Examining the origin of selectivity in the reaction of racemic alcohols with chiral N-phosphoryl oxazolidinones

Article abstract of DOI:10.1016/j.tetasy.2014.08.003

A range of known and novel N-phosphoryl oxazolidinones and imidazolidinones were prepared and screened in the kinetic resolution of a range of racemic magnesium chloroalkoxides. Models are proposed to account for the enantioselectivity achieved based on a combination of chiral relay effects, generation of transient stereochemistry and the structure of the intermediate magnesium alkoxide.

Full text of DOI:10.1016/j.tetasy.2014.08.003

Tetrahedron: Asymmetry 25 (2014) 1298–1308
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Examining the origin of selectivity in the reaction of racemic alcohols
with chiral N-phosphoryl oxazolidinones
Samuel Crook a, Nigel J. Parr b, Jonathan Simmons a, Simon Jones a,
⇑
a Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
b GlaxoSmithKline Research & Development Ltd, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2014
Accepted 5 August 2014
Available online 10 September 2014
A range of known and novel N-phosphoryl oxazolidinones and imidazolidinones were prepared and
screened in the kinetic resolution of a range of racemic magnesium chloroalkoxides. Models are proposed
to account for the enantioselectivity achieved based on a combination of chiral relay effects, generation of
transient stereochemistry and the structure of the intermediate magnesium alkoxide.
Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/3.0/).
1. Introduction
and Anderson showed that they could be used as enantioselective
acyl transfer reagents for affecting the kinetic solution of a small
Many biochemical processes are mediated by the selective for-
mation or cleavage of a phosphate monoester bond.1 Pioneering
work by Whitesides demonstrated that these specific biological
phosphorylation events can also be replicated in the laboratory
at preparative scale using isolated enzymes and appropriate cofac-
tors.2 Whilst the substrate specificity of many of these systems has
been explored, they are still limited to key interactions of struc-
tural features of the substrate molecule within the enzyme active
site. A radical solution to solving this problem has been presented
by Miller et al., generating bespoke short-peptide catalysts that are
tuned to the appropriate substrate and reaction class. The first
demonstration of this strategy was applied to the kinetic resolution
of racemic secondary alcohols employing histidine containing pep-
tides,3 and a related strategy was then used for the asymmetric
phosphorylation of a protected myo-inositol.4 This desymmetrisa-
tion could afford either enantiomer of the corresponding
monophosphate, by employing different peptide catalysts. The
monophosphates that were obtained were elaborated to afford a
range of inositol phosphate-derived natural products.5 Although
this approach afforded the desired phosphate esters in high yield
and enantioselectivity, it was only reported to be useful in the
phosphorylation of protected myo-inositols.
family of racemic secondary alcohols.6 This study was extended
by Davies et al. using 5,5-disubstituted oxazolidinones.7
Based on these reports, research from these laboratories has
been examining the potential of the use of chiral oxazolidinones
to develop an enantioselective phosphorylation procedure. In stark
contrast to acylation reactions, it was found that the kinetic reso-
lution of 1-phenylethanol gave very poor selectivity, with mecha-
nistic data indicating this to be a consequence of the reaction
proceeding via an SN2(P) pathway.8 This work presents further
studies in this area with an aim to better understand the origins
of the selectivity and hence develop more selective reagents.
2. Results
The impact of making structural and electronic variations was
first examined by preparing a range of chiral N-phosphoryl oxazo-
lidinones as described previously or using analogous methods.9 In
addition to these, a serine-derived N-phosphoryl oxazolidinone 4
was also considered that may facilitate additional elements of
coordinative control via the C4 hydroxymethyl group to the incom-
ing alkoxide nucleophile. Attempts to access this started by trans-
formation of N-Boc-L-TBDMS serine methyl ester 1 into the
Within this arena of chemistry, smaller reagent based solutions
to this problem have been presented, albeit in the context of con-
ducting much simpler kinetic resolution processes. Chiral oxazo-
lidinones have been shown to be useful in a wide variety of
transformations, mainly acting as chiral auxiliaries. Work by Evans
oxazolidinone 2 by a double Grignard addition, followed by imme-
diate cyclisation (Scheme 1).
Deprotonation of oxazolidinone 2 with n-BuLi, followed by
trapping with diethyl chlorophosphate afforded N-phosphoryl
oxazolidinone 3. However, treatment with TBAF led to migration
of the phosphoryl group to give phosphate ester 5 as evidenced
from the 1H NMR spectrum of the unpurified reaction mixture.
Attempted purification by flash column chromatography resulted
⇑
Corresponding author. Tel.: +44 (0)114 22 29483.
E-mail address: simon.jones@sheffield.ac.uk (S. Jones).
http://dx.doi.org/10.1016/j.tetasy.2014.08.003
0957-4166/Ó 2014 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

S. Crook et al. / Tetrahedron: Asymmetry 25 (2014) 1298–1308
1299
O
OTBDMS
OMe
1. 4.0 eq. PhMgBr
THF, 0 °C to rt
O
O
P
OEt
O
1.1 eq. MeMgCl
O
P
OEt
CH2Cl2, 0 °C to rt
O
NH
OH
2
OEt
X
N
t-BuO
N
H
OEt
2. t-BuOK, THF
O
Ph
R2
0 °C to rt
O
then 3, 7, 11,
14-18 or 19
OTBDMS
Ph
R1
11 14 19
Ph
R2
7
*
1
Ph
12
(10 eq)
21% over two steps
n-BuLi, THF,
-78 °C to rt
3
,
13
,
,
-
48%
then (EtO)2P(O)Cl,
-78 °C to rt
O
O
P
Scheme 4. Screening selectivity of reagents 3, 7, 11 and 14–19.
OEt
OEt
O
N
4
- not formed
TBAF, THF
O
O
P
Ph
Ph
OH
Ph
OEt
O
N
O
OEt
OTBDMS
Table 1
Initial screening of reagents 3, 7, 11 and 14–19 as described in Scheme 4a
Ph
O
NH
Ph
Entry
Reagent
Yieldb,c (%)
eeb,d (%)
5
- formed but not
OEt
OEt
3
O
Ph
isolated
P
O
O
P
O
OEt
O
N
1
57 (50)
0 (2)
3 (4)
OEt
Ph
Scheme 1. Attempted synthesis of hydroxy-serine oxazolidinone 4.
14
O
O
P
OEt
OEt
O
N
n-BuLi, THF, -78 °C to rt
2
3
67 (36)
91 (74)
O
O
O
P
OEt
then (EtO)2P(O)Cl,
-78 °C to rt
Ph
15
OEt
N
NH
Ph
N
N
O
O
P
OEt
68%
Ph
OEt
O
N
6
14 (15)
8 (5)
7
Ph
Ph
Ph
16
Scheme 2. Formation of N-phosphoryl imidazolidinone 7.
O
O
P
OEt
OEt
in decomposition. However, the silyl ether protected N-phosphoryl
oxazolidinone 3 was added to the selection of phosphorylating
reagents to be screened. Commercially available imidazolidinone
6 was also used. Deprotonation by treatment with n-BuLi, followed
by the addition of diethyl chlorophosphate, provided N-phosphoryl
imidazolidinone 7 in good yield (Scheme 2).
Since this imidazolidinone had a different substitution pattern
to the other oxazolidinones used, an analogue was required to
directly compare the reactivity and selectivity. The opposite enan-
tiomer of the analogous oxazolidinone was targeted due to the
ready availability of epoxide 8 starting material. This was ring-
opened with ammonia to afford a 1,2-amino alcohol and immedi-
ately treated with Boc2O to afford the t-butyl carbamate 9 in good
yield over both steps. Treatment with t-BuOK gave the oxazolidi-
none 10, which was phosphorylated under standard conditions
to provide the target N-phosphoryl oxazolidinone 11 in good yield
(Scheme 3).
O
N
4
69 (57)
17
O
O
O
P
OEt
OEt
O
N
5
6
7
88 (87)
62 (58)
68 (59)
15 (15)
11 (10)
5 (5)
Ph
Ph
Ph
18
O
P
OEt
OEt
O
N
P
3
Ph
OTBDMS
O
EtO
EtO
O
N
O
19
O
8
0 (0)
85 (66)
—
O
P
OEt
9e
ꢀ7 (ꢀ8)
OEt
N
N
Ph
O
7
O
1. NH3(aq), MeOH, rt
O
10
50 (40)
75 (75)
4 (4)
5 (4)
O
P
OEt
HN
Ot-Bu
11e
OEt
HO
Ph
O
N
2. 3.0 eq. NaHCO3, Boc2O
EtOH, 0 °C to rt
Ph
8
Ph
9
11
67% over 2 steps
a
Reactions performed by addition of MeMgCl (0.15 mL, 3.0 M in THF, 0.45 mmol)
O
O
O
P
OEt
n-BuLi, THF
t-BuOK, THF
to a solution of 1-phenyl ethanol 12 (0.50 g, 4.1 mmol) in CH2Cl2 (20 mL) at 0 °C.
After warming to room temperature for 1 h, the reaction was recooled to 0 °C, and
phosphorylating agent 3, 7, 11, 14–18 or 19 (0.43 mmol) was added as a solution in
CH2Cl2 (10 mL). The reaction was left to warm to room temperature overnight,
quenched with aqueous ammonium chloride, followed by standard work-up
procedures.
-78 °C to rt
0 °C to rt
OEt
O
NH
Ph
O
N
then (EtO)2P(O)Cl
-78 °C to rt
84%
Ph
11
10
81%
b
Scheme 3. Synthesis of N-phosphoryl oxazolidinone 11.
Values in parentheses represent the results of duplicate reactions.
Refers to isolated product.
Determined by chiral phase HPLC analysis.
THF used as solvent and n-BuLi as base.
c
d
e
As in earlier studies, the possibility of obtaining higher levels of
enantioselectivity was increased by adopting the conditions set out
by Evans and Davies which employed a large excess of racemic
alcohol, but this did require a protocol to directly determine the
selectivity of the phosphate ester product by chiral phase HPLC
analysis. The use of 10 equiv of 1-phenylethanol 12 allowed each
of the reactions to proceed to completion, but the selectivity
remained low in each case (Scheme 4, Table 1).
Although the selectivities were low, a clear pattern emerged,
with an increase in the steric bulk of the substituents at the 5-posi-
tion on the oxazolidinone leading to an increase in selectivity
(entries 1–5). The TBDMS-serine derived N-phosphoryl oxazolidi-
none 3 (entry 6) gave the phosphate ester 13 in 11% ee, comparable

1300
S. Crook et al. / Tetrahedron: Asymmetry 25 (2014) 1298–1308
to the benzyl system (compare entries 3 and 6). Both of these sys-
tems have a methylene linker providing torsional freedom, allow-
ing the group to be orientated away from the reacting centre. Use
of the rigid aminoindanol derived N-phosphoryl oxazolidinone 19
(entry 7) afforded the phosphate ester 13 with only 5% ee. N-Phos-
phoryl imidazolidinone 7 did not react under standard conditions.
However, when the reaction was carried out with n-BuLi in THF
(entry 9) it proceeded to complete conversion with 7% ee. The
use of N-phosphoryl oxazolidinone 11 under standard conditions
led to complete conversion to phosphate ester 13, which was
obtained with 4% ee (entry 10). A switch of the conditions to n-BuLi
in THF gave a similar result (entry 11). The selectivity and reactiv-
ity of the imidazolidone system compared favorably to the oxazo-
lidinone (entries 8–11), but did not offer any substantial benefit.
These latter results also confirmed that better selectivity was
provided with oxazolidinones that are doubly substituted at the
5-position.
The benzyl and isopropyl oxazolidinones 16 and 18 were the
most selective phosphorylating agents of those tested. N-Phos-
phoryl oxazolidinone 18 is a solid and so was easier to handle
and purify and was therefore used in an attempt to optimize the
reaction conditions (Scheme 5, Table 2). The standard reaction con-
ditions involved initially cooling the reaction mixture to 0 °C whilst
the reagents were combined, before being allowed to warm to rt
(entry 1). Maintaining the reaction at ꢀ78 °C (entry 2) or 0 °C led
to essentially no reaction, whilst increasing the temperature to
40 °C (entry 4) caused a drop in selectivity from 15% ee to 8% ee.
Interestingly, the yield also dropped in this case which may be
due to the phosphate product decomposing at elevated
temperature.
reaction with n-BuLi in THF (entry 7) led to essentially racemic
material. The use of NaH and KH (entries 8 and 9) led to a reversal
in selectivity, giving the opposite enantiomer of phosphate 13 with
9% and 6% ee, respectively. If the origin of these results lies in the
ability of the phosphoryl oxazolidinone to chelate with the cation
of the base, then pre-treatment with a Lewis acidic additive could
prove to be a useful strategy. Addition of MgCl2 to the phosphoryl
oxazolidinone for an hour prior to addition to the solution of alkox-
ide (entry 10) led to a slight decrease in ee (entry 1 vs entry 10).
However, the reactivity was shut-off entirely when LiCl was used
as the additive in conjunction with n-BuLi as the base and only
starting materials were recovered (entry 11); this was also the case
using ZnCl2 (entries 12 and 13). The final reaction parameter inves-
tigated was the effect of varying the concentration of the reaction
mixture (entries 14 and 15). Phosphate ester 13 was obtained with
15% ee, regardless of the concentration.
With the optimisation studies complete, a range of racemic
alcohol substrates were investigated which were selected based
on variations of the 1-phenylethanol skeleton to help glean more
mechanistic information. The substrates were either commercially
available, prepared by sodium borohydride reduction of the parent
ketone, or Grignard addition to the parent carbonyl compound or
epoxide. The corresponding racemic phosphate esters were pre-
pared for analysis by treating the racemic alcohols with n-BuLi
and quenching with diethyl chlorophosphate.
Each of the alcohol substrates were screened under the opti-
mised reaction conditions (Scheme 6) and the results are summa-
rised below (Table 3). Variation of the structure of the substrate
had a considerable effect on the reactivity and selectivity of the
procedure. The absolute stereochemistry of the major stereoisomer
of phosphate ester obtained in the reaction with 1-phenylethanol
was determined to be (S) by preparation of the phosphate ester
from commercially available enantiomerically pure alcohol and
comparison of the specific rotation and HPLC retention times.
O
O
O
P
OEt
OH
R-M, solvent, T o
C
P
OEt
OEt
O
∗
OEt
O
N
Ph
then 18
solvent, T o
C
Ph
Ph
Ph
12
(10 eq.)
13
18
O
P
OEt
R3
O
O
P
OEt
1.1 eq. MeMgCl
Scheme 5. Optimisation with reagent 18.
OH
R3
CH2Cl2, 0 °C to rt
OEt
OEt
O
O
N
R1
R2
then 18 CH2Cl2
0 °C
R1
Ph
Ph
R2
,
Switching from CH2Cl2 to a coordinating solvent THF had little
effect on the reaction (entry 5), but changing the base used did.
When n-BuLi was used (entry 6) to form a lithium alkoxide, the
selectivity of the reaction decreased to 8% ee. Performing the same
12, 20-27
18
13 28 35
-
(10 eq.)
Scheme 6. Substrate scope of reagent 18.
Table 2
Reaction optimisation of reagent 18 as described in Scheme 5a
Entry
T (°C)
R-M
Solvent
Additive
Concentration (mmol dmꢀ3
)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0 to rt
ꢀ78
MeMgCl
MeMgCl
MeMgCl
MeMgCl
MeMgCl
n-BuLi
n-BuLi
NaH
KH
MeMgCl
n-BuLi
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH2Cl2
THF
THF
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
—
—
—
—
—
—
—
—
13.6
13.6
13.6
13.6
13.6
13.6
13.6
13.6
13.6
13.6
13.6
13.6
13.6
4.5
88
0
0
15
—
—
8
14
8
0
40
37
66
56
65
56
57
43
0
0
0
56
47
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
2
ꢀ9
ꢀ6
10
—
—
—
—
MgCl2
LiCl
ZnCl2
ZnCl2
—
MeMgCl
n-BuLi
MeMgCl
MeMgCl
15
15
—
40.9
a
Reactions performed by addition of a solution of organometallic reagent to a solution of 1-phenyl ethanol 12 (0.50 g, 4.1 mmol) in solvent at the specified temperature.
After warming to room temperature for 1 h, the reaction was re-cooled to 0 °C, and phosphorylating agent 18 (0.43 mmol) was added as a solution in solvent. The reaction
was left to warm to room temperature overnight, quenched with aqueous ammonium chloride, followed by standard work-up procedures.
b
Refers to isolated product.
Determined by chiral phase HPLC analysis.
c

S. Crook et al. / Tetrahedron: Asymmetry 25 (2014) 1298–1308
1301
As the size of the R2 substituent was increased, the selectivity of
the phosphorylation increased. Changing the R2 methyl group of
substrate 12 to the R2 cyclohexyl group of substrate 20 led to an
increase from 15% ee to 19% ee (entries 1 and 2). A similar level
of selectivity, 20% ee, was achieved when the R2 substituent was
an isopropyl group in alcohol 21 (entry 3). However, when the size
of the R2 substituent was increased to a t-butyl group in alcohol 22,
conversion to the corresponding phosphate ester proceeded in less
than 5% (entry 4). Increasing the size of the R1 substituent from the
phenyl group of 1-phenylethanol 12 to the ortho-tolyl group of
alcohol 23 again caused a large decrease in reactivity (entry 5). Sur-
prisingly, when the size of the R1 substituent was decreased to a
benzyl group in substrate 24, the corresponding phosphate ester
32 was obtained with an increased 28% ee (entry 6). Changing
the isopropyl group of this substrate to a t-butyl group 25 again
shut off the reactivity (entry 7), whilst extending the benzyl chain
by an additional methylene unit 26, led to a decrease in reactivity
(entry 8). Tertiary alcohol 27 was subjected to the standard condi-
tions but was left to deprotonate with MeMgCl for 3 h at rt prior to
the addition of N-phosphoryl oxazolidinone 18. However, only
starting materials were recovered upon work-up (entry 9).
Based on these studies a model can start to be constructed for
the changes in reactivity and selectivity observed in these pro-
cesses. The more promising selectivities observed came from reac-
tions conducted in the presence of magnesium salts, whilst low
and opposite selectivities were obtained when potassium and
sodium salts were used. The structures of magnesium alkoxides
and magnesium chloro-alkoxides have been well studied, being
shown to adopt dimeric tetrahedral species in the solid state and
when dissolved.10–12 However, magnesium complexes formed by
reaction of alcohols with magnesium chloride tend to give octahe-
dral complexes.13 The reactions performed in this current study
used 10 equiv of alcohol and 1 equiv of MeMgCl. Thus, because of
the excess of alcohol present, it was unclear whether the reactive
species would exist in an octahedral or tetrahedral form. In order
to probe this, reactions were conducted with diminishing quanti-
ties of alcohol in THF to ensure the presence of a coordinating sol-
vent, akin to the previously reported structural studies (Table 3).
All reactions proceeded to completion based on the number of
equivalents of oxazolidinone 18 with a little change in the enanti-
oselectivity. Given that the species present when the alcohol is
completely deprotonated must be the dimeric tetrahedral based
system (Table 4, entry 3), it seems reasonable to assume that this
is the reactive species observed in all cases.
Table 4
Examination of the effect of the number of equivalents of alcohol 12 on the reactivity
and selectivity under the optimal conditions described in Scheme 6a
Entry
Reagent equivalencies
MeMgCl
eeb,c (%)
12
18
13
1
2
3
10
10
2
1
10
2
1
1
1
12 (12)
11 (13)
10 (10)
a
Reactions performed by addition of MeMgCl (3.0 M in THF) to a solution of
alcohol 12 in THF (20 mL) at 0 °C. After warming to room temperature for 1 h, the
reaction was re-cooled to 0 °C, and phosphorylating agent 18 (0.43 mmol) was
added as a solution in THF (10 mL). The reaction was left to warm to room tem-
perature overnight, quenched with aqueous ammonium chloride, followed by
standard work-up procedures.
b
Values in parentheses represent the results of duplicate reactions.
Determined by chiral phase HPLC analysis.
c
(a) With magnesium
Ph
Ph
O
O
P
OEt
O
Cl
Cl
O
Mg
N
Mg
O
Cl
O
O
solv
Cl
OEt
O
Mg
Ph
Mg
O
N
O
P
solv
Ph
Ph
O
O
Ph
Ph
solv = THF or ROH
Ph
36
(b) With lithium, sodium & potassium
R
O
M R
M M
O
O
R
O
M
O
O
O
P
Ph
O
N
O
Ph
Ph
Figure 1. Possible reactive intermediates.
complex 36, positioning the alkoxide nucleophile in the correct tra-
jectory for an intramolecular SN2(P) attack at the phosphorus cen-
tre. This is in accordance with previous studies indicating inversion
of stereochemistry at the phosphorus centre8 (Fig. 1a).
The drop in selectivity for the lithium, sodium and potassium
alkoxides might then be attributed to the different solution struc-
ture leading to a competitive reaction pathway that is either non-
selective or leads to the opposite enantiomer of product. In these
cases, formation of a phosphoryl oxazolidinone–magnesium alkox-
ide complex may not occur due to unfavorable disruption of the
alkoxide cubic cluster arrangement,14 thus leading to an intermo-
lecular reaction (Fig. 1b). As a consequence, since no chelation
control of the phosphoryl oxazolidinone exists, the reactive
conformation is likely to be different (e.g., by dipole minimisation),
leading to significantly different interactions between the
stereogenic elements. A related study by Eames et al. provides
support for this, demonstrating that kinetic resolution of N-acyl
oxazolidinones with the lithium alkoxide of 1-phenylethanol
proceeded in poor selectivity, but when ZnCl2 was employed as
an additive a drastic improvement in selectivity was observed.15
However, the reason for failure of ZnCl2 in the case of the
phosphoryl oxazolidinones is not clear.
Based on these assumptions of reactive intermediates, models
can then be proposed that accounts for the crucial role that the
5,5-gem-disubstitution pattern plays in attenuating the selectivity.
The substituents at the 5-position have a steric clash with the ste-
reodirecting group at the 4-position, forcing it towards the phos-
phoryl group, in an analogous manner to that suggested by
Davies.7 The stereochemical relay possibly perturbs the conforma-
tion of one of the ethoxy groups whilst leaving the other undis-
turbed, with this conformational bias setting up a transient chiral
Thus, upon addition of the phosphoryl oxazolidinone, displace-
ment of the superfluous solvent ligands would occur, leading to
Table 3
Demonstration of substrate scope of reagent 18 as described in Scheme 6a
Entry R1
R2
R3
Alcohol Product Yieldb,c (%) eeb,d (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Me
Cy
H
H
H
H
H
H
H
H
12
20
21
22
23
24
25
26
13
28
29
30
31
32
33
34
35
88 (87)
92 (92)
83 (24)
0 (0)
0 (0)
76 (75)
0 (0)
15 (15)
19 (18)
20 (21)
—
i-Pr
t-Bu
Me
i-Pr
t-Bu
o-Tolyl
Bn
Bn
Ph(CH2)2 i-Pr
Ph i-Pr
—
28 (28)
—
14 (13)
—
66 (66)
0 (0)
Me 27
a
Reactions performed by addition of MeMgCl (0.15 mL, 3.0 M in THF, 0.45 mmol)
to a solution of alcohol 12, 20–27 (4.1 mmol) in CH2Cl2 (20 mL) at 0 °C. After
warming to room temperature for 1 h, the reaction was re-cooled to 0 °C, and
phosphorylating agent 18 (0.43 mmol) was added as a solution in CH2Cl2 (10 mL).
The reaction was left to warm to room temperature overnight, quenched with
aqueous ammonium chloride, followed by standard work-up procedures.
b
Values in parentheses represent the results of duplicate reactions.
Refers to isolated product.
Determined by chiral phase HPLC analysis.
c
d

1302
S. Crook et al. / Tetrahedron: Asymmetry 25 (2014) 1298–1308
Ph
3. Conclusion
O
O
Cl
Cl
O
Mg
N
Mg
O
Further experimental evidence has been collated to help better
O
O
O
P
O
explain the stereoselectivity of the reactions of N-phosphoryl oxa-
zolidinones with magnesium chloroalkoxides. Models for the selec-
tivity have been proposed based upon the structure of the reactive
species, generation of a transient chiral environment about the
phosphorus centre, formation of diastereomeric reactive species,
and steric interactions between adjacent alkoxide moieties. Work
is now underway to explore these concepts further and develop
reagents that can both help substantiate the proposed theories
and additionally provide enhanced levels of stereoselectivity.
Ph
NP
O
O
O
O
Ph
Ph
)( H
4. Experimental
4.1. General information
Dry solvents were obtained either from the Grubbs dry solvent
system or by distillation. Triethylamine was distilled from KOH, at
atmospheric pressure and all other reagents were used as supplied
without purification, unless specified. Glassware was flame dried
and cooled under vacuum before use. Thin layer chromatography
was performed on aluminium backed plates pre-coated with silica
(0.2 mm, Merck DC-alufolien Kieselgel 60 F254). Plates were visual-
ised using UV light or by dipping in KMnO4 solution, followed by
exposure to heat. Flash column chromatography was performed
on silica gel (Merck Kieselgel 60 F254 230–400 mesh), unless other-
wise stated. 1H and 13C NMR spectra were measured using CDCl3 as
solvent unless otherwise stated, on a Bruker AV-250 or AV-
400 MHz machine with an automated sample changer. Chemical
shifts for carbon and hydrogen are given, on the d scale. Coupling
constants were measured in Hertz (Hz). 13C NMR spectra were
recorded using the JMOD method. Specific rotations were per-
formed on an Optical Activity Ltd. AA-10 automatic polarimeter
Figure 2. Possible model for the observed selectivity based upon a conformational
enforced transient chiral environment.
environment around the phosphorus atom that contributes
towards the selectivity of the reaction (Fig. 2).
Additionally, the dimeric magnesium alkoxide reactive com-
plexes contain two chiral alkoxide moieties, leading to the intrigu-
ing possibility of forming diastereomeric reactive complexes, one
of which may have enhanced or reduced reactivity or selectivity
(Fig. 3a). Also, interactions between the two alkoxide groups might
explain why some of the better selectivities were observed with
alcohol 24, since in this case, the increased size of the alcohol
allows for better interaction between the two alkoxide moieties
(Fig. 3b). Further experimental work is underway to probe each
of these factors. Naturally, it is possible that a combination of all
of these models operate either in a cooperative or non-cooperative
manner. Of course, if the reaction proceeds through a pentagonal
bipyramidal intermediate, then similar arguments to these exist.
However, in this case, these interactions now lead to differences
in energies of the ensuing intermediates, or the activation energies
for pseudorotation.
at 589 nm (Na line) and measured at 22 °C. [a] values are given
D
in 10ꢀ1 deg cm2 gꢀ1. Infrared spectra were recorded on either a
Perkin Elmer 1600 FTIR machine using 0.5 mm NaCl cells or a Per-
kin 100 Spectrometer fitted with an ATR accessory. Peaks between
1600 and 4000 cmꢀ1 with an absorbance of >10% were quoted. Low
resolution mass spectra (m/z) were recorded on a Kratos MS 25 or
MS 80 spectrometer supported by a DS 55 data system, operating
in either EI or ES mode. High resolution mass spectra (HRMS)
recorded for accurate mass analysis, were performed on either a
MicroMass LCT operating in Electrospray mode (TOF ES), or a
MicroMass Prospec operating in EI mode. HPLC was carried out
on a Gilson analytical system using chiral phase analytical columns
(4.8 mm ꢁ 250 mm). The flow rate was 1.00 mL/min and the detec-
tor was set at 254 nm. Melting points (mp) were measured on a
Gallenkamp melting point apparatus and are uncorrected. Elemen-
tal analysis was performed using a Perkin–Elmer 2400 CHN ele-
mental analyser.
(a) Diastereomeric reactive intermediates
Ph
Ph
(R)
(S)
O
Cl
Cl
O
O
Cl
Cl
Mg
N
Mg
N
Mg
Mg
O
O
O
O
P
O
P
(S) Ph
(S) Ph
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
(S)
(R)
O
O
Cl
Cl
O
Cl
Cl
O
Mg
N
Mg
N
Mg
Mg
O
O
O
P
O
P
(R) Ph
Unless otherwise stated, all reagents and substrates were used
as supplied. N-Phosphoryl oxazolidinones 14, 16, 17 and 19 were
prepared as previously described.8
(R)Ph
O
O
O
O
O
O
Ph
Ph
Ph
Ph
4.2. (4S)-4-tert-Butyldimethylsilyloxymethyl-2-oxazolidinone 2
(b) Enhanced interactions with alcohol 24
Enhanced
Magnesium turnings (1.46 g, 60.1 mmol) were stirred in THF
(15 mL). Bromobenzene (6.3 mL, 59.8 mmol) was added drop-wise
to the reaction mixture, which was heated to initiate an exother-
mic reaction. The remaining bromobenzene was diluted with THF
(30 mL) and the resulting solution was added to the reaction vessel
at a rate as to ensure a steady reflux. The reaction mixture was
interactions
Ph
Cl
O
Cl
Mg
N
Mg
O
O
O
P
O
O
Ph
O
Ph
Ph
Figure 3. Possible reactive intermediates.
cooled to 0 °C. N-Boc-O-t-Butyldimethylsilyl-L-serine methyl
ester16 1 (5.01 g, 15.0 mmol) was dissolved in THF (15 mL) and

S. Crook et al. / Tetrahedron: Asymmetry 25 (2014) 1298–1308
1303
the resulting solution was added drop-wise to the reaction vessel.
The reaction mixture was allowed to warm to rt and left stirring for
48 h, before being quenched by addition of NH4Cl(aq) (30 mL). The
resulting mixture was extracted with EtOAc (3 ꢁ 30 mL), washed
with brine (20 mL), dried over MgSO4 and the solvent was removed
under reduced pressure. The residue was dissolved in THF
(100 mL) and cooled to 0 °C. t-BuOK (1.25 g, 11.1 mmol) was added
as a single portion and the reaction was left stirring at this temper-
ature for 3 h, before being allowed to warm to rt and left stirring
overnight. The reaction was quenched with NH4Cl(aq) (30 mL) and
the resulting mixture was extracted with EtOAc (3 ꢁ 40 mL). The
combined organic extracts were washed with NaHCO3(aq) (20 mL)
and brine (20 mL), dried over MgSO4 and the solvent removed
under reduced pressure. The title compound 2 (1.19 g, 21%) was
obtained as a white solid, following recrystallisation from EtOAc;
7.7, C(Ph)2], 125.4 (2ꢁ ArCH), 125.8 (2ꢁ ArCH), 127.7 (ArCH),
128.2 (2ꢁ ArCH), 128.4 (ArCH), 128.7 (2ꢁ ArCH), 138.2 (ArC),
143.1 (ArC), 154.0 (d, JC–P 7.7, C@O); 31P NMR (101 MHz; CDCl3)
dP ꢀ5.51; m/z (EI+) 519.2205 (<1%, M+ C26H38NO6SiP requires
519.2206), 462 (100), 418 (15), 390 (10), 234 (22), 167 (61).
4.5. (4S,5S)-3-Diethyl phosphoryl 1,5-dimethyl-4-phenyl-2-imi-
dazolidinone 7
Prepared by general procedure A using (4S,5S)-1,5-dimethyl-4-
phenyl-2-imidazolidinone 6 (0.49 g, 2.58 mmol) providing the title
compound 7 (0.57 g, 68%) as a white solid, following purification
by flash column chromatography on silica gel, eluting with ethyl
acetate; mp 95.0ꢀ96.0 °C;
[
a
]
22 = ꢀ19.0 (c 1.0, CHCl3);
D
mmax (ATR)/cmꢀ1 2981, 1698; Found: C, 55.11; H, 7.02; N, 8.51;
mp 166.0–168.0 °C; [
a]
22 = ꢀ324.0 (c 0.25, CHCl3); mmax (ATR)/
C
15H23N2O4P requires C, 55.21; H, 7.10; N, 8.58; 1H NMR
D
cmꢀ1 3297, 2954, 2932, 2857, 1761, 1730; 1H NMR (400 MHz;
CDCl3) dH ꢀ0.05 (3H, s, SiCH3), ꢀ0.04 (3H, s, SiCH3), 0.87 [9H, s,
SiC(CH3)3], 3.22 (1H, dd, J 10.3, 8.0, CHHO), 3.33 (1H, dd, J 10.3,
4.8, CHHO), 4.60 (1H, dd, J 8.0, 4.8, CHNH), 5.87 (1H, s, NH),
7.27–7.43 (8H, m, ArCH), 7.54–7.58 (2H, d, J 7.1, ArCH); 13C NMR
(100 MHz; CDCl3) dC ꢀ5.7 (SiCH3), ꢀ5.6 (SiCH3), 18.1 [SiC(CH3)3],
25.8 [3ꢁ SiC(CH3)3], 61.6 (CHNH), 63.7 (CH2), 87.8 [C(Ph)2], 126.1
(2ꢁ ArCH), 126.2 (2ꢁ ArCH), 128.1 (2ꢁ ArCH), 128.5 (2ꢁ ArCH),
128.6 (2ꢁ ArCH), 138.6 (ArC), 142.3 (ArC), 158.0 (C@O); m/z (ES+)
384.2001 (100%, MH+ C22H30NO3Si requires 384.1995), 354 (55),
208 (33).
(400 MHz; CDCl3) dH 0.82 (3H, d, J 6.6, CHCH3), 1.17 (3H, td, J 7.1,
JP–H 1.0, OCH2CH3), 1.33 (3H, td, J 7.1, JP–H 1.0, OCH2CH3), 2.79
(3H, s, NCH3), 3.82–3.95 (2H, m, OCH2CH3), 3.95–4.02 (1H,
m, CHCH3), 4.06–4.16 (1H, m, OCHHCH3), 4.17–4.27 (1H, m,
OCHHCH3), 5.01 (1H, dd, J 8.3, JP–H 2.2, CHPh), 7.21–7.39 (5H, m,
ArCH); 13C NMR (100 MHz; CDCl3) dC 14.9 (CHCH3), 16.0–16.1
(2ꢁ OCH2CH3), 28.2 (NCH3), 56.5 (d, JC–P 6.9, CHCH3), 62.0 (d, JC–P
3.0, CHPh), 63.6 (d, JC–P 5.0, OCH2CH3), 63.9 (d, JC–P 6.0, OCH2CH3),
127.8 (2ꢁ ArCH), 128.3 (3ꢁ ArCH), 137.4 (ArC), 158.3 (d, JC–P 7.7,
CO); 31P NMR (101 MHz; CDCl3) dP ꢀ2.32; m/z (EI+) 326.1399
(36%, M+ C15H23N2O4P requires 326.1395), 311 (56), 255 (25),
189 (53), 147 (100), 138 (30), 132 (47).
4.3. General procedure A for the phosphorylation of oxazolidin-
ones and imidazolidinones
4.6. (1R,2S)-N-Boc-2-amino-1-methyl-2-phenyl-1-ethanol 917
Oxazolidinone or imidazolidinone (1 equiv) was dissolved in
THF (10 mL mmolꢀ1) and cooled to ꢀ78 °C. n-BuLi (2.5 M in hex-
anes, 1.1 equiv) was added drop-wise and the solution was allowed
to warm to rt. The reaction mixture was left stirring for 1 h, before
being cooled to ꢀ78 °C. Diethyl chlorophosphate (1 equiv) was
added drop-wise and the solution was allowed to warm to rt.
The reaction mixture was left stirring overnight, before being
quenched by the addition of NH4Cl(aq) (10 mL mmolꢀ1). The result-
ing mixture was extracted with EtOAc (3 ꢁ 15 mL), and the com-
bined organic extracts were washed with NaHCO3(aq) (10 mL),
brine (10 mL) and dried over MgSO4. After filtration, the solvent
was removed under reduced pressure, and the title compound
purified as described in the individual experiments.
(1R,2R)-(+)-1-Phenylpropylene oxide 8 (1.80 g, 13.4 mmol) was
dissolved in 33% NH3(aq) (20 mL) to form a cloudy mixture. MeOH
(30 mL) was added until the solution became clear and left to stir
at rt for 48 h. The reaction mixture was extracted with EtOAc
(50 mL), washed with H2O (30 mL), dried over MgSO4, filtered
and solvent removed under reduced pressure. The residue was dis-
solved in EtOH (100 mL) with stirring and cooled to 0 °C. NaHCO3
(2.60 g, 30.9 mmol) was added as a single portion, immediately fol-
lowed by Boc2O (2.39 g, 11.0 mmol). The resulting mixture was
allowed to warm to rt and left to stir for 48 h, before being filtered
through Hyflo SuperCelÒ and washed with Et2O (50 mL). The
solvent was removed under reduced pressure, the residue was
re-dissolved in Et2O (50 mL), filtered through Hyflo SuperCelÒ
and solvent removed under reduced pressure. The title compound
9 (2.25 g, 67%) was obtained as a clear oil that did not require any
4.4. (4S)-3-Diethyl phosphoryl 4-t-butyldimethylsilyloxymethyl-
2-oxazolidinone 3
further purification; [a]
22 = +24.0 (c 1.0, CHCl3); 1H NMR
D
(400 MHz; CDCl3) dH 1.06 (3H, d, J 6.4, CH3), 1.43 [9H, s, C(CH3)3],
2.48 (1H, d, J 5.4, OH), 4.05–4.07 (1H, m, CHOH), 4.38 (0.2H, br s,
rotamer A, CHNH), 4.62 (0.8H, br s, rotamer B, CHNH), 5.60 (0.8H,
br s, 1H, rotamer B NH), 5.98 (0.2H, br s, 1H, rotamer A NH),
7.26–7.36 (5H, m, ArCH); 13C NMR (100 MHz; CDCl3) dC 19.6
(CHCH3), 28.4 [C(CH3)3], 60.0 (CHPh), 70.2 (CHCH3), 79.7
[C(CH3)3], 127.5 (ArCH), 127.7 (3ꢁ ArCH), 128.4 (ArCH), 138.5
Prepared by general procedure A using (4S)-4-t-butyldimethyl-
silyloxymethyl-2-oxazolidinone 2 (0.35 g, 0.91 mmol) providing
the title compound 3 (0.23 g, 48%) as a white solid, following puri-
fication by flash column chromatography on silica gel, eluting with
a petroleum ether/ethyl acetate mixture (4:1); mp 110.0–122.5 °C;
[
a]
D
22 = ꢀ105.5 (c 0.55, CHCl3); mmax (ATR)/cmꢀ1 2929, 2857, 1758;
Found: C, 60.32; H, 7.50; N, 2.48. C26H38NO6PSi requires C, 60.09;
H, 7.37; N, 2.70; 1H NMR (400 MHz; CDCl3) dH ꢀ0.41 (3H, s, SiCH3),
ꢀ0.15 (3H, s, SiCH3), 0.82 [9H, s, SiC(CH3)3], 1.01 (3H, td, J 7.1, JH–P
1.0, OCH2CH3), 1.37 (3H, td, J 7.1, JH–P 1.1, OCH2CH3), 3.44–3.54 (1H,
m, OCHHCH3), 3.70 (1H, dd, J 11.3, 1.5, CHHOTBDMS), 3.73–3.82
(1H, m, OCHHCH3), 3.90 (1H, dd, J 11.3, 3.2, CHHOTBDMS), 4.30
(2H, pent, J 7.3, OCH2CH3), 5.00 (1H, br s, CHN), 7.23–7.38 (6H,
m, ArCH), 7.41–7.44 (2H, d, J 6.9, ArCH), 7.61–7.64 (2H, d, J 7.0,
ArCH); 13C NMR (100 MHz; CDCl3) dC ꢀ6.5 (SiCH3), ꢀ6.1 (SiCH3),
15.6 (d, JC–P 6.1, OCH2CH3), 16.1 (d, JC–P 7.7, OCH2CH3), 17.9
[SiC(CH3)3], 25.7 [3ꢁ SiC(CH3)3], 61.3 (CH2O), 63.8 (d, JC–P 5.4,
OCH2CH3), 64.9 (d, JC–P 6.1, OCH2CH3), 65.5 (CHN), 88.5 [d, JC–P
(ArC), 155.7 (C@O). No [a]
or 13C NMR were previously reported,
D
all other data were in accordance with the literature.
4.7. (4S,5R)-4-Phenyl-5-methyl-2-oxazolidinone 1018
(1R,2S)-N-Boc-2-amino-1-methyl-2-phenyl-1-ethanol 9 (1.91 g,
7.60 mmol) was dissolved in THF (100 mL) and cooled to 0 °C.
t-BuOK (1.05 g, 9.36 mmol) was added as a single portion and
the reaction was left stirring at this temperature for 3 h, before
being allowed to warm to rt overnight. The reaction was quenched
with NH4Cl(aq) (20 mL) and the resulting mixture was extracted
with EtOAc (3 ꢁ 30 mL). The combined organic extracts were

1304
S. Crook et al. / Tetrahedron: Asymmetry 25 (2014) 1298–1308
washed with brine (40 mL), dried over MgSO4, filtered and the sol-
vent was removed under reduced pressure. The title compound 10
(1.12 g, 84%) was obtained as a clear crystalline solid, following
recrystallisation from EtOAc/petroleum ether 40–60 °C; mp
1720; Found: C, 63.38; H, 6.88; N, 3.18. C22H28NO5P requires C,
63.30; H, 6.76; N, 3.36; 1H NMR (250 MHz; CDCl3) dH 0.82 [3H, d,
J 6.6, CH(CH3)2], 0.95 (3H, td, J 7.2, JP–H 1.0, OCH2CH3), 1.08 [3H,
d, J 7.2, CH(CH3)2], 1.38 [3H, td, J 7.2, JP–H 1.3, CH(CH3)2], 1.91–
2.03 [1H, m, CH(CH3)2], 3.00–3.16 (1H, m, OCHHCH3), 3.43–3.58
(1H, m, OCHHCH3), 4.32 (2H, pent, J 7.0, OCH2CH3), 5.01 (1H, dd,
J 3.1, JH–P 2.2, CHNP), 7.23–7.47 (8H, m, ArCH), 7.66–7.71 (2H, m,
ArCH); 13C NMR (62.5 MHz; CDCl3) dC 15.6 [CH(CH3)2], 15.7 (d,
JC–P 6.3, OCH2CH3), 16.1 (d, JC–P 6.9, OCH2CH3), 21.1 [1ꢁ CH(CH3)2],
30.0 [1ꢁ CH(CH3)2], 63.3 (d, JC–P 5.8, OCH2CH3), 65.0 (d, JC–P 6.7,
OCH2CH3), 69.4 (d, JC–P 3.1, CHN), 90.6 [C(Ph)2], 125.5 (2ꢁ ArCH),
125.6 (2ꢁ ArCH), 127.8 (ArCH), 128.3 (ArCH), 128.4 (2ꢁ ArCH),
128.8 (2ꢁ ArCH), 138.3 (2ꢁ ArC), 143.4 (C@O); 31P NMR
(101 MHz; CDCl3) dP ꢀ4.31; m/z (EI+) 417.1717 (3%, M+ C22H28NO5P
requires 417.1705), 374 (75), 274 (25), 207 (26), 195 (100), 167
(50), 138 (27).
106.5–108.0 °C; [a]
22 = +144.0 (c 0.25, CHCl3); 1H NMR (400 MHz;
D
CDCl3) dH 0.97 (3H, d, J 6.6, CH3), 4.93 (1H, d, J 6.6, CHPh), 5.03
(1H, quint, J 6.6, CHCH3), 5.83 (1H, s, NH), 7.23–7.28 (2H, m, ArCH),
7.31–7.46 (3H, m, ArCH); 13C NMR (100 MHz; CDCl3) dC 16.6 (CH3),
59.9 (CHPh), 77.2 (CHCH3), 126.9 (2ꢁ ArCH), 128.7 (ArCH), 128.8
(2ꢁ ArCH), 136.6 (ArC), 159.7 (C@O). No mp, [
a]
D or 13C NMR data
were previously reported, all other data were in accordance with
the literature.
4.8. (4S,5R)-3-Diethyl phosphoryl 4-phenyl-5-methyl-2-oxazolidi-
none 11
Prepared by general procedure A using (4S,5R)-4-phenyl-5-
methyl-2-oxazolidinone 10 (0.48 g, 2.71 mmol) providing the title
compound 11 (0.68 g, 81%) as a clear oil, following purification by
flash column chromatography on silica gel, eluting with a petro-
4.11. Phenyl cyclohexyl methanol 2021
Magnesium turnings (4.35 g, 0.179 mol) were stirred in dry THF
(25 mL). A few drops of bromobenzene (18.8 mL, 0.179 mol) were
added to the reaction mixture, which was heated to initiate an exo-
thermic reaction. The remaining aryl bromide was diluted with dry
THF (50 mL) and the resulting solution was added to the reaction
vessel at a rate as to ensure heating at a steady reflux. The reaction
mixture was cooled to 0 °C. Cyclohexane carboxaldehyde (10.5 mL,
0.087 mol) was dissolved in dry THF (25 mL) and the resulting
solution was added drop-wise to the reaction vessel. The reaction
mixture was allowed to warm to rt and left stirring for 24 h, before
being quenched by addition of NH4Cl(aq) (50 mL). The resulting
mixture was extracted with EtOAc (3 ꢁ 80 mL), washed with brine
(40 mL), dried over MgSO4, filtered and the solvent was removed
under reduced pressure. The title compound 20 (2.88 g, 17%) was
obtained as a white solid after purification by flash column chro-
matography on silica gel, eluting with a hexane/ethyl acetate mix-
ture (9:1); mp 48.0–49.0 °C (lit.22 46–48 °C); 1H NMR (400 MHz;
CDCl3) dH 0.90–1.31 (5H, m, CH2), 1.37–1.42 (1H, m, CHH), 1.59–
1.71 (3H, m, CH2), 1.77–1.83 (1H, m, CHH), 1.88 (1H, d, J 3.1, OH),
1.99–2.04 (1H, m, CHH), 4.39 (1H, dd, J 7.1, 3.1, CHOH), 7.27–
7.39 (5H, m, ArCH). All data were in accordance with the literature.
leum ether/ethyl acetate mixture (2:1); [a]
22 = +62.1 (c 0.95,
D
CHCl3); mmax (Solution)/cmꢀ1 3673, 2989, 2913, 1778, 1606; 1H
NMR (250 MHz; CDCl3) dH 1.02 (3H, dd, J 6.3, JP–H 0.6, CHCH3),
1.18 (3H, td, J 7.2, JP–H 1.3, OCH2CH3), 1.35 (3H, td, J 7.2, JP–H 0.9,
OCH2CH3), 3.79–4.02 (2H, m, OCH2CH3), 4.08–4.35 (2H, m,
OCH2CH3), 5.02 (1H, pent, J 6.6, CHCH3), 5.11 (1H, dd, J 7.2, JP–H
1.6, CHPh), 7.25–7.29 (2H, m, ArCH), 7.34–7.45 (3H, m, ArCH);
13C NMR (62.5 MHz; CDCl3) dC 15.8 (CH3CH), 15.9, (d, JC–P 7.3,
CH3), 16.0, (d, JC–P 7.3, CH3), 64.3 (d, JC–P 5.9, OCH2CH3), 64.6
(d, JC–P 6.0, OCH2CH3), 64.7 (d, JC–P 4.1, CHPh), 76.9 (d, JC–P 8.6,
CHCH3), 127.6 (2ꢁ ArCH), 128.7 (2ꢁ ArCH), 128.9 (ArCH), 135.8
(ArC), 155.6 (d, JC–P 8.7, C@O); 31P NMR (101 MHz; CDCl3) dP
ꢀ4.56; m/z (EI+) 313.1074 (6%, M+ C14H20NO5P requires 313.1079),
269 (100), 240 (32), 212 (42), 138 (69), 132 (86), 104 (45), 77 (56).
4.9. (4S)-3-Diethyl phosphoryl 4-benzyl-5,5-dimethyl-2-oxazoli-
dinone 15
Prepared by general procedure
A using (S)-4-benzyl-5,5-
dimethyl-2-oxazolidinone19 (0.66 g, 3.2 mmol) providing the title
compound 15 (0.81 g, 74%) as a white solid, following purification
by flash column chromatography on silica gel, eluting with a petro-
leum ether/ethyl acetate mixture (2:1); mp 49.0–50.5 °C;
4.12. 2-Methyl-1-phenyl-1-propanol 2123
[a
]
22 = ꢀ20.0 (c 0.5, CHCl3); mmax (ATR)/cmꢀ1 2991, 1760, 1719;
Isobutyrophenone (5.00 mL, 33.3 mmol) was dissolved in EtOH/
CH2Cl2 (5:1, 120 mL) with stirring. NaBH4 (2.42 g, 64.0 mmol) was
added as a single portion and the resulting mixture was left to stir
for 24 h. The reaction was quenched by addition of NH4Cl(aq)
(100 mL) and the organic solvents were removed under reduced
pressure. The residue was extracted with EtOAc (3 ꢁ 40 mL),
washed with brine (30 mL) and dried over MgSO4. After filtration,
the solvent was removed under reduced pressure, and the title
compound 21 (4.46 g, 89%) was obtained as a clear oil; 1H NMR
(250 MHz; CDCl3) dH 0.82 (3H, d, J 6.6, CH3), 1.03 (3H, d, J 6.9,
CH3), 1.88–2.07 [2H, m, CH(CH3)2 and OH], 4.37 (1H, d, J 6.6,
CHOH), 7.25–7.40 (5H, m, ArCH); 13C NMR (62.5 MHz; CDCl3) dC
18.2 (CH3), 19.0 (CH3), 35.3 [CH(CH3)2], 80.0 (CHOH), 126.6 (2ꢁ
ArCH), 127.4 (ArCH), 128.2 (2ꢁ ArCH), 143.7 (ArC). All data were
in accordance with the literature.
D
Found: C, 56.34; H, 7.15; N, 3.91. C16H24NO5P requires C, 56.30;
H, 7.09; N, 4.10; 1H NMR (250 MHz; CDCl3) dH 1.28 [3H, s, 1ꢁ
C(CH3)2], 1.33–1.41 [9H, m, 1ꢁ C(CH3)2 and 2ꢁ OCH2CH3], 2.96
(1H, dd, J 14.4, 10.4, CH2Ph), 3.35 (1H, dd, J 14.4, 3.5, CH2Ph),
4.11–4.36 (5H, m, CHN and 2ꢁ OCH2CH3), 7.17–7.32 (5H, m, ArCH);
13C NMR (100 MHz; CDCl3) dC 16.0 (d, JC–P 2.9, OCH2CH3), 16.2 (d,
JC–P 2.9, OCH2CH3), 22.5 [1ꢁ C(CH3)2], 28.5 [1ꢁ C(CH3)2], 37.4 (CH2-
Ph), 64.5 (d, JC–P 6.7, 2ꢁ OCH2CH3), 66.6 (d, JC–P 3.8, CHN), 83.4 [d,
JC–P 8.6, [C(CH3)2], 126.7 (ArCH), 128.6 (2ꢁ ArCH), 129.1 (2ꢁ ArCH),
136.9 (ArC), 154.3 (d, JC–P 8.6, C@O); 31P NMR (101 MHz; CDCl3) dP
ꢀ3.12; m/z (EI+) 341.1407 (29%, M+ C16H24NO5P requires
341.1392), 250 (53), 150 (49), 91 (100), 81 (42), 69 (52).
4.10. (4S)-3-Diethyl phosphoryl 4-isopropyl-5,5-diphenyl-2-oxa-
zolidinone 18
4.13. 1-Phenyl 2,2-dimethyl propanol 2224
Prepared by general procedure A using (S)-4-isopropyl-5,5-
diphenyl-2-oxazolidinone20 (3.72 g, 13.2 mmol) providing the title
compound 18 (4.15 g, 75%) as a white solid, following purification
by flash column chromatography on silica gel, eluting with a petro-
leum ether/ethyl acetate mixture (2:1); mp 107.0–109.0 °C;
Magnesium turnings (2.41 g, 99.1 mmol) were stirred in THF
(20 mL). 2-Bromo-2-methylpropane (11 mL, 98.0 mmol) was
added drop-wise to the reaction mixture, which was heated to ini-
tiate an exothermic reaction. The remaining alkyl bromide was
diluted with THF (40 mL) and the resulting solution was added to
[a
]
D
22 = ꢀ170.0 (c 0.5, CHCl3); mmax (ATR)/cmꢀ1 2981, 2967, 1758,

S. Crook et al. / Tetrahedron: Asymmetry 25 (2014) 1298–1308
1305
the reaction vessel at a rate as to ensure heating at a steady reflux.
The reaction mixture was cooled to 0 °C. Benzaldehyde (5.00 mL,
49.2 mmol) was dissolved in THF (20 mL) and the resulting solu-
tion was added drop-wise to the reaction vessel. The reaction mix-
ture was allowed to warm to rt and left stirring for 24 h, before
being quenched by addition of NH4Cl(aq) (30 mL). The resulting
mixture was extracted with EtOAc (3 ꢁ 40 mL), washed with brine
(30 mL), dried over MgSO4, filtered and the solvent removed under
reduced pressure. The title compound 22 (3.39 g, 42%) was
obtained as a white solid, following purification by flash column
chromatography on silica gel, eluting with a petroleum ether
(40–60)/ethyl acetate mixture (9:1); mp 44.0–45.0 °C (lit.,25 44–
45 °C); 1H NMR (400 MHz; CDCl3) dH 0.95 [9H, s, C(CH3)3], 1.85
(1 h, d, J 1.9, OH), 4.42 (1H, d, J 1.9, CHOH), 7.24–7.35 (5H, m, ArCH).
All data were in accordance with the literature.
which was heated to initiate an exothermic reaction. The remain-
ing bromobenzene was diluted with THF (125 mL) and the result-
ing solution was added to the reaction vessel at a rate as to ensure
heating at reflux. The reaction mixture was cooled to 0 °C and cop-
per(I) bromide (3.81 g, 20 mmol) was added portion-wise. The
reaction was left to stir for 30 min at below 7 °C, before being
cooled to 0 °C and 3,3-dimethyl-1,2-epoxybutane (1.00 g,
1.22 mL, 10 mmol) was added drop-wise to the reaction vessel.
The reaction mixture was allowed to warm to rt and left stirring
for 12 h, then quenched by addition of HCl (1 M, 50 mL). The
resulting mixture was extracted with EtOAc (3 ꢁ 30 mL), washed
with NaHCO3 (30 mL) and dried over MgSO4. The solvent was
removed under reduced pressure, followed by purification by flash
column chromatography on silica gel, eluting with petroleum ether
40–60 °C/EtOAC (9:1) to yield the title compound as a yellow oil
(1.05 g, 59%); mmax (ATR)/cmꢀ1 3457, 2953, 1604, 1494, 1478; 1H
NMR (400 MHz; CDCl3) dH 1.04 [9H, s, C(CH3)3], 1.54 (1H, s, CHOH),
2.50 (1H, dd, J 13.6, 10.7, CHH), 2.95 (1H, dd, J 13.6, 2.0, CHH), 3.47
(1H, dd, J 10.7, 2.0, CHOH), 7.24–7.28 (3H, m, ArCH), 7.33–7.37 (2H,
m, ArCH); 13C NMR (100 MHz, CDCl3) dH 25.9 (CH3), 34.8, [(CH3)3C],
38.4 (CH2), 80.6 (CHOH), 126.3 (ArCH), 128.6 (ArCH), 129.4 (ArCH),
4.14. 1-(o-Methylphenyl)ethanol 2326
20-Methylacetophenone (1.00 mL, 7.65 mmol) was dissolved in
EtOH/CH2Cl2 (6:1, 35 mL) with stirring. NaBH4 (0.46 g,
12.16 mmol) was added as a single portion and the resulting mix-
ture was left to stir for 24 h. The reaction was quenched upon addi-
tion of NH4Cl(aq) (40 mL) and organic solvents were removed under
reduced pressure. The product was extracted into EtOAc
(3 ꢁ 20 mL), washed with brine (20 mL) and dried over MgSO4.
After filtration, the solvent was removed under reduced pressure,
and the title compound 23 (0.83 g, 79%) was obtained as a clear
oil. 1H NMR (250 MHz; CDCl3) dH 1.49 (3H, d, J 6.4, CHCH3), 1.90
(1H, s, OH), 2.37 (3H, s, ArCH3), 5.15 (1H, q, J 6.4, CHCH3), 7.13–
7.30 (3H, m, ArCH), 7.53 (1H, dd, J 6.8, 1.0, ArCH); 13C NMR
(100 MHz; CDCl3) dC 18.9 (CH3), 23.9 (CH3), 66.8 (CHCH3), 124.5
(ArCH), 126.4 (ArCH), 127.2 (ArCH), 130.4 (ArCH), 134.2 (ArC),
143.9 (ArC). All data were in accordance with the literature.
139.9 (ArC); m/z (EI+) 178.1355 (<1%, M+, C12H18
O requires
178.1358), 160 (10), 145 (15), 121 (10), 103 (10), 92 (100). Data
were in accordance with the literature.
4.17. 5-Phenyl-2-methyl pentan-3-ol 2629
Magnesium turnings (2.72 g, 112 mmol) were stirred in dry THF
(20 mL) under an atmosphere of nitrogen. 2-Bromopropane
(13.8 g, 10.5 mL, 112 mmol) was added drop-wise to the reaction
mixture, which was heated to initiate an exothermic reaction.
The remaining 2-bromopropane was diluted with THF (150 mL)
and the resulting solution was added to the reaction vessel at a rate
as to ensure heating at reflux. The reaction mixture was cooled to
0 °C. 3-Phenylpropionaldehyde (5.00 g, 37.3 mmol) was dissolved
in THF (35 mL) and the resulting solution was added drop-wise
to the reaction vessel. The reaction mixture was allowed to warm
to rt and left stirring for 48 h, and quenched by addition of
NH4Cl(aq) (50 mL). The resulting mixture was extracted with
EtOAc (3 ꢁ 40 mL), washed with brine (25 mL) and dried over
MgSO4. After filtration, the solvent was removed under reduced
pressure and the title compound (5.20 g, 78%) was obtained as
faint yellow oil, after purification by flash column chromatography
on silica gel, eluting with petroleum ether 40–60 °C/EtOAc (8:1);
mmax (ATR)/cmꢀ1 3364, 2956, 2870, 1604, 1496, 1454; 1H NMR
(400 MHz; CDCl3) dH 0.94 [3H, dd, J 6.8, CH(CH3)2], 0.95 [3H, dd,
J 6.8, CH(CH3)2], 1.41 (1H, br s, OH), 1.67–1.87 [3H, m, CH(CH3)2
and CH2], 2.68 (1H, ddd, J 13.7, 9.4, 6.8, CHH), 2.88 (1H, ddd,
J 13.7, 9.9, 5.2, CHH), 3.43 (1H, ddd, J 9.4, 5.2, 3.5, CHOH),
7.20–7.34 (3H, m, ArCH), 7.25–7.35 (2H, m, ArCH); 13C NMR
(100 MHz; CDCl3) dC 17.2 (CH3), 18.8 (CH3), 32.5 (CH2), 33.7
[(CH3)2CH], 36.0 (CH2), 76.2 (CHOH), 125.8 (ArCH), 128.4 (ArCH),
4.15. 3-Methyl-1-phenyl-2-butanol 2427
Magnesium turnings (0.80 g, 32.9 mmol) were stirred in THF
(10 mL). Benzyl bromide (3.9 mL, 32.8 mmol) was added drop-wise
to the reaction mixture, which was heated to initiate an exother-
mic reaction. The remaining benzyl bromide was diluted with
THF (20 mL) and the resulting solution was added to the reaction
vessel at a rate as to ensure heating at a steady reflux. The reaction
mixture was cooled to 0 °C. Isobutyraldehyde (2.50 mL,
27.5 mmol) was dissolved in THF (10 mL) and the resulting solu-
tion was added drop-wise to the reaction vessel. The reaction mix-
ture was allowed to warm to rt and left stirring for 24 h, before
being quenched by the addition of NH4Cl(aq) (20 mL). The resulting
mixture was extracted with EtOAc (3 ꢁ 30 mL), washed with brine
(10 mL) and dried over MgSO4. After filtration, the solvent was
removed under reduced pressure and the title compound 24
(2.94 g, 65%) was obtained as a clear oil, following purification by
flash column chromatography on silica gel, eluting with a petro-
leum ether (40–60)/ethyl acetate mixture (7:3); 1H NMR
(250 MHz; CDCl3) dH 1.03 [6H, d, J 6.6, CH(CH3)2], 1.58 (1H, s,
OH), 1.69–1.88 [1H, m, CH(CH3)2], 2.62 (1H, dd, J 13.5, 9.4, CHHPh),
2.89 (1H, dd, J 13.5, 3.5, CHHPh), 3.57–3.65 (1H, m, CHOH), 7.23–
7.38 (5H, m, ArCH); 13C NMR (62.5 MHz; CDCl3) dC 17.4 (CH3),
18.9 (CH3), 33.1 [CH(CH3)2], 40.8 (CH2), 77.5 (CHOH), 126.4 (ArCH),
128.6 (2ꢁ ArCH), 129.4 (2ꢁ ArCH), 139.2 (ArC). All data were in
accordance with the literature.
128.5 (ArCH), 142.4 (ArC); m/z (EI+) 178.1365 (5%, M+, C12H18
O
requires 178.1358), 160 (17), 117 (43), 104 (53), 91 (100). Data
were in accordance with the literature.
4.18. 1,2-Dimethyl-1-phenyl-1-propanol 2723
Isobutyrophenone (5.00 g, 33.7 mmol) was dissolved in THF
(35 mL) and the resulting solution was cooled to ꢀ78 °C. MeMgCl
(13 mL, 3.0 M in THF, 39.0 mmol) was added drop-wise and the
resulting mixture was allowed to warm to rt and left to stir for
24 h. The reaction was quenched upon addition of NH4Cl(aq)
(10 mL), extracted into EtOAc (3 ꢁ 30 mL), washed with brine
(20 mL) and dried over MgSO4. After filtration, the solvent was
removed under reduced pressure and the title compound 27
4.16. 1-Phenyl-3,3-dimethylbutan-2-ol 2528
Magnesium turnings (4.86 g, 200 mmol) were stirred in dry THF
(35 mL) under an atmosphere of nitrogen. Bromobenzene (31.40 g,
21 mL, 200 mmol) was added drop-wise to the reaction mixture,

1306
S. Crook et al. / Tetrahedron: Asymmetry 25 (2014) 1298–1308
(5.31 g, 96%) was obtained as a pale yellow oil that did not require
any further purification. 1H NMR (400 MHz; CDCl3) dH 0.86 [3H, d, J
6.9 CH(CH3)2], 0.94 [3H, d, J 6.9 CH(CH3)2], 1.57 (3H, s, CCH3), 1.82
(1H, s, OH), 2.06 [1H, sept, J 6.9, CH(CH3)2], 7.25–7.29 (1H, m,
ArCH), 7.35–7.39 (2H, m, ArCH), 7.45–7.48 (2H, m, ArCH); 13C
NMR (62.5 MHz; CDCl3) dC 17.2 [CH(CH3)2], 17.5 [CH(CH3)2], 26.7
(CCH3), 38.6 [CH(CH3)2], 76.8 (COH), 125.3 (2ꢁ ArCH), 126.4
(ArCH), 127.9 (2ꢁ ArCH), 147.9 (ArC). All data were in accordance
with the literature.
4.22. Diethyl (phenyl cyclohexylcarbinyl) phosphate 28
Obtained from general procedure B using phenyl cyclohexylcar-
binyl 20 (0.12 g, 0.98 mmol) after purification by flash column
chromatography on silica gel eluting with petroleum ether 40–
60 °C/EtOAc (1:1) as a clear oil (0.56 g, 86%); mmax (film)/cmꢀ1
2985, 2928, 2854, 1452; 1H NMR (250 MHz; CDCl3) dH 0.83–1.28
(11H, m, 2ꢁ OCH2CH3 and cyclohexyl), 1.30–1.39 (1H, m, CHH),
1.60–1.87 (4H, m, cyclohexyl), 2.01–2.08 (1H, m, CHCHO), 3.73–
4.15 (4H, m, OCH2CH3), 4.97 (1H, t, J 7.9, CHO), 7.26–7.39 (5H, m,
ArCH); 13C NMR (100 MHz; CDCl3) dC 15.9 (d, JC–P 6.9, CH2CH3),
16.0 (d, JC–P 6.9, CH2CH3), 25.8 (d, JC–P 7.7, CH2), 26.2 (CH2), 28.7
(CH2), 29.0 (CH2), 44.2 (d, JC–P 6.9, CHCHO), 63.3 (d, JC–P 5.4, OCH2-
CH3), 63.5 (d, JC–P 5.4, OCH2CH3), 85.1 (d, JC–P 6.1, CHO), 127.2 (2ꢁ
ArCH), 128.0 (ArCH), 128.1 (2ꢁ ArCH), 139.6 (ArC); 31P NMR
(101 MHz; CDCl3) dP ꢀ0.01; m/z (EI+) 326.1643 (22%, M+
C17H27O4P requires 326.1647), 243 (100), 172 (33), 155 (27), 91
(55), 81 (33).
4.19. General procedure B for the phosphorylation of authentic
samples of racemic alcohols
Alcohol (1 equiv) was dissolved in dry THF (20 mL mmolꢀ1
)
with stirring and the solution was cooled to ꢀ78 °C. n-BuLi
(0.40 mL, 2.5 M in hexanes, 1.05 equiv) was added drop-wise and
the solution was allowed to warm to rt. The reaction mixture
was left stirring for 1 h, then cooled to ꢀ78 °C. Diethyl chlorophos-
phate (1.1 equiv) was added drop-wise and the solution was
allowed to warm to rt. The reaction mixture was left stirring for
2 h, quenched by the addition of NH4Cl(aq) (10 mL) and the result-
ing mixture extracted with EtOAc (3 ꢁ 20 mL). The combined
organic extracts were washed with NaHCO3(aq) (10 mL), brine
(10 mL) and dried over MgSO4. After filtration, the solvent was
removed under reduced pressure, and the target compound puri-
fied as noted in the individual experiments.
Employing general procedure C, alcohol 20 (0.50 g, 2.63 mmol)
was treated with MeMgCl (0.10 mL, 3.0 M in THF, 0.30 mmol) and
N-phosphoryl oxazolidinone 18 (0.11 g, 0.26 mmol) to afford phos-
phate ester 28 (0.08 g, 92%) in 19% ee; [
a
]
D
22 = ꢀ10.0 (c 1.0, CHCl3);
HPLC, Chiralcel OJ, 3% i-PrOH in hexane; 0.5 mL minꢀ1; tr 11.1 min
(major) and 15.5 min (minor).
4.23. Diethyl 2-methyl-1-phenyl-1-propyl phosphate 2930
Obtained from general procedure B using 2-methyl-1-phenyl-1-
propanol 21 (0.25 g, 1.66 mmol) after purification by flash column
chromatography on silica gel eluting with petroleum ether 40–
60 °C/EtOAc (1:2) as a clear oil 29 (0.28 g, 58%); mmax (film)/cmꢀ1
2980, 2966, 2934, 1455; 1H NMR (250 MHz; CDCl3) dH 0.81 [3H,
d, J 6.9, CH(CH3)2], 1.05–1.13 [6H, m, CH(CH3)2 and OCH2CH3),
1.24 (3H, td, J 7.2, JP–H 1.3), 2.07–2.21 [1H, m, CH(CH3)2], 3.75–
4.16 (4H, m, OCH2), 4.98 (1H, t, J 7.5, CHO), 7.26–7.37 (5H, m,
ArCH); 13C NMR (100 MHz; CDCl3) dC 15.9 (d, JC–P 6.9, CH2CH3),
16.0 (d, JC–P 7.7, CH2CH3), 18.4 [CH(CH3)2], 18.5 [CH(CH3)2], 34.8
[d, JC–P 6.9, CH(CH3)2], 63.4 (d, JC–P 5.4, 2ꢁ OCH2), 85.8 (d, JC–P 6.1,
CHO), 127.1 (2ꢁ ArCH), 128.0 (ArCH), 128.1 (2ꢁ ArCH), 139.6
(C@O); 31P NMR (101 MHz; CDCl3) dP ꢀ0.01; m/z (EI+) 286.1348
(27%, M+ C14H23O4P requires 286.1334), 243 (100), 132 (39), 109
(44), 91 (55). No analytical data are reported in the literature.
Employing general procedure C, alcohol 21 (0.50 g, 3.33 mmol)
was treated with MeMgCl (0.13 mL, 3.0 M in THF, 0.39 mmol) and
N-phosphoryl oxazolidinone 18 (0.14 g, 0.33 mmol) to afford phos-
4.20. General procedure C for the asymmetric phosphorylation
of alcohol substrates using reagent 18
Alcohol (0.50 g, 10 equiv) was dissolved in CH2Cl2 (20 mL)
and cooled to 0 °C. MeMgCl (1.1 equiv, 3.0 M in THF) was added
drop-wise and the reaction mixture was allowed to warm to rt.
After 1 h the resulting solution was cooled to 0 °C and N-phos-
phoryl oxazolidinone 18 (1 equiv) was added drop-wise as a
solution in CH2Cl2 (10 mL). After 1 h, the reaction vessel was
allowed to warm to rt and left to stir overnight. The reaction
was quenched upon addition of NH4Cl(aq) (10 mL), extracted
into CH2Cl2 (3 ꢁ 30 mL) and washed with NaHCO3(aq) (10 mL)
and brine (10 mL). The organic layer was separated, dried over
MgSO4, filtered and solvent removed under reduced pressure.
The residue was purified by column chromatography and the
ee of the resulting phosphate ester was analysed via chiral
HPLC.
phate ester 29 (0.07 g, 83%) in 20% ee; [
a]
D
22 = ꢀ6.6 (c 1.5, CHCl3);
4.21. Diethyl 1-phenylethyl phosphate 138
HPLC, Chiralcel OJ, 0.5% i-PrOH in hexane; 1.0 mL minꢀ1
; tr
17.9 min (major) and 24.9 min (minor).
Obtained from general procedure B using 1-phenylethanol 12
(0.12 g, 0.98 mmol) after purification by flash column chroma-
tography on silica gel eluting with petroleum ether 40–60 °C/
EtOAc (1:1) as a clear oil (0.14 g, 53%); 1H NMR (250 MHz;
CDCl3) dH 1.20 (3H, td, J 7.2, JP–H 0.9, OCH2CH3), 1.30 (3H, td, J
7.2, JP–H 0.9, OCH2CH3), 1.65 (3H, d, J 6.6, CHCH3), 3.88–4.19
(4H, m, OCH2CH3), 5.49 (1H, pent, J 6.6, CHCH3), 7.28–7.42 (5H,
m, ArCH); 13C NMR (100 MHz; CDCl3) 16.0 (d, JC–P 7.7, 2ꢁ CH2CH3),
24.2 (d, JC–P 4.6, CHCH3), 63.6 (2ꢁ OCH2), 76.6 (CHCH3), 125.9
(2ꢁ ArCH), 128.1 (ArCH), 128.5 (2ꢁ ArCH), 141.8 (ArC); 31P
NMR (101 MHz; CDCl3) dP ꢀ0.01. All data were in accordance
with the literature.
4.24. Diethyl (1-phenyl-2,2-dimethylpropyl) phosphate 3031
Obtained from general procedure B using 1-phenyl-2,2-dimeth-
ylpropanol 22 (0.50 g, 3.04 mmol) after purification by flash col-
umn chromatography on silica gel eluting with petroleum ether
40–60 °C/EtOAc (1:1) as a clear oil 30 (0.69 g, 76%); mmax (film)/
cmꢀ1 2978, 2959, 2909, 1481, 1454; 1H NMR (250 MHz; CDCl3)
dH 0.97 [9H, s, C(CH3)3], 1.09 (3H, td, J 7.2, JP–H 1.2, CH2CH3), 1.20
(3H, td, J 6.9, JP–H 1.0, CH2CH3), 3.72–4.14 (4H, m, 2ꢁ OCH2), 5.00
(1H, d, JP–H 8.5, CH), 7.30–7.36 (5H, m, ArCH); 13C NMR (100 MHz;
CDCl3) dC 15.8 (d, JC–P 7.7, CH2CH3), 16.0 (d, JC–P 6.9, CH2CH3), 25.9
[3ꢁ C(CH3)3], 36.0 [d, JC–P 6.9, C(CH3)3], 63.4 (d, JC–P 5.4, OCH2),
63.5 (d, JC–P 5.4, OCH2), 87.8 (d, JC–P 6.1, CHO), 127.5 (2ꢁ ArCH),
127.7 (ArCH), 127.9 (2ꢁ ArCH), 138.3 (ArC); 31P NMR (101 MHz;
CDCl3) dP ꢀ0.01; m/z (EI+) 300.1496 (3%, M+ C15H25O4P requires
300.1490), 244 (100), 215 (33), 107 (46), 91 (58). Only 31P and
selected 1H NMR signals are reported in the literature.
Employing general procedure C, alcohol 12 (0.50 g, 4.09 mmol)
was treated with MeMgCl (0.15 mL, 3.0 M in THF, 0.45 mmol) and
N-phosphoryl oxazolidinone 18 (0.18 g, 0.43 mmol) to afford phos-
phate ester 13 (0.11 g, 88%) in 15% ee; [
a
]
22 = ꢀ7.9 (c 0.9, CHCl3) for
D
the (S) enantiomer; HPLC, Chiralcel OJ, 8% i-PrOH in hexane;
1 mL minꢀ1; tr 8.7 min (major) and 13.3 min (minor).

S. Crook et al. / Tetrahedron: Asymmetry 25 (2014) 1298–1308
1307
Employing general procedure C, alcohol 22 (0.50 g, 3.05 mmol)
was treated with MeMgCl (0.11 mL, 3.0 M in THF, 0.33 mmol) and
N-phosphoryl oxazolidinone 18 (0.13 g, 0.31 mmol) to failed to
provide any phosphate ester 30 and thus no chiral phase HPLC data
were obtained.
8.8, 3.4, CHO), 7.19–7.29 (5H, m, ArCH); 13C NMR (100 MHz; CDCl3)
dC 16.0 (d, JC–P 8.0, CH3CH2), 16.1 (d, JC–P 8.0, CH3CH2), 26.2
[(CH3)3C], 35.8 [d, JC–P 4.0, (CH3)3C], 37.9 PhCH2), 62.9 (d, JC–P 6.0,
OCH2), 63.3 (d, JC–P 6.0, OCH2), 88.1 (d, JC–P 8.0, OCH), 126.3 (ArCH),
128.3 (2ꢁ ArCH), 129.6 (2ꢁ ArCH), 138.7 (ArC); 31P NMR
(101 MHz; CDCl3) dP ꢀ1.60; m/z (ESI+) 315.1726 (100%, MH+,
4.25. Diethyl 1-[1-(o-methylphenyl)ethyl] phosphate 31
C16H28O4P requires 315.1725).
Employing general procedure C alcohol 24 (0.50 g, 2.81 mmol)
Obtained from general procedure
B
using 1-(o-methyl-
was treated with MeMgCl (0.10 mL, 3.0 M in THF, 0.31 mmol)
phenyl)ethanol 23 (0.20 g, 1.47 mmol) after purification by flash
column chromatography on silica gel eluting with petroleum ether
40–60 °C/EtOAc (1:1) as a clear oil 31 (0.32 g, 79%); mmax (film)/
cmꢀ1 2983, 2932, 1480,1463; 1H NMR (250 MHz; CDCl3) dH 1.20
(3H, td, J 7.2, JP–H 1.3, CH2CH3), 1.29 (3H, td, J 6.9, JP–H 0.9, CH2CH3),
1.61 (3H, d, J 6.9, CHCH3), 2.39 (3H, s, ArCH3), 3.87ꢀ4.18 (4H, m, 2ꢁ
OCH2), 5.71 (1H, app pent, J 6.9, CHCH3), 7.13ꢀ7.27 (3H, m, ArCH),
7.47–7.50 (1H, m, ArCH); 13C NMR (62.5 MHz; CDCl3) dC 15.9 (d, JC–P
7.5, CH2CH3), 16.0 (d, JC–P 6.9, CH2CH3), 19.0 (ArCCH3), 23.6
(d, JC–P 5.0, CHCH3), 63.6 (d, JC–P 5.7, 2ꢁ OCH2), 73.6 (d, JC–P 4.8,
CHCH3), 125.5 (ArCH), 126.3 (ArCH), 127.8 (ArCH), 130.4 (ArCH),
134.0 (ArCCH3), 140.1 (ArCCHCH3); 31P NMR (101 MHz; CDCl3)
dP ꢀ1.73; m/z (EI+) 272.1170 (<1%, M+ C13H21O4P requires
272.1177), 155 (57), 118 (100), 99 (32), 91 (31).
and N-phosphoryl oxazolidinone 18 (0.12 g, 0.28 mmol) only
returned starting material. HPLC, Lux 3 lm Cellulose-1, 1% i-PrOH
in hexane; 1.0 mL minꢀ1; tr 17.3 min and 19.7 min.
4.28. Diethyl 3-[5-phenyl-2-methylpentyl] phosphate 34
Obtained from general procedure B using 5-phenyl-2-methyl
pentan-3-ol 26 (0.5 g, 2.8 mmol) after purification by flash column
chromatography on silica gel eluting with petroleum ether 40–
60 °C/EtOAc (3:2) as a clear oil 34 (0.08 g, 91%); mmax (ATR)/cmꢀ1
2963, 1496, 1454; 1H NMR (400 MHz; CDCl3) dH 0.92 [3H, d, J
6.8, 1ꢁ CH(CH3)2], 0.98 [3H, d, J 6.8, 1ꢁ CH(CH3)2], 1.37 (6H, td, J
7.1, 0.5, CH2CH3), 1.88–2.05 [3H, m, CH(CH3)2 and CH2], 2.69 (1H,
ddd, J 13.8, 10.8, 5.9, CHH), 2.81 (1H, ddd, J 13.8, 11.0, 5.5, CHH),
4.15 (4H, app dtd, J 14.6, 7.1, 0.8, 2ꢁ OCH2), 4.31 (1H, ddd, J 12.1,
7.8, 4.4, CHO), 7.19–7.25 (3H, m, ArCH), 7.28–7.34 (2H, m, ArCH);
13C NMR (100 MHz; CDCl3) dC 16.2 (d, JC–P 6.0, CH3CH2), 17.5
(CH3), 17.7 (CH3), 31.7 (CH2), 31.8 [d, JC–P 3.0, (CH3)2CH], 33.4 (d,
JC–P 4.0, CH2), 63.5 (d, JC–P 6.0, 2ꢁ OCH2), 83.8 (d, JC–P 6.0, CHO),
125.9 (ArCH), 128.4 (2ꢁ ArCH), 128.4 (2ꢁ ArCH), 141.9 (ArC); 31P
NMR (101 MHz; CDCl3) dP ꢀ1.30; m/z (ES+) 315.1714 (100%, MH+
C16H28O4P requires 315.1725).
Employing general procedure C, alcohol 23 (0.50 g, 3.68 mmol)
was treated with MeMgCl (0.13 mL, 3.0 M in THF, 0.40 mmol) and
N-phosphoryl oxazolidinone 18 (0.15 g, 0.31 mmol) to failed to
provide any phosphate ester 31 and thus no chiral phase HPLC data
were obtained.
4.26. Diethyl 3-methyl-1-phenyl-2-butyl phosphate 32
Obtained from general procedure
B
using 1-(o-methyl-
Employing general procedure C alcohol 26 (0.50 g, 2.81 mmol)
was treated with MeMgCl (0.10 mL, 3.0 M in THF, 0.31 mmol)
and N-phosphoryl oxazolidinone 18 (0.12 g, 0.28 mmol) to afford
phenyl)ethanol 24 (0.30 g, 1.83 mmol) after purification by flash
column chromatography on silica gel eluting with petroleum ether
40–60 °C/EtOAc (1:1) as a clear oil 32 (0.48 g, 86%); mmax (film)/
cmꢀ1 2968, 2935, 1497, 1455; 1H NMR (400 MHz; CDCl3) dH 0.98
[3H, dd, J 6.9, JP–H 2.0, CH(CH3)2], 1.01 [3H, dd, J 6.9, JP–H 2.0,
CH(CH3)2], 1.21 (3H, td, J 7.1, JP–H 1.0, CH2CH3), 1.31 (3H, td, J 7.1,
JP–H 1.0, CH2CH3), 1.90–2.01 [1H, m, CH(CH3)2], 2.88–2.99 (2H, m,
CH2Ph), 3.74–3.90 (2H, m, OCH2), 3.95–4.11 (2H, m, OCH2), 4.48–
4.54 (1H, m, CHO), 7.21–7.33 (5H, m, ArCH); 13C NMR (100 MHz;
CDCl3) dC 16.0 (d, JC–P 7.0, CH2CH3), 16.1 (d, JC–P 7.0, CH2CH3),
16.8 [CH(CH3)2], 18.2 [CH(CH3)2], 31.0 [d, JC–P 4.0, CH(CH3)2], 37.9
(d, JC–P 4.0, CH2Ph), 63.3 (d, JC–P 6.0, OCH2), 63.4 (d, JC–P 5.0,
OCH2), 84.4 (d, JC–P 6.1, CHO), 126.4 (ArCH), 128.4 (2ꢁ ArCH),
129.6 (2ꢁ ArCH), 137.8 (ArC); 31P NMR (101 MHz; CDCl3) dP
ꢀ0.01; m/z (ES+) 324 (64%, M++Na), 301.1576 (100, MH+
C15H26O4P requires 301.1569).
phosphate ester 34 (0.06 g, 66%) in 14% ee; [
a
]
D
22 = ꢀ8.3 (c 1.2,
CHCl3); HPLC, Lux
3 lm Cellulose-1, 2% i-PrOH in hexane;
1.0 mL minꢀ1; tr 9.6 min (minor) and 12.3 min (major).
4.29. Diethyl 2-[2-phenyl-3-methylbutyl] phosphate 35
Attempted phosphorylation using procedure B or C resulted in
the return of the alcohol starting material in both cases.
Acknowledgment
We thank GSK and the EPSRC for financial support (S.C.).
References
Employing general procedure C, alcohol 24 (0.50 g, 3.04 mmol)
was treated with MeMgCl (0.11 mL, 3.0 M in THF, 0.33 mmol) and
N-phosphoryl oxazolidinone 18 (0.13 g, 0.31 mmol) to afford phos-
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