2CH), 125.2 (ArCH),
126.0 (ArCH), 128.3 (ArCH), 129.8 (ArCH), 140.1
(ArC), 140.6 (ArC), 160.0 (C@O).
4.7. ( )-1-Phenylethanol diethyl phosphate 1324
n-Butyl lithium (0.57 cm3, 0.82 mmol) was added to a
solution of 1-phenyl ethanol 8 (0.10 g, 0.82 mmol) in
THF (5 cm3) at À78 ꢂC and left to react for 15 min, then
diethyl chlorophosphate (0.17 g, 0.14 cm3, 0.98 mmol)
was added. The solution was warmed to ꢀ18 ꢂC and left
stirring for 2 h. Aqueous satd ammonium chloride
(5 cm3) was added, the aqueous layer was extracted with
ethyl acetate (3 · 10 cm3) and the combined organic
extracts were washed with aqueous satd sodium bicar-
bonate (10 cm3), brine (10 cm3) and dried over magne-
sium sulfate. The solution was filtered, the solvent was
removed using rotary evaporation and the residue puri-
fied by flashcolumn chromatography (gradient column,
20–50% ethyl acetate in petroleum ether 40–60) to give a
colourless slightly yellow oil (0.20 g, 92% yield); dH
(200 MHz; CDCl3) 1.12 (3H, td, J 7.1 and JP–H 0.9,
CH3CH2), 1.21 (3H, td, J 7.1 and JP–H 0.9, CH3CH2),
1.62 (3H, d, J 6.4, CH3CH), 3.84–4.18 (4H, m,
CH2CH3), 5.46 (1H, quintet, J 6.4, CH3CH), 7.30–7.42
(5H, m, ArH); dP (121 MHz; CDCl3) À0.68.
4.10. General procedure A for the preparation of the
N-phosphoryl oxazolidinones
n-Butyl lithium (1 equiv) was added to a solution of the
oxazolidinone (1 equiv) in THF (10 cm3) at À78 ꢂC and
left to react for 15 min, followed by addition of diethyl
or diphenyl chlorophosphate (1 equiv). The solution
was warmed to ꢀ18 ꢂC and allowed to stir for
120 min. Aqueous satd ammonium chloride (5 cm3)
was added and the aqueous layer was extracted with
diethyl ether (3 · 10 cm3). The combined organic
extracts were washed with aqueous satd sodium bicar-
bonate (10 cm3), brine (10 cm3), dried over magnesium
sulfate, filtered and the solvent was removed using
rotary evaporation.
4.8. (1S)-1-Phenylethanol diethyl phosphate (S)-1325
n-Butyl lithium (0.52 cm3, 0.74 mmol) was added to a
solution of (1S)-1-phenyl ethanol (>99% ee, 0.09 g,
0.74 mmol) in THF (5 cm3) at À78 ꢂC and left to react
for 15 min before diethyl chlorophosphate (0.15 g,
0.13 cm3, 0.89 mmol) was added. The solution was
warmed to ꢀ18 ꢂC and stirred for 2 h. Aqueous satd
ammonium chloride (5 cm3) was added, the aqueous
layer extracted withethyl acetate (3 · 10 cm3) and the
combined organic extracts washed with aqueous satd
sodium bicarbonate (10 cm3), brine (10 cm3) and dried
over magnesium sulfate. The solution was filtered, the
solvent removed using rotary evaporation and the resi-
due purified by flashcolumn chromatography (gradient
column, 20–50% ethyl acetate in petroleum ether 40–60)
to give a pale yellow oil (0.17 g, 67% yield); [a]D = À20.2
(c 1, CHCl3) (lit.25 À46.6, c 2.32, CHCl3); dH (200 MHz;
CDCl3) 1.16 (3H, td, J 7.1 and JP–H 0.8, CH3CH2), 1.26
(3H, td, J 7.0 and JP–H 0.9, CH3CH2), 1.62 (3H, d, J 6.4,
CH3CH), 3.84–4.14 (4H, m, CH2CH3), 5.46 (1H, quin-
tet, J 6.4, CH3CH), 7.24–7.39 (5H, m, ArH); dC
(75 MHz; CDCl3) 16.3 (d, JP–C 6.8, CH3CH2), 16.5 (d,
JP–C 6.8, CH3CH2), 24.6 (d, JP–C 5.3, CH3CH), 64.0
(d, JP–C 4.6, CH3CH2), 77.1 (CH3CH), 126.3 (ArCH),
128.5 (ArCH), 128.9 (ArCH), 142.1 (ArC); dP
(202 MHz; CDCl3) À1.44.
4.11. [(4R)-4-Benzyl-2-oxo-oxazolidin-3-yl]-phosphonic
acid diphenyl ester 5
Using general procedure A, a white solid was obtained,
which was purified by recrystallisation from dichloro-
methane/petroleum ether 60:80 (0.5 g, 72% yield); mp
118–119 ꢂC; [a]D = +58.1 (c 1, CHCl3); (found: C,
64.8; H, 4.8; N, 3.40. C22H20O5NP requires C, 64.55;
H, 4.9; N, 3.4); mmax (KBr disk)/cmÀ1 1785, and 1288;
dH (200 MHz; CDCl3) 2.38 (1H, dd, J 13.3 and J 10.7,
CH2Ph), 3.07 (1H, dd, J 13.3 and 3.5, CH2Ph), 3.97–
4.08 (2H, m, OCH2CH), 4.26 (1H, m, CHN), 7.04–
7.09 (2H, m, ArH), 7.20–7.31 (6H, m, ArH), 7.34–7.39
(7H, m, ArH); dC (125 MHz; CDCl3) 40.0 (CH2Ph),
58.1 (d, JP–C 5.2, CHN), 67.5 (d, JP–C 9.3, OCH2CH),
120.5 (d, JP–C 4.2, ArCH), 121.1 (d, JP–C 5.2, ArCH),
126.2 (ArCH), 127.3 (ArCH), 128.9 (ArCH), 129.3
(ArCH), 129.9 (d, JP–C 10.4, ArCH), 135.0 (ArC),
149.5 (d, JP–C 7.3, ArC), 149.7 (d, JP–C 6.3, ArC),
154.6 (d, JP–C 8.2, OCON); dP (121 MHz; CDCl3)
À11.22; m/z (EI) 409.1079 (77%, M+ÆC22H20NO5P
requires 409.1079), 318 (100), 276 (43), 233 (20), 91
(19), 77 (28).
4.12. [(4R)-4-Benzyl-2-oxo-oxazolidin-3-yl]-phosphonic
acid diethyl ester 6
4.9. (4R,5S)-Indano[1,2-d]oxazolidin-2-one26
Potassium tert-butoxide (0.41 g, 3.60 mmol) was added
to a solution of tert-butyl [(1R,2S)-2-hydroxy-2,3-di-
Using the general procedure A, a crude oil was obtained,
which was purified by flash column chromatography

S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
3135
(gradient silica column, 20–60% ethyl acetate in petro-
4.15. [(4S)-4-Isopropyl-5,5-dimethyl-2-oxo-oxazolidin-3-
yl]-phosphonic acid diethyl ester 17
leum ether 40–60) giving the title compound as a viscous
colourless oil (0.99 g, 84% yield); [a]D = À33.7 (c 1,
CHCl3); mmax (film)/cmÀ1 1772 and 1272; dH
(300 MHz; CDCl3) 1.31–1.38 (6H, m, CH2CH3), 2.77
(1H, dd, J 10.4 and 13.2, CH2Ph), 3.44 (1H, dd, J 3.5
and 13.2, CH2Ph), 4.07–4.43 (7H, m, CH2CH3,
CHCH2O and CHN), 7.13–7.29 (5H, m, ArH); dC
(125 MHz; CDCl3) 16.2 (d, JP–C 7.2, CH3CH2), 40.4
(CH2Ph), 58.1 (d, JP–C 5.2, CHN), 64.8 (d, JP–C 6.1,
CH3CH2), 67.6 (d, JP–C 9.3, CH2O), 127.4 (ArCH),
129.0 (ArCH), 129.5 (ArCH), 135.4 (ArC), 155.5
(C@O); dP (121 MHz; CDCl3) À3.61; m/z (EI)
313.1090 (38%, M+ÆC14H20NO5P requires 313.1079),
222 (100), 194 (22), 166 (30), 109 (36), 91 (31), 86 (29).
Using general procedure A, a white solid was obtained,
which was purified by flash column chromatography
(60% ethyl acetate in petroleum ether 40–60) to give
the title compound as a white crystalline solid (0.37 g,
78% yield); mp 41–42 ꢂC; [a]D = À29.4 (c 1, CHCl3);
(found: C, 49.2; H, 8.3; N, 4.7. C12H24NO5P requires
C, 49.1; H, 8.25; N, 4.8); mmax (KBr disk)/cmÀ1 1764
and 1267; dH (300 MHz; CDCl3) 1.03 [3H, d, J 7.0,
(CH3)2CH], 1.13 [3H, d, J 7.0, (CH3)2CH], 1.37–1.43
(6H, m, CH3CH2), 1.47 [3H, s, (CH3)2C], 1.50 [3H, s,
(CH3)2C], 2.12 [1H, heptet d, J 7.0 and JP–H 2.0,
(CH3)2CH], 3.79 (1H, dd, J 5.2 and J 2.0, CHN),
4.11–4.38 (4H, m, CH3CH2); dC (75 MHz; CDCl3)
16.5 (d, JP–C 7.1, CH3CH2), 16.6 (d, JP–C 7.0, CH3CH2),
20.9, [(CH3)2CH], 21.9 [(CH3)2CH], 29.2 [(CH3)2C], 30.5
[(CH3)2C], 64.5 (d, JP–C 6.1, CH3CH2), 65.1 (d, JP–C 6.6,
CH3CH2), 70.7 (d, JP–C 3.0, CHN), 77.6 [(CH3)2CH],
84.4 [d, JP–C 8.0, (CH3)2C], 155.7 (d, JP–C 7.9, C@O);
dP (121 MHz; CDCl3) À1.88; m/z (EI) 293.1387 (3%,
M+ÆC12H24NO5P requires 293.1392), 250 (100), 206
(15), 178 (14).
4.13. [(4S)-4-Phenyl-2-oxo-oxazolidin-3-yl]-phosphonic
acid diethyl ester 15
Using the general procedure A, a crude oil was obtained,
which was purified by flash column chromatography
(50% ethyl acetate in petroleum ether 40–60) to give
the title compound as a viscous colourless oil (0.10 g,
63% yield); [a]D = À45.3 (c 1, CHCl3); mmax (film)/
cmÀ1 1779 and 1263; dH (200 MHz; CDCl3) 1.05 (3H,
td, J 7.1 and JP–H 0.9, CH3CH2), 1.26 (3H, td, J 7.1
and JP–H 1.0, CH3CH2), 3.61–3.76 (2H, m, CH3CH2),
3.94–4.24 (2H, m, CH3CH2), 4.29 (1H, ddd, J 8.6, 1.4
and 1.9, OCH2CH), 4.48 (1H, t, J 8.6, OCH2CH), 5.11
(1H, ddd, J 8.6, 1.9 and JP–H 1.1, CHN), 7.19–7.35
(5H, m, ArH); dC (125 MHz; CDCl3) 15.8 (CH3CH2),
15.9 (CH3CH2), 60.2 (CHN), 64.0 (CH3CH2), 64.7
(CH3CH2), 71.4 (OCH2CH), 126.6 (ArCH), 128.5
(ArCH), 129.0 (ArCH), 129.0 (ArCH), 139.9 (ArC),
155.5 (d, JP–C 9.3, C@O); dP (121 MHz; CDCl3)
À3.39; m/z (EI) 300.1002 (9%, MH+ÆC13H19NO5P
requires 300.1001), 255 (100), 146 (77), 104 (76), 91
(52), 77 (47).
4.16. [(4S)-4-Benzyl-2-oxo-5,5-diphenyl-oxazolidin-3-yl]-
phosphonic acid diethyl ester 18
Using the general procedure A, a slightly yellow gum
was obtained, which was purified by flash column chro-
matography (60% ethyl acetate in petroleum ether 40–
60) to give the title compound as a viscous semi-solid
(0.17 g, 81% yield); [a]D = À35.0 (c 1, CHCl3); mmax
(film)/cmÀ1 1779 and 1273; dH (500 MHz; CDCl3) 0.90
(3H, td, J 7.0 and JP–H 0.9, CH3CH2), 1.25 (3H, td, J
7.0 and JP–H 1.1, CH3CH2), 2.81 (1H, dd, J 8.5 and
14.3, CH2CH), 2.96 (1H, dd, J 4.8 and 14.3, CH2CH),
3.27–3.32 (1H, m, CH3CH2), 3.58–3.63 (1H, m,
CH3CH2), 4.05–4.12 (2H, m, CH3CH2), 5.24–5.27 (1H,
m, CHN), 6.66–6.67 (2H, m, ArH), 6.98–7.01 (3H, m,
ArH), 7.07–7.14 (5H, m, ArH), 7.19–7.25 (1H, m,
ArH), 7.28–7.31 (2H, m, ArH), 7.52–7.54 (2H, m,
ArH); dC (75 MHz; CDCl3) 16.0 (d, JP–C 6.9, CH3CH2),
16.5 (d, JP–C 7.3, CH3CH2), 38.7 (CH2CH), 64.1 (d, JP–C
5.8, CH3CH2), 65.3 (d, JP–C 6.6, CH3CH2), 66.5 (CHN),
90.3 [d, JP–C 7.4, CHC(Ph)2O], 126.3 (ArCH), 126.7
(ArCH), 126.7 (ArCH), 128.5 (ArCH), 128.5 (ArCH),
129.0 (ArCH), 129.1 (ArCH), 129.4 (ArCH), 136.4
(ArC), 137.7 (ArC), 142.4 (ArC), 154.2 (d, JP–C 7.3,
C@O); dP (121 MHz; CDCl3) À4.27; m/z (EI) 465.1701
(1%, M+ÆC26H28NO5P requires 465.1705), 421 (65),
268 (83), 195 (100), 167 (73), 84 (78).
4.14. [(4R,5S)-Indano[1,2-d]-2-oxo-oxazolidin-3-yl]-
phosphonic acid diethyl ester 16
Using general procedure A, a crude oil was obtained,
which was purified by flash column chromatography
(50% ethyl acetate in petroleum ether 40–60) to give
the title compound as a viscous colourless oil (0.31 g,
44% yield); [a]D = À13.5 (c 1, CHCl3); mmax (film)/
cmÀ1 1783 and 1279; dH (200 MHz; CDCl3) 1.20 (3H,
td, J 7.1 and JP–H 1.0, CH3CH2), 1.34 (3H, td, J 7.1
and JP–H 1.0, CH3CH2), 3.30 (2H, d, J 3.6, CH2CHO),
3.96–4.14 (2H, m, CH3CH2), 4.14–4.32 (2H, m,
CH3CH2), 5.30 (1H, dt, J 3.6 and J 7.1, CH2CHO),
5.57 (1H, d, J 7.1, CHN), 7.20–7.31 (3H, m, ArH),
7.84 (1H, d, J 6.8, ArH); dC (125 MHz; CDCl3) 16.0
(d, JP–C 7.2, CH3CH2), 16.2 (d, JP–C 6.2, CH3CH2),
38.1 (CCH2CH), 64.5 (d, JP–C 6.2, CH3CH2), 64.9 (d,
JP–C 6.3, CH3CH2), 65.5 (d, JP–C 5.2, CH2CHO), 79.8
(d, JP–C 8.2, CHN), 125.4 (ArCH), 126.9 (ArCH),
128.0 (ArCH), 129.9 (ArCH), 139.2 (ArC), 139.5
(ArC), 155.1 (d, JP–C 8.3, C@O); dP (121 MHz; CDCl3)
À3.28; m/z (EI) 311.0918 (8%, M+ÆC14H18NO5P
requires 311.0923), 267 (100), 238 (29), 210 (38), 130
(46), 115 (31).
4.17. General procedure B for the reaction of the 1-phenyl
ethanol with the phosphoryl oxazolidinones
Methyl magnesium bromide (0.48 cm3, 1.43 mmol) was
added to a solution of 1-phenyl ethanol (175 mg,
1.43 mmol) in diethyl ether (4.5 cm3) at À78 ꢂC and
the solution was allowed to stir for 15 min. The solution
was warmed to ꢀ20 ꢂC, dichloromethane (3 cm3) was
added and the solution was made up to 10 cm3 witha
diethyl ether/dichloromethane 3:2 solution. From the

3136
S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
above solution, 1 cm3 was added to a solution of the N-
phosphoryl oxazolidinone (0.143 mmol) in diethyl ether
(2 cm3) and dichloromethane (1 cm3) at the required
temperature (À16, 2 or 17 ꢂC) and allowed to stir for
30 min. Aqueous satd ammonium chloride (5 cm3) was
added, the solution extracted with ethyl acetate
(3 · 10 cm3) and the combined organic layer washed
withaqueous satd sodium bicarbonate (10 cm 3) and
brine (10 cm3). The solution was dried over magnesium
sulfate, filtered and the solvent was removed using a
water pump and a cold trap. The residue was dried on
the water pump, and the 1H NMR spectrum of the
crude product was obtained from which the enantio-
meric excess of the phosphate was determined by the
addition of (R)-(À)-2,2,2-trifluoro-1-(9-anthryl) ethanol
(ꢀ4 mg per sample). The enantiomeric excess of the
unreacted 1-phenyl ethanol 8 was also determined by
chiral GC (b-cyclodextrin column, hydrogen as the car-
rier gas and temperature from 105 to 140 ꢂC by 2 ꢂC/
min; t1 = 10.7 min, t2 = 11.2 min).
uct contained a mixture of diastereoisomers (6:7, 19:20),
which were separated by repeated flash column chroma-
tography (50% ethyl acetate in petroleum ether 40–60).
[(SP,4S)-4-Isopropyl-5,5-dimethyl-2-oxo-oxazolidin-3-yl]-
phosphonic acid ethyl methyl ester 19. [a]D = À7.0 (c 1,
CHCl3); mmax (KBr disk)/cmÀ1 1772 and 1273; dH
(300 MHz; CDCl3) 0.96 [3H, td, J 7.0 and JP–H 0.9,
CH(CH3)2], 1.05 [3H, d, J 7.0, CH(CH3)2], 1.32 (3H,
t, J 7.1, CH2CH3), 1.39 (3H, s, CH3), 1.42 (3H, s,
CH3), 2.06 [1H, heptet d, J 7.0 and 2.2, (CH3)2CH],
3.67 (1H, dd, J 2.2 and 5.2, NCH), 3.87 (3H, d, JP–H
11.7, OCH3), 4.04–4.28 (2H, m, OCH2CH3); dC
(125 MHz; CDCl3) 16.3 (CH3CH2), 20.4 [(CH3)2CH],
21.4 [(CH3)2CH], 28.7 [(CH3)2C], 30.1 [(CH3)2C], 54.9
(d, JP–C 4.6, CH3O), 64.3 (d, JP–C 4.5, CH3CH2O),
70.2 (d, JP–C 2.1, CHN), 84.1 [d, JP–C 5.7, (CH3)2C],
155.3 (d, JP–C 6.0, C@O); dP (202 MHz; CDCl3)
À1.02; m/z (ES) 316 (32), 302 (100, M++Na), 294
(15), 280.1314 (67%, MH+ÆC11H23NO5P requires
280.1324).
4.18. Ethyl dichlorophosphate 2128
[(RP,4S)-4-Isopropyl-5,5-dimethyl-2-oxo-oxazolidin-3-yl]-
phosphonic acid ethyl methyl ester 20. [a]D = À33.7 (c 1,
CHCl3); mmax (KBr disk)/cmÀ1 1768 and 1259; dH
(300 MHz; CDCl3) 0.96 [3H, d, J 7.0, CH(CH3)2], 1.05
[3H, d, J 7.0, CH(CH3)2], 1.33 (3H, dt, J 7.1 and JP–H
7.1, CH2CH3), 1.40 (3H, s, CH3), 1.42 (3H, s, CH3),
2.04 [1H, heptet d, J 7.0 and 2.2, (CH3)2CH], 3.71
(1H, dd, J 2.2 and 5.1, NCH), 3.79 (3H, d, JP–H 11.7,
OCH3), 4.26 (2H, quintet, J 7.1, OCH2CH3); dC
(125 MHz; CDCl3) 16.2 (CH3CH2), 20.5 [(CH3)2CH],
21.5 [(CH3)2CH], 28.8 [(CH3)2C], 30.1 [(CH3)2C], 54.9
(d, JP–C 6.6, CH3O), 64.3 (d, JP–C 5.9, CH3CH2O),
70.2 (d, JP–C 2.1, CHN), 84.1 [d, JP–C 5.7, (CH3)2C],
155.3 (d, JP–C 6.0, C@O); dP (202 MHz; CDCl3)
À1.10; m/z (EI) 280.1313 (5%, MH+ÆC11H23NO5P
requires 280.1314), 236 (51), 192 (44), 164 (100).
A solution of triethylamine (9.07 cm3, 65.1 mmol) and
ethanol (3.80 cm3, 65.1 mmol) in petroleum ether
(100 cm3) was added over 1 h to a solution of phospho-
rus oxychloride (6.07 cm3, 65.1 mmol) in dry petroleum
ether 40–60 (50 cm3) at À30 ꢂC. The solution was
warmed to ꢀ18 ꢂC and allowed to stir for 2 h, filtered
under nitrogen and the solvent removed under reduced
pressure using a water pump. The remaining colourless
oil was purified by distillation (28 ꢂC, 0.35 mmHg)
(lit.28 117 ꢂC, 760 mmHg) to give the title compound
as a colourless oil (7.86 g, 48% yield); dH (200 MHz;
CDCl3) 1.43 (3H, td, J 7.0, JP–H 0.9, CH3CH2), 4.36
(2H, qd, J 7.0, JP–H 11.0, CH3CH2).
4.19. ( )-Ethyl methyl chlorophosphate 2228
A solution of triethylamine (2.88 cm3, 20.7 mmol) and
methanol (0.84 cm3, 20.7 mmol) in petroleum ether
(50 cm3) was added over 1 hto a solution of etyhl
dichlorophosphate 21 (3.37 g, 20.7 mmol) in dry petro-
leum ether 40–60 (30 cm3) at À30 ꢂC. The solution was
warmed to ꢀ18 ꢂC and allowed to stir for 3 h, filtered
under nitrogen and the solvent removed from the filtrate
under reduced pressure. The remaining colourless oil
was purified by distillation (22 ꢂC at 0.03 mmHg) to give
the title compound as a colourless oil (2.37 g, 72% yield);
dH (200 MHz; CDCl3) 1.35 (3H, td, J 7.0 and JP–H 1.2,
CH3CH2), 3.84 (3H, d, JP–H 13.7, CH3O), 4.14–4.37
(2H, m, CH3CH2); dC (125 MHz; CDCl3) 15.8 (d, JP–C
7.3, CH3CH2), 55.5 (d, JP–C 7.2, CH3O), 66.2 (d, JP–C
7.2, CH3CH2).
4.21. n-Butyl-phosphonic acid ethyl methyl ester 2429
n-Butyl lithium (1.6 cm3, 2.57 mmol) was added to a
solution of ethyl methyl chlorophosphate 22 (0.41 g,
2.57 mmol) in THF (10 cm3) at À78 ꢂC and left to react
for 15 min before the solution was warmed to ꢀ18 ꢂC
and allowed to stir for 2 h. Aqueous satd ammonium
chloride (5 cm3) was added and the solution extracted
withethyl acetate (3 · 10 cm3). The combined organic
layer was washed with aqueous satd sodium bicarbon-
ate (10 cm3), brine (10 cm3), dried over magnesium sul-
fate and filtered. The solvent was removed using rotary
evaporation to afford a slightly yellow oil, which was
purified via flashcolumn chromatography (gradient col-
umn, 40–80% ethyl acetate in petroleum ether 40–60) to
give a colourless oil (0.47 g, 73% yield); dH (300 MHz;
CDCl3) 0.91 (3H, t, J 7.3, CH3CH2), 1.30–1.43 (5H,
m, CH3CH2O and CH3CH2), 1.55–1.59 (2H, m,
CH3CH2), 1.67–1.73 (2H, m, CH3CH2), 3.72 (3H, d, J
10.78, CH3O), 4.06–4.13 (2H, m, CH3CH2); dC
(75 MHz; CDCl3) 13.9 (CH3CH2), 16.9 (d, JP–C 5.8,
CH3CH2), 24.1 (d, JP–C 17.3, CH2), 24.4 (CH2), 24.8
(d, JP–C 5.2, CH2), 26.2 (CH2), 52.4 (d, JP–C 6.6,
CH3O), 62.0 (d, JP–C 6.5, CH3CH2); dP (202 MHz;
4.20. [(SP,4S)-4-Isopropyl-5,5-dimethyl-2-oxo-oxazolidin-
3-yl]-phosphonic acid ethyl methyl ester 19 and [(RP,4S)-
4-isopropyl-5,5-dimethyl-2-oxo-oxazolidin-3-yl]-phosphonic
acid ethyl methyl ester 20
Using general procedure B, except using ethyl methyl
chlorophosphate 22 in THF (5 cm3), a colourless oil
was obtained (0.96 g, 86 % crude yield). The crude prod-

S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
3137
CDCl3) 34.34; m/z (EI) 181.0990 (27%, M+ÆC11H23-
4.24. (R)-Ethyl isopropyl methyl phosphate (R)-2530
NO5P requires 181.0993), 138 (83), 124 (49), 111
(100), 96 (45).
The title compound was prepared in accordance with an
established literature procedure30 to afford a colourless
oil (0.04 g); dH (300 MHz; CDCl3) 1.29–1.70 [9H, m,
CH3CH2 and (CH3)2CH], 3.72 (3H, d, JP–H 11.0,
CH3O), 4.09 (2H, quintet, J 7.3, CH3CH2), 4.63 [1H,
octet, J 6.3, (CH3)CH]; dC (75 MHz; CDCl3) 16.1 [d,
JP–C 6.7, (CH3)2CH], 23.5 (d, JP–C 5.0, CH3CH2), 53.9
(d, JP–C 6.0, CH3O), 63.5 (d, JP–C 5.8, CH3CH2), 72.6
[d, JP–C 5.8, (CH3)2CH]; dP (202 MHz; CDCl3) À0.26.
For GC, a b-cyclodextrin column was used withhydro-
gen as the carrier gas, and temperature from 65 to
120 ꢂC by 0.3 ꢂC/min; tR = 53.82 min.
4.22. (S)-Ethyl methyl isopropyl phosphate (S)-2519b
Methyl magnesium chloride (0.55 cm3, 1.65 mmol) was
added to a solution of 2-propanol (99 mg, 1.65 mmol)
in diethyl ether (4.5 cm3) at À78 ꢂC and the solution
was allowed to stir for 15 min. The solution was warmed
to ꢀ20 ꢂC, dichloromethane (3 cm3) was added and the
solution was made up to 10 cm3 with a diethyl ether/
dichloromethane 3:2 solution. From the above solution,
1 cm3 was added to a solution of [(RP,4S) 4-isopropyl-
5,5-dimethyl-2-oxo-oxazolidin-3-yl]-phosphonic
acid
ethyl methyl ester 20 (47 mg, 0.165 mmol) in diethyl
ether (2 cm3) and dichloromethane (1 cm3) at ꢀ18 ꢂC
and allowed to stir for 24 h. Aqueous satd ammonium
chloride (5 cm3) was added, the solution extracted with
ethyl acetate (3 · 10 cm3), the combined organic layer
washed with aqueous satd sodium bicarbonate
(10 cm3), brine (10 cm3), dried over magnesium sulfate,
filtered and the solvent was removed using rotary evap-
oration to afford a colourless oil (22 mg, 100% conver-
sion). Further purification using flash column
chromatography (20% ethyl acetate in petroleum ether
40–60) led to the loss of the product. Selected NMR sig-
nals of crude material: dH (500 MHz; CDCl3) 1.26–1.29
[9H, m, CH3CH2 and (CH3)2CH], 3.70 (3H, d, JP–H 8.2,
CH3O), 4.04 (2H, q, J 7.0, CH3CH2), 4.59 [1H, octet, J
6.4, (CH3)2CH]; dC (125 MHz; CDCl3) 16.2 (d, JP–C 6.2,
CH3CH2), 23.7 [d, JP–C 5.2, (CH3)2CH], 54.0 (d, JP–C
6.2, CH3CH2), 63.7 [d, JP–C 5.2, (CH3)2CH], 72.7 (d,
JP–C 6.3, CH3O). For GC, a b-cyclodextrin column
was used with hydrogen as the carrier gas, and
temperature from 65 to 120 ꢂC by 0.3 ꢂC/min;
tR = 52.95 min.
References
1. Dwek, R. A. Chem. Rev. 1996, 96, 683.
2. Berridge, M. J. Nature 1984, 312, 315.
3. Guijarro, D.; Mancheno, B.; Yus, M. Tetrahedron 1994,
50, 8551.
4. Quast, H.; Dietz, T. Synthesis 1995, 1300.
5. (a) Yanagisawa, A.; Hibino, H.; Nomura, N.; Yamamoto,
H. J. Am. Chem. Soc. 1993, 115, 5879; (b) Yanagisawa, A.;
Nomura, N.; Yamamoto, H. Tetrahedron 1994, 50, 6071.
6. For examples, see: (a) Slotin, L. A. Synthesis 1977, 737; (b)
Oza, V. B.; Corcoran, R. C. J. Org. Chem. 1995, 60, 3680;
(c) Uchiyama, M.; Aso, Y.; Noyori, Y.; Hayakawa, Y. J.
Org. Chem. 1993, 58, 373; (d) Chouinard, P. M.; Bartlett,
P. A. J. Org. Chem. 1986, 51, 75; (e) Marugg, J. E.;
McLaughlin, L. W.; Piel, N.; Tromp, M.; van der Marel,
G. A.; van Boom, J. H. Tetrahedron Lett. 1983, 24, 3989;
(f) Khwaja, T. A.; Reese, C. B.; Stewart, J. C. M. J. Chem.
Soc. 1970, 2092; (g) Evans, D. A.; Gage, J. R.; Leighton, J.
L. J. Am. Chem. Soc. 1992, 114, 9434.
7. Jones, S. In Biotechnology; Rehm, H. J., Reed, G., Eds.;
Wiley-VCH: Weinheim, 2000; Vol. 8b, p 221.
8. Crans, D. C.; Whitesides, G. M. J. Am. Chem. Soc. 1985,
107, 7008.
4.23. ( )-Ethyl methyl isopropyl phosphate 2516
9. (a) Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc.
2001, 123, 10125; (b) Sculimbrene, B. R.; Morgan, A. J.;
Miller, S. J. J. Am. Chem. Soc. 2002, 124, 11653; (c)
Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. Chem.
Commun. 2003, 1781; (d) Sculimbrene, B. R.; Xu, Y.;
Miller, S. J. J. Am. Chem. Soc. 2004, 126, 13182.
10. (a) Jones, S.; Smanmoo, C. Tetrahedron Lett. 2004, 45,
1585; (b) Jones, S.; Smanmoo, C. Org. Lett. 2005, 7, 3271.
11. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta
1997, 30, 3.
12. Evans, D. A.; Anderson, J. C.; Taylor, M. K. Tetrahedron
Lett. 1993, 34, 5563.
13. Crich, D.; Yao, Q.; Filzen, G. F. J. Am. Chem. Soc. 1995,
117, 11455.
14. (a) Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. J.
Chem. Soc., Perkin Trans. 1 1999, 387; (b) Bull, S. D.;
Davies, S. G.; Key, M.-S.; Nicholson, R. L.; Savory, E. D.
Chem. Commun. 2000, 1721.
15. Thatcher, G. R. J.; Kluger, R. Adv. Phys. Org. Chem.
1989, 25, 99.
n-Butyl lithium (1 cm3, 1.6 mmol) was added to a solu-
tion of 2-propanol (0.10 g, 1.6 mmol) in THF (5 cm3)
at À78 ꢂC and the solution was allowed to stir for
15 min. A solution of rac-ethyl methyl chlorophosphate
22 (0.29 g, 1.6 mmol) in THF (2 cm3) was added at
À78 ꢂC and the solution was warmed to ꢀ18 ꢂC and
allowed to stir for 13 h. Aqueous satd ammonium chlo-
ride (5 cm3) was added and the solution extracted with
ethyl acetate (3 · 10 cm3). The combined organic layer
was washed with aqueous satd sodium bicarbonate
(10 cm3), brine (10 cm3), dried over magnesium sulfate
and filtered. The solvent was removed using rotary evap-
oration to afford a colourless oil (0.22 g, 75% yield); dH
(300 MHz; CDCl3) 1.22–1.27 [9H, m, CH3CH2 and
(CH3)2CH], 3.65 (3H, d, JP–H 11.1, CH3O), 4.04 (2H,
quintet, J 7.1, CH3CH2), 4.55 [1H, octet, J 6.3,
(CH3)2CH]; dC (125 MHz; CDCl3) 16.1 (d, JP–C 6.2,
CH3CH2), 23.6 [d, JP–C 5.2, (CH3)2CH], 53.8 (d, JP–C
6.2, CH3CH2), 63.4 [d, JP–C 6.2, (CH3)2CH], 72.5 (d,
JP–C 6.3, CH3O). For GC, a b-cyclodextrin column
was used with hydrogen as the carrier gas, and temper-
ature from 65 to 120 ꢂC by 0.3 ꢂC/min; t1 = 52.95 min,
t2 = 53.83 min.
16. Hall, C. R.; Inch, T. D. J. Chem. Soc., Perkin Trans. 1
1979, 1104.
17. Crystallographic data (excluding structure factors) for
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 280668. Copies of the
data can be obtained, free of charge, on application to

3138
S. Jones, D. Selitsianos / Tetrahedron: Asymmetry 16 (2005) 3128–3138
CCDC, 12 Union Road, Cambridge CB2 1EX, UK [fax:
+44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
24. Crich, D.; Jiao, X.-Y. J. Am. Chem. Soc. 1996, 118,
6666.
18. Dharanipragada, R.; Bruck, M.; Hruby, V. J. Acta
Crystallogr. C 1992, C48, 1239.
25. Hammerschmidt, F.; Voellenkle, H. Liebigs Ann. Chem.
1986, 2053.
19. (a) Cooper, B. D.; Hall, C. R.; Harrison, J. M.; Inch, T. D.
J. Chem. Soc., Perkin Trans. 1 1977, 1969; (b) Nakayama,
K.; Thompson, W. J. J. Am. Chem. Soc. 1990, 112, 6936.
20. Lipton, M. F.; Sorensen, C. M.; Sadler, A. C.; Shapiro, R.
H. J. Organomet. Chem. 1980, 186, 155.
21. Kim, S.; Chung, K. N.; Yang, S. J. Org. Chem. 1987, 52,
3917.
22. Gerrard, W. J. Chem. Soc. 1945, 848.
23. OꢀHagan, D.; Tavasli, M. Tetrahedron: Asymmetry 1999,
10, 1189.
26. Ghosh, A. K.; Kincaid, J. F.; Haske, M. G. Synthesis
1997, 541.
27. Whittamore, P. R. O.; Bennett, S. N. L.; Simpson, I. PCT
Int. Appl., 2003, WO 2003074531 A1.
28. Hall, C. R.; Inch, T. D.; Pottage, C. Phosphorus Sulfur
Relat. Elem. 1981, 10, 229.
29. Baldwin, I. C.; Beckett, R. P.; Williams, J. M. J. Synthesis
1996, 34.
30. Cooper, D. B.; Hall, C. R.; Harrison, J. M.; Inch, T. D. J.
Chem. Soc., Perkin Trans. 1 1977, 1969.